Neuro+LOs

=Preamble= toc (From James Rose, CO 2011, author of these notes) Tuesday, April 21, 2009

What follows is the original preamble (more or less the same as those from M2M, etc). A few notes on Neuro: Neuro is generally considered to be the best-taught and most-organized block in the curriculum. This is mainly due to the fact that Drs. French and Ojemann are the block directors. Dr. French can’t be beat for student advocacy and doing what he can to make the first two years as painless as possible, and Dr. Ojemann is extremely bright, a natural teacher, and genuinely likes us. If you can go to every one of the Oje’s lectures, do it, it’s worth it. Dr. DeMasters is similarly brilliant and should not be missed. Status post-Step One, this block probably does the best job of preparing you for the kinds of questions you’ll see there, but buff up on the pharm in First Aid, they really like anti-seizure drugs and antipsychotics. Enjoy this block, it’s probably the highlight of the first two years.

–jcr

PS- if you find these useful and can go without a latte for a couple of days, I’d like you to give another $5 to charity.

Hey, everybody. These are my compiled learning objectives for Neuro when I took it in the fall of 2008. I hope you find them useful. A few notes:
 * 1) These aren't to be taken as everything-you-need-to-know material, or anything close to it. They can be, however, extremely useful, if only to look at the material a second time in a different format.
 * 2) Learning objectives change. Granted, in our vaunted institution, they often don't change a lot. But it's worth figuring out where these overlap with what you're studying and where they don't to avoid any unnecessary learning (God forbid).
 * 3) They can be incorrect. I hope this is infrequent, but I'm sure there are things in here that aren't accurate. I've tried to curate them reasonably well; I hope one of your classmates will do likewise. If you find an error, kindly let him or her know.
 * 4) They are nothing more or less than my personal take on what we happened to be learning on a given day. Sometimes they're very detailed, sometimes they're uncomprehending, frequently they're irreverent. I occasionally call babies vampires and things like that (dude, they are). Internet lesson: free trumps tasteful. In any case you are free to disagree with me.
 * 5) To anyone who's wondering: I honored this block and all the rest in my first two years. That's not supposed to impress you, but it is supposed to give you some kind of confidence that I have a reasonably good handle on what's going on.
 * 6) To the many of you who are thinking, "How can I repay this wonderful, wonderful man?" I would reply that I never turn down free beer if I can help it. The problem with that is that I suspect I will never meet most of your class, and beer-buying in absentia is a cold and heartless thing. So if you find these useful and would like to do something for me, I would prefer it if you donated $5 to the charity of your choice; if you're stumped, I suggest browsing [|www.charitynavigator.com] for some good options. Kindly do not donate money to armed insurrectionist groups.
 * 7) Addendum on donating to charity: always always ALWAYS have an email account that you set aside purely to sign up for or donate to things (thus ducking all the spam associated therewith). I think I have 1,200 emails in mine, mostly from a donation I made to the SPCA a couple of years ago. Gmail and Hotmail work well. I also recommend using a false street address to avoid direct-mail campaigns.
 * 8) "That seems like a lot of trouble to go through to donate five bucks"-- yeah, well, welcome to the world, sonny Jim. Doing things for other people frequently is a pain in the ass. Doesn't make it less worth doing.

=Introduction=
 * Understand the following terms:
 * cortex: outer layer, in this case of the brain.
 * grey matter: brain matter containing mainly neuronal cell bodies.
 * white matter: brain matter containing mainly neuronal axons covered in myelin (which gives it its white appearance).
 * thalamus: more or less centrally located component of the brain. In the first-day presentation of deep brain stimulation, this creates the impulses, transmitted to the motor centers in the cortex, that create essential tremors.
 * cerebellum: more or less occipitally located component of the brain. Vis-a-vis Dr. Ojemann's presentation, this entrains the thalamus to send tremor-patterns to the cortex.
 * ipsilateral: same-side, generally referring here to left or right from the sagittal midline.
 * contralateral: opposite-side. Note that this is a common, though not universal, theme in the human nervous system-- left-brain controls right-sided structures, right-brain controls left-sided structures.
 * decussation: a pathway that originates on one side of the nervous system and crosses the midline to terminate on the other side (but note fine print, below).
 * commissure: a pathway that involves a termination point that is on the mirror image of the origination point-- that is, if the origin is in the left-sided brain region X, the termination is in the right-sided brain region X.
 * For the linguists among us, Dr. Ojemann reports that 'decussation' is derived from Latin 'decussis' indicating the letter X (or more to the point, the number 10, whence the connection between decussis and, say, decahedron), illustrating how two decussation pathways should look (they should cross each other at the midline). On the other hand, commissures, while they by definition cross the midline, don't generally form this "X" shape, and thus don't qualify as decussations. I know, you were wondering.
 * homunculus: a common mapping device to illustrate how much of the cortex, and which parts, are occupied with controlling different parts of the body. This is done by drawing the various parts of the human body superimposed on the parts of the brain surface that control them and having the size of each body part depend on how much cortical material is devoted to its control. Of note, the face and hands are particularly large. Ie: []
 * somatotopy: concept that the physical areas of the cortex concerned with controlling certain portions of the body can be reliably mapped (such-and-such area of the cortex will predictably control so-and-so part of the body).
 * afferent: nerve fibers (dendrites) that deliver information towards a cell body in a given neuron.
 * efferent: nerve fibers (axons) that deliver information away from a cell body in a given neuron.
 * Note that afferent and efferent are, more generally, used as "towards" and "away from," respectively, usually in the context of the central nervous system. In this context, afferent means information traveling from the periphery to the CNS; efferent means information travelling from the CNS to the periphery.
 * synapse: the connection point between axons from one neuron and dendrites from another; the means by which one neuron communicates with another. As you all presumably know, it's not actually a 'point' but instead is a neuronally unfilled space (for you art majors, the negative ground) between the pre-synaptic end of the axon and the post-synaptic dendritic terminals.
 * synaptic plasticity: This is where the good stuff is. Essentially, repeated stimulations at a given synapse leads to structural changes in the dendritic terminals to allow easier stimulation at that synapse. This seems to be the molecular basis for learning.
 * Note that, germane to Pavlov, simultaneous activation of two neuron pathways cause development and strengthening of the synaptic connection between the two. Cheesy but memorable: "Neurons that fire together wire together."
 * [Separating frontal from temporal lobes: sylvian fissure. Separating frontal from parietal lobes: central sulcus or rolandic fissure.]
 * [Anterograde amnesia: results from, among other things, bilateral injury to the hippocampus; established memories are intact but the ability to make new memories is lost.]
 * Describe the conceptual framework for understanding the nervous system, on which this course is based
 * (1) Biological structure of the brain gives rise to behavior.
 * (2) The results of behavior, and social/environmental factors, modulate brain biological structure.
 * If this seems weird, go read __The Agile Gene__.
 * Describe the basic components of the neurologic exam, neuroanatomical localization, and neuropathological categories that will be covered in the course, and how these are employed in the formulation of a differential diagnosis
 * How they're employed:
 * (1) Do the neuro exam.
 * (2) Localize the problem based on the results of the neuro exam.
 * (3) Figure out what's wrong with that area and fix it.
 * Neuro exam (more to follow):
 * Mental Status
 * Reflexes
 * Sensory
 * Motor
 * Cranial Nerves
 * Coordination + Gait
 * Localization: essentially "can it be localized? If so, where is it?"
 * Neuropathologies: breaks it down into categories of what can screw up.
 * Specifically:
 * Vascular
 * Infectious
 * Traumatic
 * Age-related/degenerative
 * Metabolic
 * Inflammatory
 * Neoplastic
 * Congenital
 * (notice this spells "vitamin C")
 * Understand the relationship between the conceptual framework for the course and the three major types of therapeutic intervention: counseling, pharmacotherapy, and physical manipulation
 * This relates back to the conceptual framework just mentioned, in which understanding the relationship between structural components and behavior in both directions is significant for any of the therapeutic interventions just mentioned.
 * Understand the schedule for the course, the required reading and web-based assignments, the dates take home quizzes are given out and when they are due, the dates of all exams, the point distribution of quizzes and exams, and the basis for honors, pass and failing grades
 * Yeah.
 * Note that there are no exam question challenges (page 10 in the course overview).
 * Understand the methods and resources that will be used in the course for teaching neuroanatomy, neurophysiology, the neurologic exam, neuropathology, neuropharmacology, behavioral science, clinical neurology, and psychiatry
 * Check out Appendix A in the course overview (starts on page 11) for a good concise summation of what we're doing, particularly the required/recommended reading and quizzes in the side boxes. Note that what they refer to as "hyperbrain quizzes" are at [].

=Neurons, Glia, and Brain Tissue=
 * For each of the following, know which is gray matter and which is white matter:
 * __Gray matter: nucleus, ganglion, cortex, body__
 * Note that neurons, as cells go, are pretty huge, with jumbo-sized nuclei and family-platter nucleoli.
 * __White matter: lemniscus, peduncle, funiculus, fasciculus, tract__
 * A couple of general localization principles (don't always trust the color of the stain):
 * In the cortex the gray matter is on the outside and the white matter is deep to it.
 * In the spinal cord, the white matter is on the outside and the gray matter is deep to it.
 * Know the general function of each of the following parts of a neuron:
 * dendrite: neuronal process ('thing that comes off the cell body') that receives information from axons of other neurons and transmits the information to the cell body.
 * axon: neuronal process; tends to be long and thin, terminating at one or more synapses on one or more dendrites of other neurons.
 * Note that axons actively propagate APs (signal doesn't diminish), while dendrites and cell bodies passively receive signals but don't propagate them (which means the signal diminishes with time, which is one reason you don't have really long dendrites).
 * Note a quick overview of synaptic transmission: depolarization opens voltage-gated calcium channels in the presynaptic terminal, causing NT (neurotransmitter)-containing vesicles to fuse with the terminal wall and releasing the NT into the synaptic cleft.
 * Note also that glutamate is the most common NT in the CNS (outside CNS: ACh) and usually, but not always, has an excitatory effect on the receiving cells.
 * Note also also that GABA is the 2nd most common NT in the CNS and usually, but not always, has an inhibitory effect on the receiving cell.
 * Note also^3 that the effect of a NT is determined by the nature of the receiving cell and not anything intrinsic in the NT; it's just that glutamate usually winds up exciting cells and GABA usually winds up inhibiting them.
 * Note also^4 that the release of one axon's NTs in the CNS is generally not enough to trigger the receiving cell to fire its own axon; usually you need several or a constellation of incoming axons' NT release to make a cell fire, although there are exceptions.
 * axon terminal: the small processes that come off the end of an axon that front directly onto synapses; contain the NT vesicles that are released when there's an influx of Ca++.
 * **Nissl substance**: substance contained in neuronal cell bodies (outside the nucleus); contains **rough endoplasmic reticulum**. Excluded from axon hillock but do extend somewhat into the dendritic processes.
 * [Note a theme here: neurons make a ton of protein (big nuclei, big nucleoli, lots of RER) in their cell bodies because their surface area-to-volume ratio is pretty humongous. You try making enough protein to supply a three-foot axon when your cell body is 100 micrometers across.]
 * [Note another problem: these proteins have to be transported all through those three feet, and the degraded proteins they're replacing have to be shuttled back. This is done by really long cytoskeletal transport elements.]
 * Protein transport from the cell body down the axon: **anterograde**.
 * Protein transport from the axon to the cell body: **retrograde**. Notice viruses can hijack retrograde transport mechanisms to infect cell bodies after contact with the axons.
 * Know the function and distribution of each of the following cell types:
 * (all of these are glia, which seems to be defined as "cells in the CNS that aren't neurons:")
 * (note for obsessive readers of Robbins: yes, I'm leaving out cells of the meninges and blood vessels. Get a life.)
 * **astrocyte**: So called because they're star-shaped, with lots of thin processes that extend to surrounding neurons. Help maintain ionic equilibrium in the surrounding neurons by __removing extracellular potassium__; also __recycle released neurotransmitters__ from the extracellular space back into the neurons.
 * Also regulate local blood flow to neurons (see next LO).
 * Also (Robbins) are the principal repair/scar formation cells in the brain.
 * **microglia**: Phagocytic cells of the CNS; roughly equivalent to macrophages and perform similar scavenger tasks in clearing cellular debris and reacting to pathogens.
 * Note that microglia are derived from the bone marrow (unlike other glial cells, which are derived from neuroectoderm).
 * If you want to get technical, those other cells are called 'macroglia' and include astrocytes, oligodendrocytes, and ependymal cells.
 * **oligodendrocyte**: Form myelin and myelinate axons (one oligodendrocyte can myelinate several axons) in the central nervous system.
 * **Schwann cell**: Similar to oligodendrocytes, but in the periphery (thus not in the CNS). Note that each Schwann cell can only myelinate one axon.
 * Recall that myelin is an insulator, broken at intervals by myelin-free areas called nodes of Ranvier; the AP thus propagates in "leaps" (ie. "saltatory conduction") from one node to the next, avoiding a lot of the membrane issues with resistance and capacitance and increasing transmission speed by 2 or 3 orders of magnitude. I remember Dr. Betz's notes from M2M being pretty good at explaining this in terms of circuitry ("Action Potentials I, II, III" on November 16 and 19 of 2007 if you want to check) and the upcoming lectures are reasonable as well.
 * Describe how astrocytes can regulate local blood flow in proportion to the neuronal activity in the area.
 * Recall that astrocytes recycle potassium and neurotransmitter release-- this means that an astrocyte is 'aware' of how active its surrounding neurons are at any given time by sensing how much K+ and NT is in the ECF.
 * Astrocytes also communicate with the vascular structures that feed neurons.
 * Putting these two things together, when the astrocytes figure out that the local neurons are working hard (lots of NT and potassium release), they release substances to __cause local blood vessels to dilate__. This is called **functional hyperemia**.
 * To be more specific, increased activity of NT transporters on astrocyte surfaces causes the astrocytes to release arachidonic acid-derived vasodilators onto adjacent blood vessels. (Active neurons also release NO to achieve the same ends.)
 * This means that regions of the brain that are working harder receive more blood. See next LO.
 * Describe the relationship between cerebral blood flow and fMRI and PET scans
 * fMRI: look at blood flow in the brain at rest and compare it to blood flow in the brain during some kind of activity (waving your hand, listening to music, reading Hegel, etc). fMRI stands for "functional MRI," which is the least useful name I've heard since "Disease and Defense," and depends on the electromagnetic properties of oxy/deoxygenated hemoglobin.
 * PET: also looks at blood flow (can also be used for tracking metabolic activity, see "Methods of Studying the Nervous System") but relies on an injected isotopic tracer.
 * Both of these measure functional hyperemia.
 * Know why substances in the circulatory system do not freely enter the brain parenchyma
 * The endothelial cells in the CNS are not leaky. Even a little. Their tight junctions live up to the name. They wouldn't lend you a nickel to buy your grandmother penicillin.
 * Note that sometimes they can be leaky. We're going to ignore that for the moment.
 * This means that anything that wants to get from the blood into the ECF in the brain needs to have special cross-endothelial transporters.
 * Note that __this tightness of the BBB is derived from astrocyte signaling__-- effectively it's the astrocytes that say "yo, blood vessel endothelial cells, you're in the CNS, tighten up." Note also (a) that damage to astrocytes can result in loosening of the BBB, and (b) areas where the BBB isn't designed to be so tight (see choroid plexus notes, next lecture) lack astrocytes for this reason.

=CSF and the Blood-Brain Barrier=
 * [2 main supplies of blood to the brain: __internal carotid artery__ system (anterior half to two-thirds of brain) and __vertebral artery__ system (posterior one-third to half of brain). Note that the territory covered by each of these two systems are more or less independent of any functional or embryological divisions.]
 * Anterior circulation includes pretty much all of the cortex except some of the occipital and temporal lobes; posterior circulation includes the rest of the cortex and the brainstem and cerebellum.
 * Draw and label the components of the circle of Willis.
 * Circle of Willis: interconnection between these two arterial systems. Note that this is both ipsilateral (back of brain to/from front of brain, via the posterior communicating arteries) and contralateral (one side of front of brain to the other side of front of brain, via the anterior communicating arteries).
 * Anterior communicating artery: between contralateral anterior cerebral arteries.
 * Posterior communicating arteries: between internal carotid arteries (near mid/anterior cerebral bifurcation) and posterior cerebral arteries.
 * Trace the path a corpuscle might take from the internal carotid artery to somatosensory cortex to the jugular vein. Does it matter whether it is the “foot” or “hand” region of somatosensory cortex?
 * (note that the somatosensory cortex is in the postcentral sulcus, in the superior/anterior parietal lobe, and thus we can safely assume it's covered by the internal carotid without dealing with rerouting through the circle of Willis)
 * Through internal carotid, over to the middle cerebral artery, to the somatosensory cortex capillary beds, into (probably) some cerebral veins that drain into the (probably) superior sagittal sinus, thence to the sinus confluens and the transverse sinus, into the sigmoid sinus and out into the internal jugular vein.
 * A quick look at the somatosensory homunculus on Google indicates that the foot region is closer to the sagittal midline and the hand region is more on the outside. This would presumably influence the venous drainage (superior vs inferior sagittal sinus drainage) and possibly the arterial supply as well (anterior cerebral artery might supply the foot while the middle cerebral artery might supply the hand).
 * How might blood from the left vertebral artery reach the frontal lobe of the right side in case of occlusion of an internal carotid artery?
 * Up the left vertebral artery, into the basilar artery, off to the right posterior cerebral artery, up the right posterior communicating artery to the right internal carotid, whence it can go either to the anterior or middle cerebral artery depending on where in the frontal cortex it's headed.
 * Trace the path of CSF from its place of formation in the lateral ventricles to its site of resorption in the arachnoid granulations:
 * Lateral ventricle drains through the foramen of Monro (aka interventricular foramen) into the third ventricle, which drains through the aqueduct of Sylvius (aka the cerebral aqueduct) into the fourth ventricle, from which it leaks out into the subarachnoid space at three cisterns (two lateral, one caudal). From there, it flows freely around the subarachnoid space until it's picked up by the **arachnoid granulations** in the dural sinuses.
 * There's an animation of this at [] (under "CSF flow" at lower left).
 * Be able to identify on MRI images, CAT scans and sections through the brain: lateral ventricle, third ventricle, fourth ventricle, interventricular foramen, cerebral aqueduct, cisterna magna, interpeduncular cistern
 * Imaging LOs don't translate well here. The lateral ventricles are on the sides, the third ventricle is superior to the medulla and sort of ringed by the lateral ventricles, and the fourth ventricle is anterior to the cerebellum.
 * Interventricular foramen: recall, between lateral and third ventricles.
 * Cerebral aqueduct: recall, between third and fourth ventricles.
 * Cisterna magna: one of the three cisterns connecting the fourth ventricle outflow with the subarachnoid space. Located between the cerebellum and the midbrain.
 * Interpeduncular cistern: another of the three cisterns. Seems to cross the midline to connect the two temporal lobes, but I'm running off Wiki and Google here.
 * Describe the relationship between ependymal cells and capillaries in the choroid plexus and how CSF is formed by this structure. Approximately, what is the volume and rate of production of CSF? Describe what happens to the composition of CSF as the ionic composition of plasma changes
 * **Ependymal cells**: cells lining the inside of the ventricles; form a leaky barrier most of the time (see next point).
 * **Choroid plexus**: specialized areas of ependymal cells, mainly in the lateral ventricles, that produce CSF.
 * Normally in the brain you have leaky ependymal cells and tight endothelial cells. In the choroid plexus you have tight ependymal cells and leaky endothelial cells. This means that in the choroid plexus, the ependymal cells have free access to blood contents, but the ependymal cells themselves have to take over the active transport functions normally taken care of by the endothelial cells.
 * The fluid source for CSF seems to be fluid from the plasma that leaks through the loose endothelial junctions.
 * **About 500 mL** of CSF is made every day. Note that the **total volume** of CSF at any given time is about **125 mL**, of which about **100 mL is outside the ventricles** in the subarachnoid space; doing the math, you fill and empty the entire CSF system four times a day.
 * Fluctuations in plasma ion concentrations generally produce next to no effect on the ion concentrations in the CSF. This is important because the CSF is the ECF of CNS neurons; if you mess with its ionic composition, neurons can't fire properly due to hyper- or depolarization.
 * Note some other functions of CSF: cushion shock of blunt head trauma, buoy the weight of the brain.
 * Distinguish between communicating and non-communicating hydrocephalus
 * Hydrocephalus: too much CSF in the ventricles, leading to increased cranial pressure.
 * If this is caused by obstruction of the CSF outflow into the subarachnoid space, it's called **non-communicating hydrocephalus**.
 * If it's caused by impaired resorption of the CSF in the subarachnoid space, it's called **communicating hydrocephalus**.

=Methods of Studying the Nervous System=
 * [Note preamble: "My intent in this last lecture is not really to introduce material that I want to test you on." For what it's worth.]
 * Review the differences between an EPSP, IPSP, and an action potential.
 * [**EPSP**: excitatory postsynaptic potential. **IPSP**: inhibitory postsynaptic potential.]
 * Essentially EPSPs tend to push the cell to fire an AP; IPSPs tend to push the cell not to. The summation of the EPSPs and IPSPs at a given neuron determines whether or not that neuron reaches threshold, and thus whether the axon of the neuron fires an AP.
 * Understand the "coupling" between electrophysiologic activity in the nervous system and CNS hemodynamics.
 * Covered by Dr. Finger in "Neurons, Glia, and Brain Tissue" (see "functional hyperemia").
 * Describe those techniques for evaluating "brain activity" that measure the electromagnetic properties of the nervous system.
 * EEG (electroencephalogram), event related potential (ERP), magnetoencephalogram.
 * EEG: measures, with electrodes placed on the scalp, general fluctuations in postsynaptic membrane potential in populations of neurons. Essentially when a bunch of 'pyramidal' neurons (oriented perpendicularly to the skull surface) accumulate PSP, the area of those neurons closer to the skull (dendritic area) becomes more negative and the area farther away from the skull (cell body area) becomes more positive, creating a potential difference that can be picked up by skull electrodes. I don't really understand this.
 * Event-related potential: time-averaged EEG to normalize and clarify changes in potential that result from given stimuli.
 * Describe those techniques for evaluating "brain activity" that measure the hemodynamic properties of the nervous system.
 * fMRI, SPECT, PET.
 * PET: here, looking at isotopically-labeled oxygen (in water) flow (which should correspond to blood flow). Can also look at neuronal metabolism (with labeled glucose, like the techniques used to look for tumors).
 * fMRI works by looking at comparison of magnetic resonance of deoxygenated hemoglobin (attenuates signal) to that of oxygenated hemoglobin (doesn't attenuate signal). This allows you to figure out where you're getting increased blood flow (more oxygenated hemoglobin), by looking at how the signal attenuates or doesn't attenuate in that vessel.
 * Understand at //a basic level// the physiologic basis for the signal recorded in the EEG, the MEG, the fMRI, and the PET scan.
 * EEG: changes in the membrane potential of groups of pyramidal neurons.
 * MEG: not discussed, but presumably measures changes in magnetic as opposed to electrical fields.
 * fMRI: magnetic signal attenuation due to deoxy/oxygenated hemoglobin.
 * PET: water/blood or glucose flow by detecting positron emission by radiolabeled tracers.

=Molecules to Memory I through IV= Botulinum toxin cuts SNARE proteins- have vesicles, can't fuse. Tetanus toxin also cuts SNARE proteins but has a very different presentation.
 * Brush up on the mechanism of the action potential.
 * There is a concise (3 page) summary of AP stuff in the notes, p. 2-4. I highly recommend reviewing it.
 * What is electrical synaptic transmission? Name a limitation of this form of intercellular communication (compared to chemical transmission). Why would it be ineffective at the neuromuscular junction? Is this method of communication important in the mammalian CNS?
 * Electrical synaptic transmission: Relatively rare in neuronal tissue; involves transmission of electrical impulses by ion exchange between cells through gap junctions. Serves to synchronize cells that need to fire together (motor neurons of the respiratory center, cardiac/smooth muscle).
 * Big limitation: the size of the presynaptic terminal needs to be proportional to the size of the postsynaptic cell it wants to depolarize. This means that your neuromuscular junction (in which you have a very small 'end plate' where the nerve attaches to the muscle fiber) wouldn't work well- the end plate would need to be much larger.
 * It is, by and large, not enormously important in the mammalian CNS.
 * Name the presynaptic events involved in transmitter release, from the time of the arrival of an action potential to exocytosis. Describe the subsequent presynaptic events involved in cleanup operations, both outside the cell (consider the neurotransmitter molecules) and inside the cell (consider sodium ions, calcium ions, synaptic vesicles, and neurotransmitter).
 * Action potential arrives at the presynaptic terminal, depolarizing the membrane and causing voltage-gated calcium channels to open. The influx of calcium triggers the fusion of pre-loaded NT-containing vesicles with the cell membrane, allowing the neurotransmitter to spill out into the synaptic cleft.
 * The presynaptic membrane recaptures the vesicular membrane and reforms (empty) vesicles with it, which can then be filled with fresh NT.
 * The sodium ions are pumped out, and the potassium ions are pumped in, by the 3 Na - 2 K ATPase pump.
 * The calcium ions are both actively pumped out by a plasma-membrane Ca++ pump and passively transported by the Na-Ca exchanger.
 * The neurotransmitter in the cleft can (a) diffuse into the surrounding ECF; (b) be destroyed by enzymes in the cleft (mainly ACh in the neuromuscular junctions); or (c) be reuptaken by the presynaptic membrane.
 * What is the "job description" for a motor nerve terminal?
 * "Every time an action potential arrives from the CNS, you must secrete enough ACh to depolarize the muscle fiber that you innervate to threshold for an action potential."
 * Essentially you need to hew tightly to "one AP in, one AP out." The cavalry (ie. additional APs) isn't going to arrive. When you get an action potential it's your responsibility to make sure that the muscle moves, regardless of any other potential inputs.
 * In Betz's terms, the NMJ is strong but stupid. It knows how to do one thing and it does it well.
 * Describe how the neuromuscular synapse amplifies the incoming signal in order to depolarize the muscle fiber to threshold for an action potential.
 * In order for one AP to trigger an AP in the muscle it attaches to, the outgoing signal (depolarization of big muscle fiber) needs to be a lot bigger than the incoming one (depolarization of motor neuron); thus it needs to be amplified.
 * One mechanism is chemical-- motor nerve terminal release lots and lots and lots of vesicles (and each vesicle is packed chock full of neurotransmitter) per incoming AP.
 * (specifically you need to release about 30 ACh-filled vesicles in a given NMJ to induce a muscle AP; generally there's a safety factor built in so that you release two or three times that.)
 * The other mechanism is to increase the area on which the motor terminals contact the muscle (the end plate), which allows more vesicles to be released and more receptors to be available to be activated (NMJ postsynaptic membranes contain lots of little folds to allow the maximum possible receptor-covered area to be exposed to stimulation).
 * Define facilitation and synaptic depression of transmitter release. Name the underlying mechanism of each.
 * **Facilitation**: rapid, repeated APs can increase the amount of neurotransmitter released at a presynaptic terminal.
 * How it works: if the presynaptic terminal hasn't had enough time to clear all the calcium let in by the last AP by the time the next one comes down the pipe, it gets an additional influx of calcium (new AP opens voltage-gated Ca++ channels) on top of the calcium that is still kicking around in the terminal. Since NT-vesicular release is determined by intracellular calcium content, this means that the terminal releases more vesicles the second time than the first.
 * Note that if the terminal has sufficient time between APs to clear all of the extra calcium, facilitation doesn't happen.
 * **Synaptic depression**: repetitive AP stimulation can decrease the amount of neurotransmitter released at a presynaptic terminal.
 * How it works: it takes a while to recycle vesicular membranes. If a terminal is releasing vesicles faster than it can replenish them, at some point the number of vesicles released per AP will decrease.
 * As you might think, these two things are kind of at cross-purposes. Under repetitive stimulation, facilitation wins out at first, then slowly loses out to synaptic depression.
 * Note that this is normally academic since the safety factor built into NMJs means that you don't really need even the number of vesicles you ordinarily release to stimulate a muscle AP, and the nature of the AP (all-or-nothing) means that having excess NT out there doesn't really do anything more for you.
 * Note, however, that synaptic depression is the basis for why myasthenia gravis patients show progressive weakness with exercise (MG = autoantibodies to ACh receptors); they need more ACh to displace the antibodies (competitive inhibition), so anything that decreases the amount of NT released will have a profound effect (you've essentially taken away the safety factor).
 * Note, parenthetically, that //Lambert-Eaton syndrome// (also called the //myasthenic syndrome//, although I like that name less since it's too close to myasthenia gravis for my taste) is a similar progressive-weakness disease in which the autoantibodies are directed against the voltage-gated calcium channels in the presynaptic terminal instead of the postsynaptic ACh receptors. In this case, you actually show improvement with exercise due to facilitation-- since the problem is with getting calcium into the cell, anything that causes more calcium to build up in the terminal is going to help. Good little differential there.
 * Describe the basic mechanism that determines whether a synapse is direct (fast) or indirect (slow). Name a typical physiological response mediated by each.
 * The mechanism is what kind of receptor you've got on the postsynaptic membrane.
 * Fast synapses: ligand-gated ion channels. NT binds, channel opens, ions come in, membrane potential change (excitatory or inhibitory) results immediately. Note that their effects are normally extremely brief (depolarization-repolarization).
 * Example: ACh at NMJ (and, usually, glutamate in the CNS) opens a **non-selective cation channel** (K+ goes out, Na+ comes in, membrane potential goes to around -10 mV, above threshold for AP generation (generally around -55 mV). This would be your lower motor neuron, contract-the-muscle thing.
 * Slow synapses: G-protein receptors activate 2nd-messenger systems. You remember these, sort of like Rube Goldberg devices except with more calcium. This takes longer than direct ion-channels, but their effects can linger a long while.
 * Example: evidently many parts of the brain involved with emotion traffic heavily in slow synapses, which is why you still sort of have a crush on that girl from high school.
 * To sum:
 * Liking a girl: slow synapses.
 * Contracting the lip and throat muscles to say hello and quickly turning it into a cough when you lose your nerve and go back for another drink: fast synapses.
 * Describe the conductance (permeability) characteristics of the channel opened in fast excitation. Define the electrical "driving force." Define the reversal potential for direct excitation.
 * Fast excitation: as mentioned, tends to involve non-selective cation channels. As the name implies, these allow all cations through, in either direction.
 * Driving force: just the fact that, once ion channels are opened, the cell membrane has a force exerted on it that pushes its potential towards the equilibrium potential of the ion(s) in question.
 * Reversal potential: generally, the membrane potential towards which a membrane's open ion channels are pushing it. In fast excitation, refers to the membrane potential reached due to large numbers of non-selective cation channels (usually glutamate- or ACh-stimulated) opening simultaneously; it's around -10 mV, about midway between EK and ENa.
 * Describe the kind of channel that is opened during fast inhibition in the CNS.
 * These are channels that move the membrane potential towards being __below__ excitation threshold. Generally these are **chloride** channels (ECl in the neuronal system is lower than threshold and, generally, is lower than the resting potential as well). See next LO for more about fast inhibition.
 * Why is inhibition often more powerful than one might predict from the size of an individual inhibitory post-synaptic potential (IPSP)?
 * The key here is to remember two things. One is that the membrane potential follows the equilibrium potentials of the ions to which it's permeable at any given moment. The other is that the degree of permeability to a given ion (ie. the number of channels open for that ion) 'weights' the equilibrium potential of that ion.
 * How I think about this: say you've got two ion channels, one for sodium and one for potassium, and say they both open. You'd sort of expect the resultant membrane potential to go to a point about halfway between the two equilibrium potentials (this is essentially what happens in non-selective cation channels, winding up with a membrane potential of about -10 mV). But now think if you have five potassium channels and only one sodium channel. Now the resultant membrane potential is going to be closer to the equilibrium of potassium and farther away from the equilibrium of sodium. If you have about 1000 potassium channels open, even if you get five or ten sodium channels open, the membrane potential isn't going to budge much away from the equilibrium of potassium.
 * Notice that this works whatever the equilibrium potentials of the ions actually are. EK is about -90 mV, which is pretty close to the resting potential. But even though you're looking at a inhibitory potential of 5 mV (from -85 to -90 with K) in the face of the excitatory potential of maybe 145 mV (from -85 to +60 with Na), if there are lots and lots more inhibitory ion channels open, the excitatory stimulus won't be able to have much impact no matter how positive it wants to make the membrane.
 * So the reason inhibition is "more powerful than would be expected" from how much the membrane potential changes is that __when you just look at how much the potential changes, you're ignoring how strong the signal is__ (that is, how many ion channels have opened). Even a very slight inhibitory voltage change, if the strength is large enough, can drown out an excitatory stimulus.
 * I've been using potassium as an example, but the ion that's more frequently used for inhibition is chloride, as mentioned in the last LO.
 * Define temporal and spatial summation of postsynaptic potentials.
 * Spatial summation: many presynaptic terminals fire at the same time, releasing lots of NT from many points at once (the effect on the postsynaptic potential is 'summed' from all these different points in space at once).
 * Temporal summation: one presynaptic terminal fires repeatedly, faster than the effects of one firing on the postsynaptic membrane can wear off (the effect on the postsynaptic potential is 'summed' over time from a single point).
 * Describe the three mechanisms for removing transmitters from synaptic clefts.
 * As mentioned: diffusion into the ECF, destruction (mainly AChEs in NMJ clefts), or reuptake (mainly in the CNS).
 * What is a coincidence detector? How does the NMDA receptor work as a coincidence detector? How can activation of NMDA receptors lead to synaptic strengthening? How might such a mechanism lead to behavioral associative conditioning?
 * Coincidence detector: gate that allows strengthening of a synapse when it's firing at the same time that the postsynaptic membrane is being depolarized by another synapse.
 * NMDA receptors: a glutamate-gated calcium channel that's been plugged with a magnesium ion. It'll only allow calcium influx when (a) glutamate's been released from the synapse (opens the channel) and (b) the postsynaptic membrane has reached threshold for AP (in this context, due to the input of other synapses) and is depolarized (repels the magnesium ion, unplugging the channel). The influx of calcium strengthens the synapse by promoting more glutamate-gated ion channels (not NMDA but AMPA-type) in the membrane on the postsynaptic membrane near this particular synapse, which means that the signal incoming to this synapse can have more of an excitatory impact on the postsynaptic neuron.
 * So say there's a sensory neuron that detects spare time. Say there's another sensory neuron that detects fresh cookies. And say they both synapse onto an improbably simple motor neuron that controls filling out learning objectives. By itself, just smelling cookies doesn't produce a stimulus strong enough to produce an AP in the filling-out neuron. But every time the sensory neuron that senses spare time causes the filling-out neuron to depolarize to threshold AT THE SAME TIME THAT the cookie-sensor is releasing glutamate onto the same neuron (ie. whenever you sense both spare time and fresh cookies), the NMDA receptor right near the cookie-sensor synapse flips open (since the glutamate released from the cookie neuron activates its gate), the magnesium ion comes out (since the membrane is being depolarized by the spare time neuron), and calcium ions come into the postsynaptic membrane near the cookie synapse, making more AMPA ion channels insert themselves into that membrane. Due to these extra AMPA channels, the cookie neuron (but no others, since the AMPAs were only inserted next to the cookie synapse) has an increased ability to depolarize the LO neuron. If this process is repeated enough, eventually all you'll have to do is smell fresh cookies and you'll be filled with an uncontrollable urge to go fill out LOs while munching on them.
 * Note that in addition to inserting more AMPA receptors in the postsynaptic membrane, changes can also occur in the presynaptic neuron-- the NMDA receptor can trigger release of nitric oxide (damn, we use it for everything), which drifts back across the synapse and makes the presynaptic terminal more able to release more vesicles at once. Same idea as the AMPA thing, just a different mechanism.
 * [Betz's on-the-board stuff on __differences between neuromuscular junctions and CNS synapses__:]
 * Presynaptic area:
 * The process of neurotransmitter secretion is the same, although in the NMJ it's ACh and in the CNS it's largely glutamate and GABA.
 * Synaptic cleft:
 * 3 mechanisms are more or less important here: diffusion, destruction, or reuptake.
 * Both the NMJ and the CNS use diffusion to a great extent (NT diffuses away from the cleft and the receptors).
 * The NMJ uses destruction a lot, principally by acetylcholinesterases. The CNS doesn't use it at all.
 * Reuptake is important in the CNS but it relatively unimportant in the NMJ.
 * Postsynaptic receptors:
 * In the NMJ the synapses 'turn on' very quickly because the receptor itself is an ion channel.
 * In the CNS the synapses can be ligand-gated ion channels too, but can alternatively be G-protein coupled receptors (thus slower, 2nd-messenger systems).
 * In the NMJ the receptors are always excitatory; in the CNS the receptors can be excitatory or inhibitory.
 * Overall:
 * The emphasis in the NMJ is on strength-- one neural input has to move a tremendous amount of muscle. So one action potential causes lots and lots of vesicles to be released. In the CNS, incoming action potentials are rarely strong enough to trigger an AP in the postsynaptic neuron, and so postsynaptic depolarization depends on many small inputs rather than one big one.
 * The CNS neurons are **plastic**-- they can 'learn' associations, or patterns, of firing. The NMJs can't.

=Peripheral Neurotransmitters=
 * List the neurotransmitters and receptors that typically mediate neurotransmission at the ganglia and/or end organs in the somatic, parasympathetic and sympathetic nervous systems. List the few major exceptions.
 * Somatic: motor neurons release ACh at the NMJ, picked up by __muscle-type__ nicotinic ACh receptors.
 * Parasympathetic: transmission at ganglia is mediated by ACh, received by __neuronal-type__ nicotinic receptors; transmission at end organs is also mediated by ACh but received instead by **muscarinic** receptors of various types.
 * Sympathetic: transmission at ganglia is mediated by ACh, received by neuronal-type nicotinic receptors; transmission at end organs is mediated mainly by norepinephrine (can also be epinephrine in the adrenal medulla or dopamine in the renal vasculature), which is received by alpha- and beta-**adrenergic** receptors.
 * (recall also that sweat glands are stimulated by the sympathetic system, but use ACh instead of EPI, NE, or dopamine and have muscarinic receptors rather than adrenergic.)
 * Describe the concept of autonomic nervous system “tone” and the consequences of parasympathetic tone predominating at most organs and tissues, the exception being sympathetic control of blood vessels.
 * I think we pretty much know tone by now. You can cut off sympathetic stimulation without fatal results; you can't cut off parasympathetic stimulation without really nasty consequences, as it's the baseline in most tissues.
 * Compare and contrast the elements of cholinergic and adrenergic neurotransmission (neurotransmitter synthesis / storage / release / inactivation and interaction with receptors) and indicate targets of drug action.
 * NT synthesis:
 * Cholinergic: rate-limiting step is choline uptake into the presynaptic membrane.
 * Adrenergic: rate-limiting step is the conversion of tyrosine to DOPA.
 * NT storage: Both are stored within vesicles in the presynaptic terminal. Note that in adrenergic terminals, dopamine is stored within vesicles, but is afterwards converted into NE, where applicable, inside those vesicles.
 * NT release: seems more or less similar (calcium-catalyzed).
 * NT inactivation:
 * Cholinergic: ACh broken down by ACh esterases.
 * Adrenergic: NE is uptaken from the cleft by NE transporters.
 * NT-receptor interaction: Adrenergic and muscarinic cholinergic receptors: G-protein coupled receptors. Nicotinic cholinergic receptors: ligand-gated ion channels.
 * Describe the effects produced by muscarinic cholinergic receptor agonists that are similar to stimulation of the parasympathetic nervous system and those that are distinct.
 * Similar: about what you'd expect. Increased salivation, miosis/accommodation, increased GI and urinary motility, etc.
 * Distinct: **vasodilation** (vascular muscarinic receptors aren't activated by the parasympathetic system), **sweating** (sweat glands have ACh-activated muscarinic receptors).
 * Although both bethanechol and pilocarpine are muscarinic cholinergic receptor agonists, contrast their actions and therapeutic uses.
 * They differ mainly in their lipid solubility; pilocarpine is a tertiary amine and can pass the BBB, while bethanechol is a quaternary amine and can't.
 * This means that pilocarpine gets used for, effectively, head stuff - cataracts, glaucoma, deficient salivation - while bethanechol is used for stuff below the neck, mainly paralytic ileus and urinary retention.
 * Note also that pilocarpine is susceptible to acetylcholine esterases, while bethanechol isn't.
 * Describe how acetylcholinesterase inhibitors affect cholinergic neurotransmission and list their therapeutic uses.
 * Normally ACh is broken down extremely rapidly by the massive quantities of esterases sitting in the synaptic clefts. By inhibiting this breakdown, ACh gets to hang out and provide a stimulus at ACh receptors for a good long time.
 * Note that this works **both** at muscarinic and nicotinic receptors, with different results at each. This is distinct from most parasympathetic agonists and antagonists, which are targeted to either nicotinic (uncommon) or muscarinic (usual) ACh receptors.
 * (parenthetical note: we talked about the effects of AChEs a little last year. Ongoing stimulation at a muscarinic receptor should just mean that the effect of the receptor will be prolonged (G-protein system remains activated). Ongoing stimulation at a nicotinic receptor, though (recall that nicotinic ACh receptors are just ligand-gated ion channels), will produce an ongoing and perpetual depolarization on the target membrane. Since APs are dependent on the repolarization-depolarization cycle, this will effectively paralyze the synapse in question until removed.)
 * Therapeutic uses: always reversible; can be tertiary (cross BBB) or quaternary (can't cross BBB); treat glaucoma, Alzheimer's, urinary retention, paralytic ileus. Also used both to diagnose (with ultra-short acting agents) or treat (longer-acting agents) __myasthenia gravis__ (recall that in MG the problem is a shortage of available ACh receptors, so allowing ACh to stay in the cleft longer will allow more receptor stimulation to occur).
 * Note that current treatment of myasthenia gravis inclines more toward immunosuppressive therapy, not AChEs (too many side effects).
 * Describe the symptoms of organophosphate poisoning and how it should be treated.
 * These are __irreversible__ ACh esterase inhibitors; they include military nerve gases and some insecticides.
 * Symptoms:
 * From muscarinic receptors, looks like **a constellation of over-active parasympathetic stimulation with a side order of sweat and vasodilation:** salivation, tears, defecation/urination, GI cramping, bradycardia, hypotension, sweating.
 * From neuronal nicotinic receptors, get anxiety, depression, and convulsions.
 * From muscular nicotinic receptors, get skeletal muscle contractions followed by muscle weakness (see parenthetical note above for why).
 * Treatment: administer antidote to inhibitor (__pralidoxime__) along with __atropine__ (muscarinic ACh receptor antagonist), plus supportive measures (respiration) and treatment of convulsions.
 * (other parenthetical note: note that irreversible AChE inhibitor toxicity is distinct from the toxicity derived from an overdose of reversible AChE inhibitors. The latter arises because at high concentrations the AChE inhibitors stop being specific to AChE and also target the ACh receptors themselves; thus the effects look like parasympathetic blockade rather than parasympathetic overstimulation.)
 * Note that Dr. French says this is bunk and with an overdose of reversible AChE inhibitors you'll stop the guy's heart and fill his lungs with fluid long before anything else is an issue.
 * Describe both common and drug-specific effects produced by atropine and scopolamine, as well as therapeutic uses of muscarinic cholinergic antagonists.
 * Effectively these are parasympathetic blocking agents. Recall the classic mnemonic for atropine: red as a beet (flushing), dry as a bone (no sweat), hot as a hare (hm.. arteriovenous shunt closing or lack of sweat?), blind as a bat (eye effects), mad as a hatter (CNS trouble).
 * Atropine is used to treat some poisons, severe bradycardia, and some asthma patients; scopolamine is used predominantly for its CNS effects, mainly to treat motion sickness.

=Neurotransmitters= [this lecture heavily subsidized by Dr. Zahniser's notes and Wiki.]
 * List the precursors and key enzymes for the synthesis of acetylcholine, biogenic amines, amino acid, and peptide transmitter substances.
 * ACh: Choline (breakdown product of ACh in the cleft) is taken up by choline transporters (__ChT__) in the presynaptic membrane, and esterized with an acetyl group by combination with acetyl Co-A and choline acetyltransferase (__ChAT__) to form ACh.
 * Biogenic amines (key steps only):
 * Dopamine: __tyrosine__ is hydroxylated to DOPA by __tyrosine hydroxylase__ (DOPA is converted to dopamine by a further enzyme, which is inhibited by alpha-methyldopa)
 * Norepinephrine: __tyrosine hydroxylase__ as above; also the dopamine is hydroxylated further to NE by __dopamine beta-hydroxylase__.
 * Epinephrine: same as NE (note that EPI is methylated NE just like NE is hydroxylated dopamine).
 * Serotonin (aka 5-HT): uses __tryptophan__ and __tryptophan hydroxylase__.
 * Histamine: uses __histidine__ and histidine decarboxylase.
 * Amino acids (key steps only):
 * Glutamate: uses glutamine and glutaminase.
 * Gamma-aminobutyric acid (GABA): uses glutamic acid (glutamate) and glutamic acid decarboxylase.
 * Glycine: needs serine and serine hydroxymethyl transferase.
 * Peptides:
 * Lots. Of note: opioids, vasopressin/oxytocin, glucagon, insulin, growth-hormone releasing factor, etc. (list on third page of his notes)
 * These seem mainly to be made by making longer proteins and cleaving them to their active forms.
 * Note that this means you have genes related to the neuropeptides (obviously don't have genes for tyrosine, choline, tryptophan, etc-- these are taken in through the diet).
 * In his lecture he emphasized the following peptide families: enkephalins, endorphins, dynorphins.
 * Enkephalins are opioid peptides that come from cleavage of __proenkephalin__.
 * Endorphins are also opioid peptides, that come from cleavage of __proopiomelanocortin__.
 * Dynorphins are yet another set of opioid peptides that come from cleavage of __prodynorphin__.
 * Note sizes of various peptides on the third page of his notes. Evidently this is meant to emphasize that some are bigger than others.
 * Explain the mechanisms by which acetylcholine, biogenic amines and amino acid transmitters are deactivated at a synapse.
 * ACh is deactivated by being broken down by AChEs.
 * Biogenic amines are generally deactivated by being reuptaken out of the cleft by the presynaptic membrane.
 * Amino acids are generally also deactivated by reuptake, but __are frequently uptaken by **glia**__ instead of by the presynaptic membrane itself.
 * Note that glia (in particular, astroglia) convert glutamate uptaken from the cleft into neurologically inactive glutamine before giving it back to the presynaptic terminal (there to be reconverted into glutamate again).
 * Develop an understanding of how pharmacologic agents can act to potentiate or to decrease the activity of neurotransmitter substances at a synapse by interfering with vesicular storage, by blocking uptake, by blocking metabolism, or interacting with specific receptors for neurotransmitter substances.
 * Ok, look. You need to synthesize, release, uptake, etc. Blocking any of these steps blocks proper function of the NTs, whether that results in excitation or inhibition.
 * Describe the major transduction mechanisms by which neurotransmitter receptors pass information from the neurotransmitter to the cell on which receptors reside.
 * Ligand-gated ion channels (nicotinic receptors): change polarity of membrane.
 * G-protein coupled receptors: change levels of adenylate cyclase (up: Gs receptors; down: Gi receptors) or go through other 2nd-messenger systems (Gq through DAG and IP3).

=Embryology I=
 * Understand the primary axes of the central nervous system, and the designations dorsal, ventral, rostral, and caudal. Understand the planes of section used to view the nervous system
 * If you think of the CNS as a line that's bent 90 degrees near the end (an allen wrench for those of a mildly mechanical mind), it helps to figure things out. "Dorsal" always refers to the same direction away from the line, but is a different orientation in space along the spine and brainstem (towards the back of a human) than along the diencephalon and cortex (towards the top of the head).
 * The three points to keep in mind that define this bent line: (1) front of cortex over the eyes is the end of the short bit of the allen wrench; (2) **cephalic flexure** between diencephalon and mesencephalon is the bend; (3) cauda equina is the end of the long arm of the allen wrench. Between points 1 and 2, dorsal is out the top of the head and ventral is towards the ground; between points 2 and 3, dorsal is out the back and ventral to towards the front. Point 1 is called the rostral end; point 3 is called the caudal end.
 * Planes: these should be review. Sagittal: front to back (looking from one side). Coronal: left to right (looking from the front). Axial (aka horizontal/transverse): looking from the top (or bottom) of the head.
 * Understand the way in which the nervous system is segmented into rostrocaudal segments of telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon, and spinal cord
 * First division of the neural tube:
 * Into the __primary vesicles__: **prosencephalon** (forebrain), **mesencephalon** (midbrain), **rhombencephalon** (hindbrain).
 * Second division:
 * The prosencephalon segments into the **telencephalon** (2 vesicles, most rostral) and the **diencephalon** (1 vesicle, 2nd most rostral).
 * The mesencephalon doesn't segment any further (slacker).
 * The rhombencephalon segments into the **metencephalon** (2nd most caudal) and **myelencephalon** (most caudal except for the spinal cord).
 * Note that the spinal cord does not arise from any of these vesicles, but from the lumen of the neural tube caudal to the myelencephalon.
 * Understand the components of the ventricular system and how these relate to the rostrocaudal segments of the neural tube
 * Lateral ventricles arise as the lumens of each of the two vesicles of the telencephalon.
 * The third ventricle arises as the lumen of the diencephalon, connected to each of the lateral ventricles.
 * The aqueduct of Sylvius arises as the lumen of the mesencephalon.
 * The fourth ventricle arises as the lumen of the entire rhombencephalon (metencephalon and myelencephalon).
 * Understand the significance of the rhombomeres, in terms of the segmental development of the hindbrain and its relationship to specific cranial nerves
 * Rhombomeres: segments of the developing rhombocephalon, evidently delineated by different levels of expression of homeobox genes. Each rhombomere creates specific types and patterns of neurons (thus giving rise to distinct cranial nerves).
 * Understand the general scheme of dorsoventral patterning of the neural tube into alar and basal plates, and how this scheme is modified at the level of the midbrain, pons, medulla, and spinal cord
 * A central crease forms in the spinal neural tube that slightly divides the ventral portion from the dorsal portion (the //sulcus limitans//). Everything __ventral__ to this crease is the **basal plate**; everything __dorsal__ to this crease is the **alar plate**. The basal plate, as might be expected from ventral neurons in the pre-spinal cord, will develop motor neurons; the alar plate (dorsal) will develop into the sensory interneurons that receive input from the dorsal root ganglia.
 * The basic principle of the ventral-dorsal split isn't greatly altered, except slightly in orientation, in the midbrain, pons, and medulla. Of note, the dorsal part of the metencephalon develops into the cerebellum and the ventral part of the medulla develops into the pyramids.
 * Understand the basic scheme of dorsoventral patterning of the prosencephalon, and how this relates to the adult three-dimensional structure
 * Notes say that there is a dorsoventral patterning, especially in the telecephalic vesicles, where the cortex (dorsal) and the lateral and medial ganglionic eminences (ventral) arise. They then go on to discuss generalized telecephalic development: its lateral surface folds on itself to produce the Sylvian fissure, distorting the lateral ventricle and a number of nearby structures (cingulate gyrus, caudate nucleus, etc) into a "C" shape.
 * Note that the shape of these "C" sections means that in sections it's possible to see a given structure twice, once at the top of the C and once at the bottom. That is, you can see the caudate nucleus, the corpus callosum, etc, in two different locations on one section.
 * Note also that the dorsoventral patterning in the telencephalon determines which primary neurotransmitter is used in various regions.
 * He made a point of discussing the axon tract that runs down from the cortex to bisect the medial and lateral ganglionic eminences; the tract is called the internal capsule, and the medial ganglionic eminence will develop into the caudate nucleus, while the lateral ganglionic eminence will develop into the putamen and globus pallidus.
 * [Development:]
 * The two vesicles of the prosencephalon develop into the two hemispheres of the cortex and the basal ganglia.
 * The diencephalon stays the diencephalon (thalamus, hypothalamus, epithalamus).
 * The mesencephalon develops into the midbrain.
 * The metencephalon develops into the pons.
 * The myelencephalon develops into the medulla oblongata.

=Embryology II=
 * [Random numbers:]
 * 10^5: number of neurons you start with.
 * 10^11: number of neurons you wind up with (before beer and whiskey).
 * 10^12: number of glia you wind up with.
 * 10^15: number of synapses you wind up with.
 * 2 x 10^6: miles covered if you stretched out all the neurons in an adult human brain.
 * 2 x 10^7: words used by anatomists trying to get people interested in anatomy by saying things like "2 x 10^6: miles covered if you stretched out all the neurons in an adult human brain."
 * Know when and where neurogenesis occurs.
 * Occurs near the ventricles in the **ventricular zone**, which are the cell layers closest to the ventricles (or central canal in the spinal cord).
 * Mostly occurs during prenatal development, although some growth does come postnatally.
 * Of the postnatal growth, the great majority is in the first few years of life, but there is some growth in 'hot spots' (hippocampus, olfactory bulb) even as an adult.
 * Describe the changes in nuclear position that occur during the cell cycle of neuronal precursors.
 * Note that the dividing precursor cells in the ventricular zones have processes that go both medially (to the ventricle) and laterally (to the external surface/pia mater). This defines a sort of axis for the cells' movement.
 * As the cells go through the cell cycle, the cell bodies change position to get nearer one pole of the axis or the other depending on which phase they're in.
 * When the cells are in S phase (making DNA), they're closest to the external/pia side.
 * When they're in M phase (division), they're closest to the ventricle. During this period, the process attaching them to the external surface severs and is reattached once mitosis is finished and the next mitotic phase has begun.
 * Note that, in 'symmetric' mitosis, the two daughter cells stay attached to the ventricular surface (and keep dividing). They are more or less identical.
 * This distinguishes it from asymmetric mitosis (below).
 * When they're in G1 and G2 phases, they're sort of transitioning in the middle. It's like the pistons in an engine: M (inside), G1 (middle), S (outside), G2 (middle), etc, except that instead of compressing and igniting gasoline every time they come down they pop out another cell (which can in turn act as another piston).
 * Describe methods used to study neurogenesis.
 * Generally involve injecting labeled DNA precursors at a given point in development; cells dividing at that point will pick up the labeled precursors and incorporate them, but cells that have already stopped dividing won't contain the labeled material.
 * Specific labels: 3H-thymidine or bromodeoxyuridine.
 * Know what is meant by a neuron's birthdate. Does a neuron's birthdate influence its differentiation?
 * Birthdate: the point at which a neuron stops dividing (stops reattaching processes to the external surface and exits the cell cycle).
 * Yes, birthdate is influential in determining form and function; that is, differentiation.
 * Know which brain regions are areas of secondary neurogenesis.
 * Secondary zones of neurogenesis (formed postnatally): originate in the ventricular zone, but migrate to a new location and begin proliferating there.
 * The __cerebellum, hippocampus, and olfactory bulb__ all contain secondary zones:
 * In the cerebellum, the **external granular layer** (containing all granule neurons) is a secondary zone.
 * In the hippocampus, the **dentate gyrus** is a secondary zone.
 * In the olfactory bulb, the **subventricular zone** is a secondary zone.
 * Describe what is known about neurogenesis in the adult brain. What are key questions for future research?
 * As mentioned, new cells are being created in the hippocampus and olfactory bulb.
 * ..but most of these seem to be glia, and cells seem to be dying about as fast as they're being made (faster, with beer and whiskey).
 * So some questions: why glia? How do we interrupt the glial differentiation and instruct the brain to make new neurons? Do we care?
 * Draw and describe an asymmetric cell division.
 * The mitosis discussed above, in which each cell is still attached at one pole to the internal/ventricular surface, is symmetric; the mitosis occurs along a plane parallel to the pia/ventricular axis.
 * Asymmetric division is when the cell divides in the plane perpendicular to this (parallel to the ventricular surface), such that one daughter cell is still attached to the ventricular surface, but the other isn't attached at all.
 * This is easier to understand once you draw it a few times.
 * Notice that this tends to produce discrepancies in the content of mitochondria and cytoplasmic proteins between the two daughter cells (thus asymmetric, vs. symmetric division in which it's more or less equal).
 * As might be expected, the cell that's no longer attached to the ventricular surface is the daughter that stops dividing and begins to differentiate, while the still-attached cell is the one that stays a mitotically active precursor cell.
 * Know factors/mechanisms that determine when a cell stops dividing and begins differentiating.
 * As mentioned above, this is intimately wrapped up in the question of asymmetric division.
 * Part of the biochemistry of that asymmetry is this: there are factors that, in sufficiently large quantities, seem to induce the cell to stop dividing and start differentiating (//prospero, numb//, //and miranda//, showing that even researchers can be //Tempest// fans).
 * When the plane of cell division is right for symmetrical division, these factors divide evenly, so they don't reach threshold for differentiation.
 * When the plane of division is right for asymmetrical division, these factors tend to cluster on the external (pia) side, so that the daughter cell that forms without contact with the ventricular wall surface has sufficient factor levels to stop mitosis and differentiate. Pretty crafty.
 * For the cerebral cortex, know where the first-born cells are found with respect to the ventricular zone. What about the retina?
 * This seems more or less equivalent to the first part of the next LO. The first neuronal cells in the cortex migrate a small distance out of the ventricular zone and set up shop as the **preplate**.
 * The retina seems to develop in an opposite direction from the cortex-- rather than inside-out, it develops outside-in, from the ganglia to the photoreceptors.
 * Don't ask me why it's outside-in to go from the ganglia to the photoreceptors. I'm just the messenger.
 * Define preplate and subplate with respect to neuronal migration.
 * Post-mitotic cells leave the ventricular zone and migrate outward; this layer of first migratory cells is called the **preplate**.
 * As the process continues, the preplate divides into layers. From most superficial to deepest (closest to the ventricular zone): the marginal zone, the cortical plate (which winds up being the 6 layers of the adult cortex), the **subplate**, and the intermediate zone.
 * Again, don't ask me why we care about the subplate.
 * Describe the role that radial glia play in neuronal migration.
 * **Radial glia**: Glia that extend from the ventricular zone to the surface. Seem to serve as a guide for organizing cortical cells-- cells with similar functions wind up organized in columns along these radial glia.
 * Define and describe 3 stages of neuronal migration in the cerebral cortex.
 * **(1) Onset**: Cytoskeletal rearrangement to get onto the radial glia.
 * **(2) Migration**: neurons follow the glia out the ventricular zone and migrate outward.
 * **(3) Cessation**: neurons stop migrating and form permanent attachments.
 * Know genes that play a role in neuronal migration in the cerebral cortex. Which stages of migration do they affect?
 * Affecting stage (1):
 * filamin A. Deficiency is X-linked dominant and leads to __periventricular heterotopias__: differentiated neurons are found within the ventricular zone (can't get onto the radial glia).
 * Affecting stage (2):
 * LIS1 gene (on chromosome 17): leads to lissencephaly (smooth cortex; neurons stop migration before they get to the outer periphery). Note, again, that heterozygotes are affected.
 * DCX gene (on X chromosome): in males, also leads to lissencephaly; in females, leads to double cortex syndrome (novel migration patterns encoded by DCX gene).
 * Affecting stage (3):
 * //reeler// gene: leads to an inverted cortex (neurons can't pass previously born neurons and pile up beneath them, pushing them up) and extremely heavy neural density right next to the ventricular zone. The (extracellular) reelin protein seems to influence the neurons to get off the glial pathway (abnormally early, in the mutated gene).
 * Specifically, reeler mutations seem to result in lissencephaly with cerebellar hypoplasia.
 * //Dab1//, //Vldlr// and //Apoer2// genes: seem to be involved with receptor activity and intracellular neural transduction of the signal from the extracellular reelin protein.
 * Define radial, tangential and chain migration. What class of neurons undergoes radial migration? What class of neurons undergoes tangential migration? What class of neurons undergoes chain migration?
 * Radial migration: involves movement back or forth between the ventricular surface and the pia.
 * __Glutamate-containing (mostly excitatory) cortical neurons migrate using radial migration__.
 * Tangential migration: involves movement 'sideways' (off the radial axis) into other sections of radial migration. Does not involve radial glia.
 * __GABA-containing inhibitory cortical neurons migrate using tangential migration__.
 * Chain migration: I quote: "Neuronal precursors move as chains in a pathway known as the rostral migratory stream." It doesn't involve radial glia either. What it does involve, and how it's different from tangential migration, remain unanswered questions.
 * __The subventricular zone neurons in the olfactory bulb migrate using chain migration__.

=Neurogenesis, Migration, and Postnatal Development=
 * Know what neural crest cells are. What neuronal populations do they give rise to?
 * Neural crest cells: multipotential stem cells found in, you guessed it, the neural crest (recall that the neural crest are the most lateral cells on the folding neural tube, which pinch off when the tube fuses during neurulation).
 * Germane here, they give rise to peripheral nervous cells, specifically neurons and Schwann cells, and also pigment cells.
 * Contrast migration of neural crest cells to radial migration in the cerebral cortex.
 * [Two pathways discussed here:]
 * Dorsal pathway: directly under the epidermis, lateral to the dermamyotomes; these will give rise to pigment cells.
 * Ventral pathway: medial to the dermamyotomes, near or through sclerotomes; these give rise to peripheral nervous tissue.
 * Neural crest cells don't use radial glia as guides.
 * They expression adhesion molecules (__cadherins/integrins__) when they get to their destinations.
 * Compare and contrast "apoptosis" with "necrosis".
 * We've gone over this, to some extent. To recap:
 * Necrosis: 'passive,' cell death induced outside the cell (loss of membrane integrity).
 * Apoptosis: 'active,' protein- and RNA-synthesis-dependent process, mediated by intracellular pathways, that leads to cell death.
 * Know when cell death occurs in the nervous system.
 * During development, about half of the neurons that are originally generated die off.
 * Think of this as splashing a bucket of paint on a white wall and then scraping it off in selective places. It allows pattern and form to come out of an initial overabundance of material.
 * More specifically, it ensures that everywhere that needs a nerve gets a nerve; you can always kill off the spares later on, and this way you get a choice as to which nerve you want to keep (generally the one that works better).
 * Define and describe neurotrophins. What roles do they play in neuronal development?
 * Neurotrophins inhibit the intracellular pathways that lead to cell apoptosis. This works partially through **//trk//** receptors, which activate intracellular signaling pathways to prevent apoptosis when bound to their neurotrophin.
 * Notice that you can also get pro-apoptotic events when certain events happen- like when the uncleaved form of the neurotrophin binds to the receptors.
 * Neurons compete for neurotrophins, which are a limited resource; the neurons that successfully compete for neurotrophin fend off apoptosis, while their unluckier colleagues get the axe.
 * Note that this can be influenced by which neurons perform better at a given destination.
 * NGF (neural growth factor): first-studied neurotrophin; a trophic factor (see next LO) for sensory/autonomic neurons.
 * Provide examples of long-range and short-range axon guidance molecules. Which are attractive? Which are repulsive?
 * The 'growing tip' of the axon is called the **growth cone**. This is continuously extending and retracting filopodia to sample the environment around it and either follow chemical tracks that have attractive molecules or move away from chemical tracks that have repulsive ones.
 * Long-range guidance molecules: diffusible factors that go out some distance from their source to attract axons.
 * Example: **netrins**. These can be both attractive and repulsive, based on both the type of netrin receptor expressed by the growth cone and also the intracellular environment within the cone. These seem to be important in decussation-- once the axons are enticed to cross the midline, they need to be repulsed from crossing it again.
 * Another repulsive-signal example is **semaphorins**, but these can be both long- and short-range; when fixed, they're short-range, but their attachments can be cleaved to allow them to diffuse out to be long-range.
 * Short-range guidance molecules: fixed, non-diffusible factors that are either in the membrane of the target or in the extracellular matrix.
 * Example: cell adhesion molecules (CAMs) are attractive; they work kind of by an immunoglobulin velcro-like mechanism and are expressed on cell surfaces. Semaphorins, as mentioned before, are repulsive.
 * Once the growth cone finds a target, it develops into an __axon terminal__ and the contact point becomes a synapse.
 * Know factors that influence the ability of axons to regenerate.
 * Axons in the periphery can, and do, regrow.
 * CNS axons don't generally regrow. Note these three things:
 * (1) CNS axons do have the molecular capacity to regenerate.
 * (2) there are molecules that promote CNS axon regrowth (as NGF or FGF).
 * (3) the reason they generally don't is due to an environment full of inhibitory molecules that prevent axonal regrowth (mentioned specifically is a molecule called "Nogo").
 * So in principle, you can bathe a damaged axon in regrowth factors and block the inhibitory pathway and you should get some regrowth-- although targeting where the growth actually goes is a different question.
 * Define synapse elimination. When and where does it occur?
 * The axons that grow out during development develop synaptic contact with a lot more target cells than they actually wind up keeping-- that is, George Axon may contact 4 different target cells during development, but afterward ol' George may only have 1 target cell left. Conversely, though George may have only had 1 synapse on each target cell to begin with, he might wind up with 7 or 8 synapses on the one target cell he ends up with. What happened to George?
 * Selective synaptic elimination happened. Here's how it works.
 * There's a lot of contact back and forth between the developing presynaptic membrane (which needs to get its voltage-gated calcium channels and vesicular machinery in place) and the postsynaptic membrane (which needs to put NT receptors in its own membrane), mainly consisting of a bilateral release of neurotrophin and other proteins. Without this contact, neither side can develop as just mentioned.
 * In the case of motor neurons (recall that each muscle fiber should only be innervated by one motor neuron), things start out jumbled after initial development-- lots of fibers are innervated by more than one neuron.
 * The changes that result depend on neuronal activity-- essentially the wiring system is trying itself out, and correcting itself as it goes, to optimize motor control and ensure that the best possible connection exists between motor neuron and muscle fiber.
 * The neurons that are more successful at triggering the muscle fiber to fire are the ones that are kept; the one that can't get it to fire are discarded. This relies on release of neurotrophin and other proteins when the presynaptic terminal succeeds in depolarizing the postsynaptic membrane. Essentially the terminals that can do something for the postsynaptic membrane, and do it better than their competitors, are sustained; the others sort of wither away and are retracted by their axons.
 * Note that the axons that are kept wind up developing many more synapses onto the postsynaptic neuron (strengthening the connection and making the dendrite develop more spines).
 * Describe normal postnatal changes in brain morphology. How do ASD and Down's Syndrome affect these normal developmental changes in neuronal morphology?
 * As mentioned, the dendritic density of the brain shoots up thanks to all those new synaptic connections with the kept axons. Also as mentioned, secondary neurons are proliferating, so the total number of neurons is also going up. The cell bodies of the neurons seem to enlarge, possibly connected with the dendritic development.
 * Note that this process keeps going- the notes mention that the number of axon-dendrite connections present at the end of the first postnatal year is only 50% of the number of connections present at the end of childhood.
 * ASD (autism spectrum disorders), and possibly Down's Syndrome: the proteins that are needed to be released to develop mature pre- and postsynaptic membranes aren't present; thus the nervous system remains immature.
 * In ASD, cell bodies are smaller; dendrites branch less and have less synaptic contacts (due to a failure to 'prune' synaptic contacts?). Paradoxically, there is an excess of white matter and the brain itself tends to be large.
 * In Down's, the dendritic spines are thin and poorly developed, potentially due to similar mechanisms to ASD.
 * Know when myelination occurs.
 * Prenatally: in the spinal cord (by first trimester) and some brain regions (by third trimester).
 * Postnatally: relevant here, in cortical tracts, particularly the __corticospinal tract below the medulla__.
 * Describe two ways in which function of GABA receptors is developmentally regulated.
 * (1) GABA receptors are actually made up of a number of different subunits; the subunits used to comprise the receptors in development are not the same ones used in adulthood. Presumably this has an effect on stimulation and placement.
 * (2) Recall that GABA receptors are generally chloride channels. In the adult, the ECl is quite negative, near the resting potential of the cell, due to the small amount of Cl- in the cell. However, in the developing body, the concentration of Cl- in the cell is a lot higher (due to different relative activity of Cl- pumps pointing inward and outward), which makes the ECl much higher-- higher than AP threshold, actually.
 * This means that GABA receptors are excitatory in the developing child before becoming inhibitory later ("I was actually for the EPSP before I was against it").
 * This is important for proper neural circuitry development; however, it also predisposes young children to seizure activity-- the neural system effectively has no brakes.

=French's pharm review and pre-exam review= Some random notes on French's pharm review: Main targets for pharmacotherapy: receptors (more selective than targeting NTs or termination signals). Neostigmine: no effect in the CNS. Physostigmine: effect in the CNS. AChEs tend to boost parasympathetic activity more than sympathetic: PNS sets the tone (greater influence on baseline). Alzheimers: inhibited ACh function. (treat with inhibiting AChE) Depression: inhibited monoamines. (treat with inhibiting MAOs) Schizophrenia: too much dopamine. (treat with blocking DA receptors) Parkinson's: too little dopamine. (treat with DA receptor agonists or increased synthesis) Pralidoxime: causes regeneration of ACh at synapses (which is why you use it to treat irreversible AChE inhibitor toxicity). ACh blockade (atropine toxicity): Cholinergic agonist toxicity: NT synthesis:
 * CNS: drowsiness and disorientation
 * dry mouth
 * blurry vision (block ability to change shape of lens)
 * tachycardia
 * constipation/urinary retention
 * old 'blind as a bat, red as a beet, mad as a hatter, hot as a hare, dry as a bone' thing seems to work well. But add tachycardia.
 * SLUDGE:
 * **S**alivation
 * **L**acrimation
 * **U**rination
 * **D**efecation
 * **G**I symptoms
 * **E**mesis
 * can increase tyrosine/tryptophan hydroxylase activity by electrically-induced convulsions;can inhibit tyrosine hydroxylase (in pheochromocytoma) by alpha-methyltyrosine
 * VMAT (vesicular monoamine transporter): pumps DA/5-HT into vesicles; __reserpine__ blocks VMAT (blocking storage, thus also release).
 * ACh release intensified by black widow spider venom; inhibited by botulinum toxin or low Ca++ environment (Mg++ infusions through mag sulfate, sometimes to slow contractions in pregnancy).
 * NE/EPI/DA/5-HT release intensified by methamphetamines; inhibited by reserpine and monoamine oxidase inhibitors.
 * Lots of reuptake potentiators: SSRIs, SNRIs, etc.
 * Cocaine: blocks dopamine/NE reuptake.
 * Alpha-2 adrenergic receptors (presynaptic) act as inhibitors of further NT release.
 * GABA is potentiated by __benzodiazepines__.
 * Note that glutamate is mainly untargeted by pharmacology.

=ADHD=
 * Describe approaches for identifying and describing attentional dysfunction, especially attentional dysfunction associated with attention deficit-hyperactivity disorder.
 * Selective attention (paying attention to one stimulus to the exclusive of other, salient stimuli) is easily disrupted even in normal individuals.
 * Some other things it could be: sensory impairment, thyroid disorders, head injury, sleep deprivation, hunger, abuse, etc. In addition, lots of other psychiatric disorders present with disrupted ability to focus attention.
 * Look for:
 * __Difficulties in focusing__, particularly on things that aren't exciting.
 * Orienting system: orients you to the newest, most salient, most interesting stimulus that's being presented.
 * Executive network: prioritizes stimuli-- allows an override of orienting system to maintain attention on a non-novel stimulus.
 * ADHD seem to have trouble with the control of the executive over the orienting system.
 * This theory explains three symptoms of ADHD:
 * Paying attention to any novel thing that happens.
 * Can focus very well on something stimulating and interesting, sometimes for hours.
 * Difficulty in shifting attention away from the stimulating/interesting thing focused on.
 * __Poor working memory__: short-term immediate ability to manipulate facts and organize quick lists of tasks (go upstairs, get your shoes, put them on).
 * This is the symptom that teachers/parents evidently recognize the most-- they have to provide constant reminders to reprompt the child to do their given set of tasks.
 * __Impulsivity__: tendency to act before thinking about it. Mostly occurs in childhood.
 * __Hyperactivity__: note that a lack of hyperactivity doesn't mean a lack of ADHD. "ADD" is an identical disorder to "ADHD"-- about half the patients lack hypersensitivity.
 * Note this is pretty common- 8-12% of child population, maybe half that for adults.
 * Describe the functional impact of attention deficit-hyperactivity disorder.
 * Having ADHD as a child cuts a man's chances of being a high school, college, or professional graduate up to 10-fold and raises his likelihood of being in jail.
 * Also increases rate of substance abuse.
 * Describe at least 5 models for understanding why co-morbidity with other psychiatric disorders is high for individuals with attention deficit-hyperactivity disorder.
 * Generally patients with ADHD are more likely to have other psychiatric disorders: depression, enuresis (inappropriate urination), oppositional disorder, conduct disorder (arson, running away from home, etc), anxiety disorders, and academic difficulties. Assessment for those other disorders should be part of any ADHD treatment.
 * (1) Underlying shared genetic vulnerability: Mutations in the Tourette's gene predisposes to ADHD, anxiety disorders, learning and social disorders, etc. Note that treatments for ADHD tend to worsen anxiety.
 * (2) Developmental changes: increasing magnitude of conduct disorders, leading into schizophrenia or OCD as an adult, often originates as ADHD-- it's the same disease at different points in time and development.
 * (3) Depression: ADHD patients, in addition to being focused on interesting external stimuli, are also focused on interesting internal stimuli. Being extremely happy or extremely sad is more internally interesting than being in the middle; many ADHD patients migrate towards depression. Note that treatments for ADHD tend to improve this.
 * (4) Living with other people who have to deal with ADHD all the time: related to oppositional disorder. Constant external reinforcement of working memory by other people gets old fast, resulting in a defiance-oriented mindset. This tends to set in before 10 years old-- treating ADHD early can prevent it before it becomes too set in.
 * (5) Self-treatment: substance abuse as a response to stress.
 * [Note slide on "What Doesn't Work" for interesting reading.]
 * State the likely need for long-term treatment for individuals with attention deficit-hyperactivity disorder.
 * Note that nearly all patients will improve on medication.
 * But note also that about half of boys and almost all of girls with ADHD continue to have symptoms into adulthood-- not hyperactivity, but attentional deficits.
 * Note that there's a lot of ways of coping as an adult-- jobs that are high-emotional-stakes can allow patients to focus appropriately.
 * There seems to be a dominant theory that ADHD is a fundamental physiological deficit, like vision impairment, and medication for ADHD will continue to be needed throughout life. These results brought to you by Ritalin. No, no, just kidding. Sort of.

=Developmental Disorders= [see []]
 * Learn the key behavioral features of autism and will be able to list at least 5 early signs of autism.
 * Impairments in **communication**, **social skills**, and **areas of interest**.
 * May be nonverbal, or communication that's not socially connected.
 * [Pervasive developmental disorders- 2 of these three problems.]
 * [Asperger Syndrome: specialized focused interest in one area, some verbal skills relating to it.]
 * All of these conditions have at their root a social disability; that social disability has a biological basis which is as yet unidentified.
 * The main therapy at the moment is to push a lot of extensive social contact or networking, and to push it early.
 * Symptoms are generally evident within first 3 years of life (their biological basis occurring in 2nd trimester of pregnancy).
 * Not thought to be degenerative (no loss of skills), but uneven pattern of development (skills can be expressed for a while, then not, then expressed again).
 * __Features__:
 * Failure to use/understand nonverbal behavior (eye contact, gestures)
 * Doesn't follow a pointed finger towards an object-- can't make the connection between a gesture and what the gesture is mean to communicate.
 * This may have something to do with why autistic kids have trouble learning language-- the learning process involves nonverbal communication.
 * Autistic kids don't have the instinct to imitate the gestures of others, leading to increasing social isolation.
 * Delay in spoken language acquisition, not compensated by nonverbal communication
 * Lack of peer relationships appropriate for developmental level
 * Lack of sharing enjoyment/interest
 * Tend to develop specialized interests, strict routines (coping mechanism for anxiety?), repetitive motor movements.
 * Can't separate their interests from others' interests
 * Lack of reciprocity: repeating what's just heard (echolalia: expressing words but not understanding them), problems initiating or sustaining conversations (relating facts but nothing else).
 * Lack of imaginative or symbolic play
 * (Notice that autism is characterized more frequently by a lack of normal behavior than the presence of abnormal behavior.)
 * Increase understanding of how complex neurodevelopmental disorders are, with regard to etiology, onset, course, and comorbidity.
 * Etiology: unknown, complex, seems to be a problem with the brain as a system rather than a problem in a particular area; worsened by lack of experience/engagement. Many genetic disorders have features that resemble autism, and autism has a strong genetic component (increased risk of social/communication difficulty in 2nd child after a child with autism). Strong possibility that 'autism' is an amalgam of 20-30 different disorders.
 * Onset: 90% incidence in males. Ongoing question: is autism's incidence increasing or are we getting better at finding it?
 * Co-morbidities: siblings of autistic kids, kids with other genetic conditions (Fragile-X, Down's, etc) or medical conditions (tuberous sclerosis).
 * Others: mental retardation, anxiety, depression, ADHD, seizure disorders (particularly before 3 years), GI problems, allergies, etc.
 * Course: clinical picture changes during development (eg. can evolve from withdrawal to confrontation to schizophrenia with age).
 * Become familiar with some of the challenges families of children face.
 * Withdrawn, autistic kids (gravitate towards visual stimuli, avoid gestures or intimate interactions) can lead to feelings of guilt or isolation from children.
 * A kid who doesn't understand verbal or appropriate communication generally uses their behavior to communicate-- hitting, tantrum, crying, etc.
 * Gain awareness of issues physicians face when treating a person with autism.
 * When in doubt, screen for autism-- may pick up language impairment or something else that needs to be addressed.
 * It's a good idea to screen all kids at the 18-month well child checkup.
 * [Strengths of autistic kids: nonverbal puzzles, persistence and focus, learning within routines, following rules (though not always someone else's) and enforcing rules on others, systematizing things]
 * [Aspergers: good verbal skills, rule-governed, routine-oriented, excels at special interest, uses cognition to learn emotional/social skills.]

=Congenital Disorders and Pathology=
 * [Cerebral palsy: group of disorders in development of movement and posture; often arise due to stroke in utero.]
 * [Good note: when assessing for neurological congenital malformations, look for cutaneous markings or lesions-- neural tissue and skin are derived from the same ectoderm.]
 * Understand the following prototypical congenital malformations, including the period during embryogenesis and development when they occur:
 * [Note a distinction: congenital disorders are disorders present at birth; they are not necessarily genetic (can be a result of an illness or trauma that occurs during gestation, instead).]
 * **Neural tube defects**: can occur at 2-5 weeks.
 * Recall that the rostral neuropore (at rostral end of diencephalon) and caudal neuropore (at end of primary spinal cord, T12-L1 in adult), not to mention the entire region in between, all need to close properly for development to proceed.
 * __Cranioraschisis totalis__: total failure of neural tube to close. Fatal.
 * __Anencephaly__: rostral end of the neural tube fails to close and isn't distinct from the skin; results in absence of forebrain, parts of the skull, etc. Fatal. Note eyes often still form (diencephalon is unaffected).
 * __Encephalocele__: Neural tube closes, but overlying mesoderm doesn't; herniation of neural tube into skin sac. Tends to occur in occipital lobe. Can be surgically closed, but may leave kid with cognitive defects.
 * __Meningocele__: A sac of skin that contains CSF contiguous with the CSF in the spinal canal.
 * __Myelomeningocele__: Failure of caudal end of neural tube (end of primary spinal cord, neural S2) to close: Neural tube continuous with skin at lower back, CSF leaking out. Can be closed, but usually the spinal cord is malformed (see note below on spinal tethering); extent of disability depends on the level of the failure to close.
 * __Lipomyelomeningocele__: Mesoderm gets included in the neural tube and differentiates into fat, which tethers the spinal cord to the subcutaneous tissues.
 * __Dermal sinus tract__: Tract going through the dura, connecting the skin and the inside of the neural tube/CSF.
 * __Spina bifida occulta__: Laminar bone surface fails to fuse over the neural tube, usually on the L5-S1 level. Common incidental finding, often asymptomatic.
 * --Note that myelomenigoceles, lipomyelomeningoceles, and dermal sinus tracts cause __tethering__ of the spinal cord: effectively the spinal cord isn't free to move within the central canal, which causes problems when it needs to move during development (see below).
 * Neural tube defect prevention: 0.4 mg per day of folic acid for 4 weeks before pregnancy all the way through the first trimester. Note most neural tube defects aren't of genetic origin.
 * [Recall that the notochord fuses transiently with the endoderm on its way to becoming a filled structure from a hollow one. Sometimes part of the endoderm comes with the notochord when it reseparates again, forming a neurenteric cyst-- often occurs on the ventral midline.]
 * **Holoprosencephaly**: can occur around 5-7 weeks.
 * Holoprosencephaly: Failure of the patterning events that split the prosencephalic vesicle into the tel- and diecephalic vesicles. Can manifest in a variety of ways: alobar (no division of cortex), semilobar (incomplete cleavage), or lobar (separation of cerebral hemispheres but fused structures).
 * Note that proper formation of the nose, eyes, and some other facial features depends on proper division of the prosencephalon.
 * Mutations in Shh or an Shh pathway, for example, can cause this-- recall that differentiation expression of Shh (more ventrally, less dorsally) leads to proper division and differentiation in the prosencephalon.
 * Note that many holoprosencephalies are genetic, unlike most neural tube defects.
 * Disorders of neuronal proliferation: 8-16 weeks
 * Recall that proliferation is normally going on in the ventricular zone. Problems with the ability of the cell to proliferate can lead to __microcephaly__ (small brain/head); and over-ability to proliferate can lead to __megalencephaly__ (big brain/head).
 * Disorders of neuronal migration: 12-16 weeks:
 * Dr. Ribera's talked about this somewhat: problems with cortical neuron migration up the radial glia can lead to a variety of things, including __lissencephaly__, double cortex syndrome, heterotopias, etc.
 * [Note that problems with proliferation and migration often go together (microencephaly and abnormal gyrus formation).]
 * Disorders of elaboration of neurons and glia: ie. Dr. Ribera's lecture notes and images on autism and Down's syndrome, also poor myelination; can occur at 20 weeks to 5 years
 * [Disorders of cerebellar development:]
 * Normal development: rhombic lip on dorsal wall of metencephalon thickens and develops into the cerebellum; dorsal wall of the medulla thins to form some choroid plexus and the cerebellum hangs down over it.
 * __Dandy-Walker__ malformation: develops from a subarachnoid cyst obstructing the fusion of the rhombic lips at the midline; leads to no formation of the vermis, often occlusion of the CSF tract. Note that this seems to be neither folate- nor genetically related.
 * Understand the association between Chiari I malformations and syringomyelia, and the association between Chiari II malformation and myelomeningocele.
 * __Chiari II malformation__: associated with __myelomeningocele__-- central canal communicates with environment at lower back and leakage of CSF due to failure of caudal neural tube to close.
 * Causes collapse of the primitive ventricular system due to evacuating CSF; __the cerebellar vermis and the medulla herniate down into the foramen magnum__, which usually causes a collapse of the aqueduct/ventricular system with resultant hydrocephalus. In addition, the posterior fossa of the skull doesn't evolve correctly, evidently secondary to this neural tube malformation.
 * __Chiari I malformation__: associated with __syringomyelia__-- not a primary problem with the neural tube, but a mesodermal disorder of occipital somites.
 * The posterior fossa is formed too small for the brain; the cerebellum "squeezes out like toothpaste" into the foramen magnum. __A different part of the cerebellum herniates-- the cerebellar tonsils__. Although the CSF can often get out into the subarachnoid space from the cranium (if not, obstructive hydrocephalus results), the overhanging cerebellar tonsils block the outflow of CSF from the central canal of the spinal cord, creating a buildup of pressure in the central canal.
 * This creates a problem-- CSF needs to be able to flow into the spinal cord from the subarachnoid space to relieve increased venous pressure when abdominal pressure rises. Can see 'tussive headaches'- any kind of increased thoracic or abdominal pressure leads to increased intracranial pressure, leading to headache.
 * **Syringomyelia**: a cyst within the substance of the spinal cord that occurs with chiari I malformations. Seems to occur as a result of the increased CSF pressure in the central canal in Chiari I malformations; when that canal builds up too much pressure, it pushes out a bolus of CSF that dissects into the spinal cord itself.
 * Can see loss of pain/temperature bilaterally at a given level due to pressure on the anterior white commissure (near the central canal).
 * Note you tend to see a "cape-like" distribution of pain and temperature loss (white commissure loss).
 * Notice a good test-question difference there: Chiari I shows herniation of the cerebellar __tonsils__ due to CSF system collapse, Chiari II shows herniation of the cerebellar __vermis__.
 * Understand the normal levels at which the conus medullaris is found with respect to the vertebral column at different stages of development. Understand the concept of tethering of the spinal cord that can be associated with neural tube defects.
 * __Secondary neurulation__: regressed neural plate (medullary cord) forms a tube and fuses with primary-neurulation spinal cord to form the conus medullaris (S2-S4).
 * Conus is found at the L3 vertebral level in the newborn. In the adult, it's found at the T12-L1 level. Obviously it needs to ascend.
 * Tethering: as mentioned, if the spinal cord is attached, the conus can't ascend, resulting in compromised blood supply. Note that the fibers that result in urinary continence are very readily affected by this.
 * Understand symptoms that result when a process such as syringomyelia or tethering affects the spinal cord.
 * General concerns: pain, compromised blood supply due to tension on the cord.
 * Motor reflexes: Spastic hyperreflexia vs flaccid hyporeflexia (depending on level of damage).
 * Urinary tract:
 * S2-S4 lesions (parasympathetic/somatic damage): damage in the sacral region eliminates the ability of the bladder to empty by contraction of the detrusor muscle and the ability to sense and consciously control bladder fullness/emptying.
 * T10-L2 lesions (sympathetic damage): damage in this region eliminates the ability of the sympathetic system to prevent micturition until parasympathetic activation occurs, resulting in incontinence.
 * Understand the principal causes and consequences of stroke in the perinatal period.
 * Strokes in children: tend to be due to genetic malformations of heart or blood vessels, genetic hematologic disorders, or neurocutaneous syndromes (neurofibromatosis, von Hippel-Lindau, etc). Occasionally you get a Moya-Moya or fibromuscular dysplasia cause as well (see "Ischemia").
 * Only 55% of childhood stroke is ischemic; the rest is hemorrhagic (eg. aneurysms).
 * Pediatric brain: doesn't yet have a good astrocyte system for forming scars and filling in holes. Strokes tend to result in large, cavitated, unclosed holes in the brain (__porencephaly__ or __schizencephaly__ depending on whether the holes are lined by white or gray matter, respectively) that can also be filled with fluid (__hydraencephaly__).
 * Note that you can have what's called 'mushroom gyri:' after damage to an area of the still-growing brain, the surrounding gyri grow out and 'poof out' around the damaged area.
 * __Cerebral palsy__ is a frequent result of perinatal stroke/mushroom gyri, a group of motor-sensory deficit disorders (weakness, hypertonia, movement disorders).
 * Germinal matrix hemorrhage: in preterm infants (germinal matrix, a loose vascular structure next to the lateral ventricle, hasn't migrated away), can rupture easily into the lateral ventricle or the surrounding brain parenchyma, causing tissue damage and hydrocephalus.
 * Note also that premature kids can get spillage of unconjugated bilirubin across the BBB and it can collect in the brain-- prevented with light-catalyzed breakdown of bilirubin.
 * The parts of the brain that are highly metabolically active are particularly vulnerable to stroke (higher oxygen demand). Eg: __periventricular leukomalacia__, in which the axon tracts near the ventricles suffer ischemia and necrosis.

=Disease of Muscle and NMJ=
 * Recognize the tempo and pattern of weakness in myasthenia gravis (MG)
 * Tempo/pattern: slurred speech, double vision, drooping eyelids, facial weakness, shortness of breath, neck muscle weakness, proximal extremity weakness; can progress to quadriplegia and respiratory arrest.
 * I asked if this was specifically descending paralysis, and he said no-- lots of different antibodies are expressed in MG, to many different subtle varieties of ACh receptors. The first ones that are generally affected in the face, throat, and diaphragm.
 * Ie: aspiration. Pharyngeal muscles are weak, leading to increased tendency of salivation or foreign material to slide into the larynx; diaphragmatic muscles are also weak and lack the strength to cough it out, leading to aspiration pneumonia.
 * Understand the immunopathogenesis and treatment of MG
 * Immunopathogenesis: As previously described, antibodies against the acetylcholine receptors on the postsynaptic membrane. Note that eventually complement binding will destroy the postsynaptic membrane of the NMJ. Myasthenia gravis tends to correlate with __an enlarged thymus__ (which goes along with the observation that MG patients tend to have other autoimmune disorders as well); evidently the thymus is still playing an active role in autoimmune sensitization in MG patients.
 * The idea is that cells called "myoid cells" in the thymus may be the antigen that forms the antibodies that target the NMJ receptors.
 * Note that babies born to mothers with myasthenia gravis have a transient form of MG (until the mother's IgG has cleared out).
 * Treatment: Generally __immunosuppression__ with prednisone and/or azathioprine (immunosuppressant with, possibly, less side effects); usually also __thymectomy__, which seems to improve patient outcomes.
 * Note that AChE inhibitors are not good long-term therapy (for a variety of reasons, but here principally because it doesn't address the ongoing slow destruction of the postsynaptic membrane by complement fixation) but can be used short-term, along with plasmapheresis or IV immunoglobulin.
 * Remember that long-term use of steroids come with a whole lot of very unpleasant side effects.
 * Recognize the pattern of weakness in Duchenne/Becker dystrophy
 * Muscular weakness beginning in the legs and calves and eventually affecting all somatic muscle, the heart, and the diaphragm.
 * Early manifestations: waddling gait, wide straddle posture, lordosis.
 * **Gower's maneuver**: use hands and arms to stand up ('walking' their upper bodies up their legs).
 * Muscle biopsy: excessive connective tissue and fat, damaged hyperreactive muscle fibers filled up with calcium due to plasma membrane defects.
 * __No cure__ for MD-- most MD kids die no later than their 20's.
 * Progressive muscular contracture and scoliosis (the latter made worse by wheelchairs and currently avoided by an implanted spinal rod).
 * Ultimately the restricted pulmonary function due to diaphragmatic weakness is what proves fatal-- accumulation of CO2 leads to vasodilation, headaches. Worse when lying down (diaphragm not helped by gravity).
 * Describe the specific genetic defect in Duchenne muscular dystrophy (DMD)
 * Genetic defect in //Dystrophin// protein, a membrane protein involved in tethering the muscle fiber's intracellular actin cytoskeleton to the plasma membrane and the surrounding extracellular matrix.
 * Most forms of muscular dystrophy result from a mutation causing an early stop codon, which can result either in a nonfunctional protein (Duchenne's) or a truncated, only partially functional protein (Becker's).
 * Duchenne's MD: absence of functional dystrophin protein.
 * Becker's MD: modified, truncated dystrophin protein. Generally less severe than DMD.
 * What pathologic changes of muscle occur in Duchenne/Becker dystrophy?
 * Some inflammation in the muscle (slight benefit from using corticosteroids).
 * As mentioned, an overabundance of fat and connective tissue and damaged, hyperreactive muscle fibers.

=NMJ Pharmacology=
 * Describe how botulinum toxin and black widow spider venom affect cholinergic neurotransmission.
 * //Clostridium botulinum// toxin: cuts SNARE proteins in the excitatory presynaptic cytosol, inhibiting release of ACh into the NMJ.
 * Black widow spider venom: a latrotoxin that prompts clumping and widespread fusion of ACh vesicles with the presynaptic membrane, increasing release of ACh into the NMJ.
 * Note that both of these result in respiratory failure by diaphragmatic paralysis (the former by an absence of released NT, the other by depolarization blockade at the postsynaptic membrane-- see next LO).
 * Explain what happens with brief versus prolonged stimulation of nicotinic cholinergic receptors.
 * Brief stimulation (as with normal NMJ signaling): membrane depolarizes, sending an AP down the postsynaptic neuron or muscle fiber. Once the ACh has been inactivated by the AChE in the cleft or has diffused away, the membrane then repolarizes (since the ligand-gated, non-selective cations channels are no longer stimulated by ACh) by closing Na+ inactivation gates and pumping out Na/Ca/etc, at the end of which the membrane is ready to depolarize and send another AP.
 * Prolonged stimulation: membrane depolarizes, sending an AP down the postsynaptic neuron or muscle fiber, but **can't repolarize** because the non-selective cation channels activated by ACh haven't turned off-- the Na+ inactivation gates close, but sodium is still flooding into the cell through the ACh-activated NSC channels, so the membrane's potential remains above threshold and can't be reset to create another AP impulse. This is called **depolarization blockade**.
 * French's metaphor: if you try and flush the toilet twice in a row by constantly pressing the handle, it won't work- you're not allowing the water to build sufficiently to create the right environment to allow another big outflow.
 * Note an important after-consequence of depolarization blockade: **desensitization blockade**. Even when the continuous stimulation's been removed, the NMJ won't work properly for a while. After a receptor's been coupled with for all it's worth, it's kind of spent and can't couple effectively with anything else for a while. Go take that with your sick little minds and run with it.
 * Note that depolarization blockade (too much ACh release; a "cholinergic crisis") looks a lot like myasthenia gravis (not enough ACh release; a "myasthenic crisis"). Obviously, using AChE inhibitors to treat muscle weakness is a really bad idea in a cholinergic crisis. So be careful.
 * Note that with muscular nAChRs it's slightly more complex because the membrane repolarizes before the calcium content of the cell has been pumped out of the cell or back into the sarcoplasmic reticulum. You can have a muscle that receives discrete, periodic ("brief") stimulations with a certain amount of time between them - the muscle fiber membrane is being depolarized and repolarized properly - but which stays continually tetanic because the calcium content of the muscle fiber (which is, along with ATP supply, what determines actin-myosin contraction) stays elevated. This was demonstrated in the synaptic transmission lab- a fairly low frequency of depolarizing signals can induce complete muscle tetany.
 * Explain the complex effects produced by nicotine in the peripheral nervous system.
 * They're complex.
 * Nicotine has high lipid solubility and acts in both the periphery and the CNS.
 * In periphery: stimulates sensory receptors and autonomic ganglia/adrenal medulla; increases heart rate and blood pressure.
 * In CNS: stimulation, then depression; addictive through the dopaminergic reward pathway.
 * Toxicity (ie. a kid just ate a pack of cigarettes): difficulty breathing and convulsions; usually self-limiting because the little brat barfs them up. Nicotine itself probably causes heart disease but may or may not cause lung cancer.
 * Describe the effects produced by antagonists that are selective for nicotinic cholinergic receptors at the NMJ and explain their clinical usefulness.
 * Generally these are competitive antagonists for the ACh receptors in the NMJ; they don't activate the receptors but prevent anything else from activating them either.
 * __Have to be given IV__ (charged compounds, can't get across intestinal wall).
 * Produce flaccid paralysis, moreso in limb (mainly fast-twitch) than respiratory (mainly slow-twitch) muscles.
 * Note this __produces neither analgesia nor anesthesia__-- patients can't move but are fully conscious.
 * Curare, atracurium and rocuronium are all nondepolarizing (competitive) neuromuscular blocking agents. Describe their different properties that make them useful/not useful in different clinical situations.
 * Note that all the nondepolarizing NM blocking agents have "cur" in the name.
 * __Curare__: slow onset, long duration (80-120 minutes); broken down by kidney. As side effects, you get histamine release (resulting in hypotension) and can at high doses target neuronal nACh receptors as well as muscular nACh receptors.
 * __Atracurium__: faster onset of action, shorter duration (40-60 minutes); broken down in plasma by pseudocholinesterases. Still get some histamine release, but no targeting of neuronal nACh receptors.
 * __Rocuronium__: Very fast onset, shorter duration (40-60 minutes); broken down in liver; results in neither histamine release nor neuronal nACh receptor targeting.
 * Describe the properties that make succinylcholine distinct from other clinically used neuromuscular blocking agents.
 * __Succinylcholine__: two ACh molecules covalently linked. This prevents it from being broken apart by acetylcholinesterases in the synaptic cleft.
 * It's a depolarizing blocking agent-- it causes depolarization blockade. This means it causes an initial muscle stimulation, then depolarizing blockade, then desensitization blockade, then (if used long enough) causes a curare-like effect for unknown reasons.
 * Used because it's cheap, it has an extremely rapid onset of action (a minute to a minute and a half), and lasts only a very short time (5-8 minutes). Broken down by pseudocholinesterases (note that if someone has defective pseudocholinesterases, they can be in trouble).
 * Note also that succinylcholine can cause bradycardia (react with muscarinic receptors in heart).
 * Explain the effects of (i) acetylcholinesterase inhibitors or (ii) drugs that decrease acetylcholine release on nondepolarizing vs. depolarizing neuromuscular blocking agents.
 * (i) Quaternary-amine (peripheral) AChE inhibitors tend to be given at the end of surgery to speed recovery from the curare-like nondepolarizing agents.
 * Note that they won't have much negative effect on succinylcholine, which isn't broken down by AChE anyway, but can intensify the resultant depolarization blockade, thus __strengthening__ its effects.
 * (ii) Certain drugs (some aminoglycosides) compete for the Ca++ that needs to flow into the presynaptic terminal to release the vesicles; others (opioid analgesics) activate opioid receptors on the presynaptic membrane to decrease ACh release. Both of these result in decreased ACh release (mini-neuromuscular blockade) and hence, for a patient who's taking them, you need to lower the dose of neuromuscular blocking agents. Note it doesn't matter for depolarizing agents like succinylcholine, since the action isn't dependent on competition with ACh.

=Peripheral and Motor Neuron Disease=
 * [Keep in mind that muscle weakness can be caused by problems in the upper or lower motor neurons, the neuromuscular junction, and/or the muscle itself.]
 * Know the clinical features of motor neuron disease in adults. What laboratory tests help to diagnose the condition? What drug and symptomatic treatments are used?
 * In adults, you have amyotrophic lateral sclerosis (ALS, present with a mix of upper and lower motor neuron findings).
 * __ALS__ (also known as Lou Gehrig's disease): both upper and lower motor neuron involvement. __Clinical features__: limb muscle weakness, rapid fatigue, muscle cramps, slurred speech, and/or a history of choking on food.
 * **Lower motor neuron involvement** can be detected by:
 * (1) Muscle atrophy on dorsal surface between thumb and index finger, as well as in the tongue.
 * (2) The weakness is often asymmetric.
 * (3) Look for fasciculations of the tongue or limb muscles- "twitching."
 * **Upper motor neuron involvement** can be detected by:
 * (1) Spastic tone in arms/legs.
 * (2) Hyperactive tendon reflexes.
 * (3) Abnormal or pathological reflexes (Babinski, etc).
 * (4) The "__psuedobulbar effect__"-- rare (< 10% of ALS patients), involves inappropriate, uncontrollable laughter or crying.
 * Note what are **not** features:
 * No bowel or bladder incontinence
 * No pain until late in the disease (contracture of muscles)
 * No sensory loss
 * Can see memory and behavioral status changes.
 * It's still unclear why motor neurons fail. There's a cluster of findings but nothing definitive. The neuron withdraws from the muscle and eventually commits apoptosis among a cluster of toxins.
 * Note that the vast majority of ALS patients (90-95% of cases) have no family history of ALS. Every once in a while you can find a case with a mutation in the superoxide dismutase 1 gene.
 * However, **the diagnosis of ALS is a clinical one** with only a few lab tests:
 * Negative (no tumor) MRI of head and neck
 * Electromyography (shows de-innervation of muscle)
 * Normal nerve conduction studies
 * Creatine kinase elevated (though not terribly helpful)
 * Median __3-5 years survival__ after diagnosis.
 * Treatment: supportive: speech devices, noninvasive ventilation, scopolamine for saliva problems, etc. Also treat for depression; can treat psuedobulbar ddisease with quinidine and dextromethorphan. Physical therapy, home assistance, occupational therapy. They'll need some form of help walking and should do think about living wills and power of attorney.
 * Obviously we have nothing to treat the actual disease. There have been dozens of trial drugs that have failed to work.
 * Riluzole: prolongs life about 3 months (but exorbitant cost).
 * Vitamin C and E seems to work somewhat in mouse models, but its efficacy is unclear.
 * [Motor neuron disease in children: __Spinal muscular atrophy__, a disease of lower motor neurons; look for respiratory difficulty, hypotonicity; death usually occurs within a year.]
 * What is a mononeuropathy? Know about common examples, which nerves and what treatment.
 * A single identifiable motor nerve is affected. Generally this is as a result of some kind of trauma to the nerve, isolated or repetitive.
 * Commonly affected:
 * Peroneal nerve
 * Ulnar nerve
 * Median nerve
 * All of these tend to be due to nerve entrapment at the head of the fibula, elbow, or wrist respectively.
 * Note that diabetic patients are predisposed to carpal tunnel syndrome.
 * Rarely, can also be a result of hypothyroidism, necrotizing vasculitis, etc.
 * Cranial nerves III, IV or VI
 * Due to isolated ischemic infarct, seen mainly in diabetic patients. Will generally resolve with time.
 * Electrical studies: look for slowing of nervous transmission across damaged nerve. In addition, look for rheumatic/arthritic markers to rule out arthritis.
 * Treatment: splints, sometime surgery; better to stop doing whatever it is that's causing the trauma (leg crossing, resting elbows on table, bad typing posture, etc).
 * What is a polyneuropathy? What are some common causes? What laboratory studies would help in diagnosing the cause?
 * More than one nerve is affected, generally "**glove and stocking**" areas. Symmetric motor/sensory loss of function, generally ascending from the tips of the extremities.
 * Seem to be caused mainly by **(1)** axonal degeneration or **(2)** demyelination:
 * __Axonal degeneration__: Caused by just about anything that can damage the axon. Axon dies after a given point, sparking a proliferation of Schwann cells to attempt to provide a conduit for the axon tip to regain contact with its former muscle target. The axon can grow back and be remyelinated.
 * __Demyelination__: the myelin sheath degenerates from around an axon. Tends to result in a lack of coordination between some neuronal firing to a muscle group and others depending on the relative extent of demyelination between them; this is perceived as muscle weakness.
 * Caused by a genetic abnormality or an autoimmune condition.
 * Example of a genetic cause: Charcot Marie Tooth Disease (genetic defect on chromosome 17 resulting in defective/overcompensated myelin production).
 * Example of autoimmune cause: Guillain-Barre disease (antibody against myelin sheath; marked by rapidly evolving ascending numbness and weakness, can target diaphragm). __Look for high protein levels in the CSF with normal sugar levels and cell count__.
 * Note that similar symptoms, at least in extremities, can be seen in spinal cord compression due to a tumor-- but there is __no incontinence in Guillain-Barre__, which is a feature of spinal compression.
 * Findings: sensory loss, reduced or absent deep tendon reflexes.
 * Electrical studies can establish if it's demyelinating or axonal degeneration. Blood work is often also done to rule out other causes.
 * How do you treat common polyneuropathies such as those resulting from diabetes or alcohol abuse? How do you treat polyneuropathies for which there is no identifiable cause?
 * Tight control of diabetes or treatment for alcoholism; also analgesics (wide range; see list on p. 12).
 * For unidentified, look for amyloidosis, cancer, porphyrins; always provide symptomatic treatment even if no cause can be found.
 * Note that you don't find an identifiable cause in 80% of peripheral polyneuropathies.
 * What are the three clinical manifestations of Diabetic Neuropathy?
 * __Peripheral polyneuropathy__ (burning sensation in the feet)
 * __Autonomic neuropathy__ (becomes lightheaded upon standing, diarrhea, urinary urgency)
 * __Mononeuropathy__ (cranial nerves III, IV, VI, or entrapment of median nerve)

=CNS Injury I + II=
 * Define concussion, or mild traumatic brain injury [__mild TBI__]
 * 1964: "A clinical syndrome characterized by immediate and transient impairment of neural function due to mechanical forces" (impairment: alteration of consciousness, disturbance of equilibrium, etc).
 * Note that **concussion does not necessarily entail loss of consciousness.**
 * Note that a loss of consciousness of over 30 minutes is no longer a concussion but a more severe traumatic brain injury.
 * Note further that a loss of consciousness of more than 5 minutes is considered a neurological emergency.
 * Note further than that that loss of consciousness and amnesia does not seem to correspond to poorer long-term outcomes. However, short-term responses tend to be poorer with amnesia, loss of consciousness, or both.
 * 3 grades of concussion:
 * Grade 1: transient confusion, no LOC or amnesia, resolves in less than 15 minutes.
 * Grade 2: confusion and amnesia, no LOC.
 * Grade 3: LOC.
 * Concussion: a mild torqueing of the brain within the skull, momentarily stretching or 'disconnecting' the axons of the brain. Essentially mild and reversible diffuse axonal injury (as from rotational deceleration injuries, see below).
 * Note this means that **successive concussions can cause additive, permanent damage** on an axonal level, in addition to causing catastrophic cerebral swelling and failure of autoregulatory mechanisms: "Second Impact Syndrome." Notice that Shaken Baby Syndrome often looks like this as well.
 * Note that, mild or not, the event that causes a concussion can still kill you, largely from bruising and hemorrhage in the frontal and temporal lobes. Note also that MRIs are better than CTs than picking up intracranial hemorrhage, particularly parenchymal hemorrhage.
 * Note also that __rotational injury__ tends to produce more concussion effects (both hemorrhagic and axonal) than __translational injury__. More on this below.
 * Pathophysiology:
 * As described below under "diffuse axonal injury," axons (and small vessels) are sheared and destroyed, largely at the gray-white cortical junction. The intracellular cytoskeletal framework is also disrupted, screwing with transport of nutrients and proteins along the length of the axon.
 * Note that concussion frequently causes brief amnesia, both pre- and post-trauma-- thus the person who underwent the concussion is not a good person to ask about loss of consciousness, as they can't distinguish between a loss of consciousness and an amnesiac period. Need eyewitnesses to definitively pin down a LOC episode.
 * List five of the most common symptoms of concussion
 * Headache
 * Dizziness
 * Poor attention
 * Poor memory
 * Easy fatigability
 * Irritability
 * Anxiety/depression
 * Sleep disturbance (note that treating this often makes all the rest better)
 * [Notice possible clinical signs: incoordination, inappropriate emotionality, memory problems, any witnessed loss of consciousness.]
 * [Note finally that you want to re-introduce the patient to normal functioning slowly.]
 * Know the peak age groups in which head injuries occur and the mechanisms whereby these injuries are received
 * Age 24-35, male:female 2:1
 * (Hint: think "who over 18 is annoying enough that I would like to hit them in the head with a baseball bat?" Twenty-something males, that's right. Alternatively, think "who's desperately trying to prove that they're just as cool as they were in college by doing a one-handed kegstand/doing 80 down Colfax?")
 * Main causes: __motor vehicle accidents__ (Colfax), __recreational activities__ (kegstand), and __violence__ (someone hitting them).
 * Mechanisms: __contact phenomena__ (lower-velocity, damage mainly to protective structures like the skull and the dura), __acceleration/deceleration injuries__ (higher-velocity, damage mainly inside the protective structure in the brain itself), and __penetrating injuries__ (the gun and knife club).
 * Contact injuries: result from smacking the head against something or, more commonly, having something smacked against the head. Generally fairly low-velocity, at least relative to vehicular accidents.
 * Skull fractures: 4 types:
 * __Linear fractures__
 * __Depressed fractures__
 * __Basilar fractures__ (anywhere in the base of the skull; significant due to strong association with CSF leaks/meningitis and damage to cranial nerves)
 * Look for CSF leakage, periorbital hematoma/'racoon eyes,' facial nerve palsy, bleeding from ears, hematoma behind the ears.
 * __Growing fractures__ (fractures in infancy-- herniation of arachnoid out of the dura, causing growing separation of bone)
 * **Epidural hematomas**: generally caused by a skull fracture in the temporal region (contact phenomenon). Relatively low mortality rate. "__Lucid interval__" occurs due to the absence of damage to underlying structures, but after a few hours, it progresses to obtundation and coma. Frequently this is occasioned by a laceration of the middle meningeal artery and accompanied by __uncal herniation__ (see below) due to its temporal location.
 * On CT, you generally see a **convex** shape of blood pooling-- sharp edges of where the dura is coming away from the skull.
 * Acceleration/Deceleration injuries:
 * __Translational injuries__: result from head movement along a single axis (restrained passengers, falls, etc).
 * Tend to result in (1) tearing of bridging veins that run through the dura from the arachnoid (causing **subdural hematomas**) and (2) bruising of the brain where it impacts the skull (the hemorrhagic component of **concussions**, see first LO).
 * Concussions usually result in low mortality, but note that the rebound of the brain off one side of the skull onto the opposite side can cause contusions at both poles of the brain (and the scraping of the brain over the rough lower surfaces of the skull can cause contusions on the basilar surface of the brain as well)-- referred to as "**coup-contrecoup**" injury. Note that this term also includes damage due to the sudden low cranial pressure ('vacuum effect') in the opposite pole (disruption and tearing of blood vessels).
 * Subdural hematomas have a higher mortality rate, often due to elevated intracranial pressure and intracranial parenchymal damage.
 * Note that subdural hematomas tend to be more **concave** or crescent-shaped on CT.
 * __Rotational injuries__: results from head movement in more than one axis (ejection from vehicle, auto-pedestrian, etc). The brain undergoes rotational as well as translational motion.
 * **Diffuse axonal injury**: Microscopic tearing of the axons and associated microvessels in the brain-- the other component of concussions. Specifically associated with rotational concussions (though bruising and hemorrhage are usually more severe as well in rotational injuries). Often **no gross injury** but axonal damage is permanent and can result in coma or permanent brain damage.
 * As mentioned, note that you sometimes have bleeding visible on CT/MRI at the gray-white junction in the cortex (axonal tearing).
 * Penetration injuries:
 * Guns and knives, pretty much. Velocity of injurious agents tend to correlate with outcome, as do obvious things like what major arteries and cranial nerves they impact.
 * Appreciate the pathophysiology of various types of head injury and how they occur
 * [__Gross__ pathophysiology of traumatic brain injury:]
 * Intracranial increases in volume (**mass lesions**) are generally caused by increases in (a) brain matter, via tumor; (b) CSF in a blocked ventricular system; or (c) blood and/or clots in a hemorrhage situation.
 * Can think of the brain as a closed compartment- any increase in intracranial volume displaces or compresses CSF (generally into the central canal of the spinal cord) or cerebral blood volume (either venous or arterial; venous is easier to displace), since the brain is more or less unable to compress under physiological conditions.
 * Note that there's only so far you can displace or compress CSF and blood before it won't displace or compress any more and you start increasing intracranial __pressure__ with each increase in intracranial __volume__.
 * Your main problem with elevations in intracranial __pressure__ is **herniation**.
 * Pressure gradients cause forcible displacements of brain tissue along its 'fault lines.' Largely:
 * (1) __Subfalcine herniation__: the cingulate gyrus herniates under the falx cerebri.
 * This often compresses or kinks the anterior cerebral artery, resulting in stroke.
 * (2) __Uncal herniation__: Uncus herniates into the posterior fossa.
 * This often compresses the crus cerebri (causing contralateral hemiparesis) and also the third cranial nerve (causing ipsilateral fixed pupillary dilation) and smashes the other side of the midbrain against the tentorium cerebelli.
 * This would be the 'jaws of death' that Dr. Carry was so fond of and causes extensive hemorrhage (called "Duret hemorrhages") in the central midbrain; this is often what causes death in these patients.
 * (3) __Tonsillar herniation__: Cerebellar tonsils herniate into the foramen magnum.
 * Causes compression of the medulla; look for Cushing's reflex (high intracranial pressure driving sympathetic activation, resulting in massive peripheral vasoconstriction, creating hypertension, leading to reflex bradycardia).
 * (4) (not discussed in class but in the notes) __Central herniation__: central downward pressure, can result in bilateral uncal herniation (bad news).
 * Note this results in damage both to the tissue that's being pushed and also damage in the tissue it's being pushed into; often the latter is pushed into an unforgiving structure such as the tentorium and is the one that is more damaged.
 * Notice, however, that brain tissue itself, like any parenchyma, tends to swell with injury. This tends to make things worse.
 * __Cellular__ pathophysiology of traumatic brain injury:
 * __Massive release of NTs follows brain injury__.
 * Recall that astrocytes normally pick up the secreted NTs and ions and secrete factors that dilate the capillary endothelial cells in response.
 * In brain injury, the level of NT/ion release is so large that the astrocytes can't keep up. This has three consequences:
 * **Excitotoxicity**: tons and tons of glutamate get dumped into a synaptic cleft, causing uninhibited depolarization and calcium channel opening (NMDA receptors and their ilk). The perpetually open calcium channels lead to cytotoxic levels of incoming calcium, causing neuronal cell death by apoptosis (or, if the influx is rapid enough, necrosis).
 * **Vasogenic edema**: the astrocytes, facing an overabundance of uptaken NT, do what they normally do in the face of lots of NT release, namely signal the capillaries to open wide, wide, wide-- __hyperemia__. So much blood comes in that the endothelial cells themselves tear open, allowing liquid to come into the brain parenchyma. Note that the endothelial cells are also damaged by the cellular enzymes activated by calcium-activated cell death in excitotoxicity.
 * As a consequence of this hyperemia, the smooth muscle cells responsible for __autoregulation__ are also damaged. This has bad consequences later for ischemia.
 * **Cytotoxicity edema**: the astrocytes and neurons are pumping in potassium and pumping out sodium as fast as they can, in the process burning through their available ATP (recall that the Na/K pump is ATPase-driven). Their inability to re-equilibrate the ion gradient, combined with the fact that they eventually run through their energy supply completely, causes cell swelling, further contributing to the edema.
 * The astrocytes in particular fill up with uptaken potassium, slowing their ability to uptake glutamate and causing them to swell. As part of the swelling, their foot processes around the cerebral capillaries become tighter, decreasing cerebral capillary blood flow.
 * The next thing that happens is __cerebral ischemia__. Here's how:
 * The swelling (extracellular and intracellular) due to vasogenic and cytotoxic edema compresses blood vessels, decreasing flow.
 * The hyperemia-induced damage to the autoregulatory cells means that they can't compensate for low cerebral blood flow with vasodilation.
 * Since head injury is often associated with hypoxia and hypotension, what tends to result is cerebral ischemia.
 * This ischemia leads to even lower ATP levels in the neurons, causing additional cytotoxic cell death, leading to greater edema, leading to greater ischemia, etc. Mortality with both hypoxia and hypotension is very high.
 * Recognize the goal of treatment in head injuries
 * (1) ABC stuff (airway, breathing, circulation/blood pressure). The main point is to maintain cerebral perfusion and avoid ischemia to interrupt the edema-ischemia cycle.
 * (2) Lower intracranial pressure:
 * Drain CSF or blood to decrease pressure on vasculature and structures.
 * Injection of mannitol draws fluid into the plasma from the brain to decrease cellular swelling.
 * Note that treating at this stage is not terribly effective. Primary prevention works better (tell your buddy not to do that one-handed kegstand).
 * Understand the reason for the control of intracranial pressure in the treatment of head injury
 * Discussed above. Among other reasons, want to prevent Cushing's reflex, increase perfusion of structures, and interrupt the edema-ischemia cycle.
 * Recognize the signs and symptoms of increased intercranial pressure. Understand the clinical and pathologic features of the four herniation syndromes presented here
 * As mentioned, look for __obtundation__ (poor responsiveness) and __lethargy__.
 * The herniation syndromes are discussed above.
 * Note that **lumbar puncture in the presence of increased intracranial pressure can precipitate a herniation** (creating an environment in which the cranial subarachnoid space is higher-pressure than the spinal subarachnoid space).
 * Understand the Glasgow Coma Scale, its utility in predicting injury severity and outcome, and the elements of the clinical evaluation of concussion
 * Allows quick, fairly reliable gauging of cerebral injury.
 * Three categories:
 * Eye opening (they open or they don't)
 * Motor response (ability to respond to vocal commands)
 * Verbal response (ability to speak appropriately and without disorientation)
 * [Brainstem reflexes:]
 * Pupillary reflex (arc: CN 2 in, 3 out; through midbrain)
 * Corneal blink reflex (arc: CN 5 in, 7 out; through pons)
 * Cold caloric testing (flush ice water into ear, causes vestibulo-ocular reflex where eyes have to follow where the head is oriented) (arc: CN 8 in, 6/3 out; through midbrain)
 * Gag reflex (arc: CN 9 in, 10 out; through medulla)

=Ischemia=
 * [Useful note:]
 * __Thrombus__: occlusion that originated at the same vessel site it occludes.
 * __Embolus__: occlusion due to a clot that originated elsewhere and lodged at a site due to the relative sizes of clot and vessel.
 * Know the general presentation of a large vessel or small vessel ischemic stroke or TIA.
 * Large vessel ischemic stroke: look for deficits in **multiple systems** (ie. of middle cerebral artery: hemiparesis __and__ hemisensory loss __and__ hemianopsia {vision loss of half of visual field}).
 * Small vessel ischemia stroke: look for **isolated** motor/sensory deficits (hemiparesis __or__ hemisensory loss __or__ hemianopsia).
 * ("Small vessel stroke" = "lacunar stroke" = "too small for a catheter.")
 * Know the non-atherosclerotic causes of a stroke in a young patient.
 * Dr. Hughes: "You don't have to know all the funny little causes of stroke in a young patient, but be aware of the general categories."
 * __Vasculopathies__: occlusions of arteries. Specifically, fibromuscular dysplasia (common cause of occlusion in renal arteries, but also in carotids and vertebrals, especially in women in their 30's-40's), Moya-Moya (middle cerebral occlusion by intimal hyperplasia, generally in children and women in their 30's-40's), and arterial dissection. Note the first two are associated with arterial dissection and also saccular aneurysms (see next lecture).
 * __Hematological Disorders__: genetic absence of anti-thrombotic factors (mainly problems with PE side, not stroke side), malignancies (hypercoagulable state), sickle cell anemia, hyperviscous states, oral contraceptives or being post-partum, antiphospholipid antibodies. Pro-thrombotic factors.
 * __Inflammatory Mechanisms__: CNS vasculitis (usually infectious, as in varicella zoster virus) and migraines.
 * Know the principles of primary prevention of stroke, and of secondary prevention.
 * Dr. Holmes on this: "Primary & secondary prevention involve understanding an individual's risks, and properly addressing them. So for many it's HTN, Smoking, DM sorts of things, others it's excluding that myxoma, or surgically fixing something *before* their first event."
 * I think this means: identify risk factors (hypertension, lipid disorders, elevated homocysteine, obesity, diabetes, physical inactivity; also screening for myxomas, congenital heart defects, and infectious endocarditis) and address them. Presumably the first is primary and the second is secondary prevention.
 * Describe reperfusion injury and hemorrhagic transformation.
 * Reperfusion injury: refers to the free radical/other-mediated damage caused by reperfusing an ischemic area.
 * I think that hemorrhagic transformation refers to the fact that reperfusion can cause petechial hemorrhages in reperfused tissue, from the reperfusing blood going through necrosed blood vessels. Note this tends to be more in gray than white matter. But this is from Dr. DeMasters' presentation, not Dr. Hughes's, who had no comment.
 * When are thrombolytics or anticoagulation used?
 * Thrombolytics: generally TPA (tissue plasminogen activator). Has to be started within 3 hours of the stroke event; at that point it becomes a pretty effective treatment. Note it's a different dose in stroke patients than what's used in myocardial infarctions.
 * At the moment, anticoagulant therapy is generally used in patients with __atrial fibrillations__ or __mechanical valves__.

=Hemorrhage=
 * [Note that as it was described here, if you see loss of consciousness, think hemorrhage, not stroke.]
 * Describe the most common causes for intracranial hemorrhage.
 * Increased blood pressure, ischemia/reperfusion injury and/or dead tissue, aneurysm or other arterial vascular malformations.
 * Basically a problem either with too much vascular pressure or vascular walls that are weak or thin.
 * List the major risk factors for hemorrhage.
 * (1) **Age**
 * (2) **Hypertension** (note can be chronic or acute)
 * [someone whacking you in the head probably ranks too, but I assume we're talking about spontaneous intracranial hemorrhage.]
 * Describe the most common locations where __hypertensive, spontaneous intracerebral hemorrhages__ are seen.
 * In deep gray matter:
 * __Putamen__
 * __Thalamus__
 * __Pons__
 * __Cerebellum__
 * Can get white matter hemorrhage (lobar hemorrhages) through HTN, but it's rarer, and is sometimes __amyloid angiopathy__ (which is made worse, not better, by anticoagulants or antiplatelets) instead.
 * Describe the following types of vascular malformations, their annual risk of hemorrhage if unruptured, the risk if they present with hemorrhage: Saccular aneurysm, arteriovenous malformation, cavernous malformation, venous malformation.
 * Saccular aneurysms: most people just drop over dead when they rupture. Generally are berry aneurysms present at arterial bifurcations, particularly near the circle of Willis (anterior/posterior communicating artery attachment). Tends to occur around age 30.
 * Arteriovenous malformations: less common cause of subarachnoid hemorrhage involving fragile, capillary-free anastomoses between arteries and veins. Notice this is, like saccular aneurysms, a high-pressure system and the danger of bleed-out is high.
 * About 1% risk of rupture per year for both saccular and arteriovenous malformations. But note that size tends to correlate with risk of rupture (1% is for larger aneurysms).
 * Cavernous malformation: grossly dilated venous vessels with extremely thin walls, but low-pressure, thus less danger of immediate bleed-out.
 * Venous malformations: who knows, other than to say that they subsume cavernous malformations.
 * Know the presentation and initial evaluation of subarachnoid hemorrhage.
 * Subarachnoid hemorrhage: presents with __instantaneous, blinding pain__ (as opposed to intraparenchymal hemorrhage, which tends to progress from a headache over a few minutes).
 * Initial evaluation and treatment: reduce size of hematoma, treat hydrocephalus, deal with blood pressure (see next point).
 * Blood pressure dilemma:
 * Want to increase cerebral blood pressure to perfuse the brain
 * Want to decrease cerebral blood pressure to stop the bleed
 * Know the histopathological appearance of cerebral amyloid angiopathy.
 * Vessels: intramural depositions with apple-green birefringence on Congo stain (good boards question).

=Delirium and Dementia=
 * Define the syndrome of delirium
 * **Delirium**: __Acute inability to maintain a coherent line of thought__-- constant distractions towards irrelevant stimuli. Most commonly you see hypoaroused (lethargic/somnolence) form; occasionally you get hyperaroused forms with agitation and restlessness.
 * Discuss the common etiologies and evaluation of delirium
 * Delirium seems largely due to a disruption of normal brain homeostasis, __frequently__ __secondary to a metabolic disturbance__.
 * Frequent causes: drugs, toxins; metabolic disorders; infection/inflammation; structural lesions; seizure disorders.
 * Note 10-60% of older hospitalized patients have delirium; it's 60-80% in ICUs, probably due to metabolic disturbances resulting from intensive treatment.
 * Define the syndrome of dementia
 * **Dementia:** __Acquired, persistent impairment in intellectual function__ that interferes with social/occupational function. This can be month- or year-long, in contrast to delirium, which is shorter-term; but notice it's not necessarily progressive or irreversible.
 * Needs to involve three of the following: memory, language, visuospatial skills, complex cognition, and emotion/personality.
 * Discuss the common etiologies and evaluation of dementia
 * Etiologies:
 * Reversible: drugs/toxins (particularly incompatible drugs taken together), mass lesions, pressure hydrocephalus, systemic illness (B12 deficiency, hypothyroidism), inflammatory/infectious disease, concussions, and depression.
 * Irreversible: Alzheimer's, frontotemporal degeneration (FTD), Parkinson's, Huntington's, etc.
 * Note the distinction between cortical dementias (Alzheimer's, FTD) and subcortical dementias (Parkinson's, Huntington's); the physical burden of the disease can fall on either the cortex or the subcortical structures like the basal ganglia, thalamus, or brainstem.
 * Also note some causes of dementia can preferentially affect white matter instead of gray matter or vice versa; also note others show no particular preference for region or tissue type. More on this under "Neurodegenerative Disease."
 * Evaluate with history/physical exam, chemical panel, MRI/CT scan. Can go further into depth as required.
 * Understand the principles guiding treatment of delirium and dementia
 * __Treatment of delirium__: identify underlying cause and correct it. While patient is delirious, getting enough sleep is very important.
 * Avoid daytime sedation and naps to make sure they get enough sleep at night.
 * If drugs are needed for calming, can use benzodiazepines or atypical neuroleptics, but note can cause agitation instead. Haldol in low doses can work well.
 * __Treatment of dementia__: if the underlying cause is a reversible disease, reverse it; if not, offer supportive care and avoid anticholinergics or sedatives. Can use low-dose atypical antipsychotic drugs and possibly SSRIs for depression.
 * Alzheimer's, in particular, is treated with AChE inhibitors (donepezil is better tolerated and is once a day dosing; can use transdermally to avoid GI effects).

=Clinical-Pathological Correlation I= Be aware of the VITAMIN-C algorithm (mentioned in the first, introductory lecture) for differential diagnosis of neuropathy: Differential tends to rely on the tempo of the disease as well as the patient's age and clinical history. = = =Patients with Delirium/Dementia=
 * V**ascular
 * I**nfectious
 * T**raumatic
 * A**ge-related/degenerative
 * M**etabolic
 * I**nflammatory
 * N**eoplastic
 * C**ongenital
 * Employ basic interviewing skills with patients with dementia and their caregivers, using the "cognitive" screen and any other applicable screen from the //CU Assessment of Common Psychiatric Problems//.
 * Generate a differential diagnosis.
 * Understand the common symptoms and presentation of patients with delirium and dementia.
 * See "Delirium and Dementia" for more on this subject.
 * Note delirium tends to fluctuate in intensity throughout its course. Can also get hallucinations, delusions, and memory impairment in addition to attentional deficits.
 * Note dementia generally doesn't present with prominent disturbances of consciousness.
 * He seems to like a pyramid of cognitive function: at the bottom is arousal, followed by attention, language, memory, praxis, agnosia (lack of ability to recognize objects and people), and executive function.
 * Why this seems to be important: delirium is a bottom-up impairment (hits attention and arousal first, which impact the rest), while dementia is a top-down impairment (hits executive function, recognition, memory first, arousal and attention more or less intact).
 * Note that all these definitions require a baseline (ie. how are they normally?).
 * Why this seems to be important: delirium is a bottom-up impairment (hits attention and arousal first, which impact the rest), while dementia is a top-down impairment (hits executive function, recognition, memory first, arousal and attention more or less intact).
 * Note that all these definitions require a baseline (ie. how are they normally?).

=Neoplasms I + II=
 * [Notice that adult brain tumors tend to be located above the level of the cerebellum (supratentorial); tumors in children tend to be located on or below the level of the cerebellum (infratentorial).
 * Discuss the grading scheme for astrocytomas and how this relates to prognosis. Understand the different treatment options for these tumors.
 * WHO scheme: runs from I to IV (better to worse). I tend to be well delimited (noninfiltrative), surgically excisable, and only rarely progress to grade II or above.
 * Grade II have a greater tendency to invade and progress; treatment tends to be surgical debulking but entire excision is often impossible.
 * Grade III have increased mitotic activity (anaplasia).
 * Grade IV show necrosis and increased angiogenesis. By definition, a necrotic (grade IV) astrocytoma is called __glioblastoma multiforme__.
 * Describe the major histological features, most common presenting ages, and most common location of the following neoplasms:
 * **Pilocytic astrocytoma**: predominantly found in children below the tentorium, specifically in the cerebellar hemispheres, optic tract and nerves, and hypothalamic area. Tend to be well delimited, low-grade, and noninfiltrative. That said, they're not a picnic either, since having a tumor on the hypothalamus means (a) it impacts the hypothalamus and (b) you can't really take it out without damaging said hypothalamus.
 * Histologically, look for Rosenthal fibers and long, hairlike processes.
 * **Diffuse astrocytoma**: grade II+ astrocytomas: tend to involve white matter of the cerebral hemispheres in adults 30-60; the individual cells are highly infiltrative and go into the surrounding tissue readily. Dedifferentiate rapidly, thus have many CNS-cell types in their tumor. Tend to be poorly delimited; difficult to take it out even if it's not in a crucial region because it's hard to tell - even histologically - where the tumor ends and the normal tissue begins. Can extend extensively and rapidly.
 * 3 reasons diffuse astrocytomas are bad news other than just being tumors:
 * (1) Infiltrate as individual cells so they can't be cut out.
 * (2) The tumor is heterogeneous so it's hard to tell where it ends.
 * (3) Only sometimes mitotic, so not very responsive to chemo, which targets active mitotic cells.
 * Can progress to grades III or IV-- significant mitotic activity is the indicator for III (worsens prognosis markedly) and tissue necrosis is the indicator for IV (glioblastoma multiforme).
 * **Oligodendroglioma**: Grade II/III, in adults, tend to begin in cerebral white matter but often invade into gray matter. Infiltrative; infrequently resectable. __Tend to cause seizures__. Better prognosis than diffuse astrocytomas.
 * Characteristic histological pattern: calcified; "fried egg" appearance (rounded nucleus, "halo").
 * Grade III: again, more mitosis than Grade II.
 * Genetic marker has been identified that seems to correlate with increased effectiveness of radiation and chemotherapy: __1p-19q__. It's a translocation that causes, for whatever reason, sensitivity of the tumor to chemo and radiation.
 * **Mixed glioma**: Most astrocytomas or oligodendrogliomas actually have some of the other cell type in it (astocytomas have oligodendrocytes, oligodendrogliomas have astrocytes); when the ratio is about 50-50, the tumor is called a mixed glioma. Prognosis seems to correlate with the grade of the astrocytic cells inside.
 * **Glioblastoma multiforme**: The most common of all gliomas; also the most advanced. Grade IV gliomas; highly infiltrative and grow rapidly. Tends to outgrow its own blood supply and become **necrotic**. Can seem to have multifocal origins because it's so highly infiltrative. Very very bad prognosis: 9 months average survival with surgery, radiation, and chemotherapy. Can cut parts of it out, use radiation, chemo, etc, but not much use. Note that glioblastomas frequently __cross from one side of the brain to the other__.
 * Most glioblastomas develop //__de novo__// (generally in older patients; mean age is 55); however, some also come out of diffuse astrocytomas that worsen (generally in patients under 45 years old).
 * Histologically, look for necrosis and lots and lots of angiogenesis-- the latter almost looks like glomeruli (tons of little vessels) and resembles fetal blood vessel development.
 * Like many other tumors, GMs release VEGF to encourage blood vessel growth.
 * **Ependymoma**: Generally found in childhood in the ventricles-- most frequently, the 4th ventricle. These often causes obstructive hydrocephalus. Can also be found in the spinal canal in adults.
 * Histologically: look for little canals ("**rosettes**") in ependymomas or processes attaching them to nearby blood vessels.
 * Note you can also get a tumor of the choroid plexus in the ventricles. These are generally grade I and thus fairly good news, all things considered.
 * **Medulloblastoma**: Aggressive, proliferative tumors.
 * There are cells called the external granular cells in the cerebellum; during childhood development, Shh induces these cells to begin to migrate deep to the other cerebellar layers (becoming internal granular cells) and also to proliferate. These external granular cells seem to be the basis for medulloblastoma tumors, often caused by a mutation in the Shh pathway ("patched" gene).
 * These are the most common malignant tumors in children; tend to occurs from 3-8 years old. About a 50% survival rate, which is actually pretty high and is largely due to recent advances in fine-tuning the radio- and chemotherapy.
 * The most aggressive variants can spread throughout the subarachnoid space and can be more or less impossible to eradicate.
 * Note you can get compression of the 4th ventricle and noncommunicating hydrocephalus here.
 * Histologically: '**small blue cell tumors**' with poorly differentiated small blue cells (go figure).
 * Understand the different genetic mutations found in the de novo versus secondary glioblastoma and how these mutations seem to relate to the mechanisms that regulate cell division.
 * [Background: when precursor cells in the ventricular zone begin to express endothelial growth factor receptors (__EGFR__), they have differentiated into pre-**glial** cells.]
 * Secondary glioblastomas and primary (//de novo//) glioblastomas have different genetic mutation signatures-- the mutations that cause one are generally not the mutations that cause the other.
 * Secondary: p53, platelet-derived growth factor receptors (PDGFRs)
 * Primary: EGFR, p16
 * (both have RB-- a complete list is on slide 31 of this day's presentation)
 * Here follows a long recapitulation of M2M oncogenesis material. Of note, p53 and p16 are cyclin-dependent kinase inhibitors (inhibit cell cycle) and retinoblastoma protein keeps the E2F protein from activating the cell cycle.
 * EGFR and PDGFR are pro-cell-cycle factors that are amplified in primary and secondary glioblastomas, respectively.
 * I think the point is that in principle you could target treatment to specific malfunctioning gene products in different types of glioblastomas.
 * Describe the major histological features, most common presenting ages, and most common location of the following neoplasms:
 * **Meningioma**: mainly WHO grade I-- surgically resectable, little recurrence. **Peak incidence is women in their 50's** (in all caps in the slides). Occurs in the meininges (no kidding) and generally attach to the dura. Can occasionally penetrate the dura or invade bone, but mainly they push on underlying structures rather than infiltrating them.
 * Wide variety of histological appearances.
 * **Schwannoma**: Slow-growth, **tends to arise on cranial nerve 8**. Rarely is malignant. Like the meningiomas, tends to push other structures rather than invading them.
 * Histologically less variant than meningiomas.
 * Describe the four most common tumors that metastasize to the brain.
 * Lung, breast, skin, kidney. Fifth is GI.
 * Describe general characteristics of metastatic tumors (circumscribed versus infiltrative, proclivity to hemorrhage, etc.)
 * Metastasis-originating tumors are much more common than primary brain tumors.
 * Usually discrete, non-infiltrating tumors with surrounding vasogenic edema; can be cut out without too much trouble, but you're not addressing the primary tumor.
 * Much more common to find metastatic tumors in the cerebrum than the cerebellum. But note that this pretty much reflects the relative amount of mass in the two.
 * Occasionally goes to dura/meninges.
 * Understand the general features of the following phakomatoses: NF-1, NF-2, Tuberous Sclerosis, Von Hippel-Lindau disease.
 * [Phakomatosis: aka neurocutaneous syndromes; disorders of the central nervous system that result in lesions on the skin and the retina.]
 * Neurofibromatosis 1: Neurofibromas, lesions on the optic nerve, cafe-au-lait spots. Autosomal dominant.
 * Neurofibromatosis 2: Bilateral CN VIII Schwannomas; meningiomas; ependymomas of the spinal cord. Autosomal dominant.
 * Tuberous Sclerosis: Hamartomas (disorganized but non-neoplastic tissue), particularly in the cortex; benign tumors; cysts; lots and lots of cutaneous lesions. Autosomal dominant with incomplete penetrance.
 * Von Hippel-Lindau disease: Increased tendency to develop tumors in cerebellum, retina, spinal cord, and brainstem, probably due to an increased level of VEGF expression due to perpetual activation of Hif1-alpha (see previous notes on this disorder).

=Neurodegenerative Disease=
 * Understand the fundamental concepts of neurodegenerative disorders
 * Neurodegeneration: Spontaneous death of neurons. Obviously where those neurons are determines the presentation.
 * We have no cure for any of these diseases. Fall back on support, planning, education, etc.
 * Seem to be largely disorders of protein conformation and metabolism; tend to be characterized by abnormal protein accumulation inside and outside the cell.
 * Look for:
 * Dementia
 * Movement disorders
 * Motor problems
 * These diseases can be genetic, sporadic, or transmissible, though it's rare to find one disease with all three forms (see prions).
 * Emphasis seems to be on understanding that neurodegenerative diseases cross these lines and resist easy categorization.
 * Develop a general understanding of the clinical features, genetics, neurochemistry and neuropathology of these diseases
 * Clinical features:
 * __Alzheimer's__: Memory/visuospatial problems
 * __Frontotemporal dementia (FTD)__: behavioral, executive, and language problems
 * __Lewy Body dementia__ (part of Parkinson's): psychosis (hallucinations, delusions), fluctuating arousal
 * __Parkinson's__: tremor, rigidity, slow movements (bradykinesia)
 * __Progressive supranuclear palsy (PSP)__: rigidity, slow movements, falls, **abnormal vertical eye movements**.
 * __Amyotrophic lateral sclerosis__: weakness and atropy, fasciculations, signs of both upper and lower neuron lesions
 * __Huntington's disease__: dementia, depression, characteristic chorea (high-velocity twitching)
 * __Creutzfeldt-Jakob disease (CJD)__: rapidly progressive (normal to dead in 5 months) dementia and myoclonus (preternaturally fast twitching movements) due to a **prion** infecting the frontotemporal lobe. Tends to hit older patients (over 55).
 * Some notes on prions and prion diseases:
 * Prion diseases: "proteinaceous infectious particles." Causative agent is protein only, no nucleic acid.
 * Note that prion proteins are normally present; the pathological change is a **conformational shift** (recall this from clinical vignettes in M2M?). Note that this change can be sporadic, heritable, and transmissible.
 * Uniformly fatal. "If the patient survives, the diagnosis was wrong."
 * Other prion diseases:
 * Variant CJD: seems to be bovine-to-human transmission (mad cow disease) and presents differently (younger patients, slower progression, more peripheral neuropathy, depression, and anxiety).
 * "Kuru" in Papua, New Guinea, caused by cannibalism.
 * Gerstmann-Straussler-Scheinker syndrome: autosomal dominant disease; clumsiness, incoordination, and gait ataxia. Variable presentation. Tends to affect cerebellum. Presents 35-50.
 * Fatal familial insomnia: also autosomal dominant; progressive insomnia after 35 years; memory loss, confusion, hallucinations. Tends to affect thalamus.
 * Genetics:
 * Most of these diseases are sporadic/environmental. That said, all of the ones presented here are both inherited and sporadic. The only one that's transmissible is prion disease.
 * Neurochemistry:
 * To repeat, lots of disturbed protein metabolism. Of note, look at polyglutamine stretches caused by CAG repeats in Huntington's, ubiquitin in ALS, tau protein in Alzheimer's, FTD, and PSP. and synuclein in Parkinson's and Lewy body dementia.
 * Neurotransmitters:
 * ACh deficit: Alzheimer's, Lewy body dementia
 * Dopamine deficit: Parkinson's, Lew body dementia
 * Serotonin deficit: FTD
 * Neuropathology:
 * Alzheimer's: neurofibrillary tangles, amyloid plaques. Look for brain atrophy. Targets cortex and hippocampus.
 * Parkinson's: Lewy bodies.
 * FTD: neurofibrillary tangles, Pick bodies, ubiquitin inclusions
 * Huntington's: caudate atrophy on CT/MRI
 * [Check out "Summary" at end of notes for a good wrap-up and concision.]

=Infectious Disease in the CNS=
 * Know the clinical presentation, most common organisms, basic CSF profile (cell number and type, glucose, protein), and basic medical management for bacterial meningitis in different age groups.
 * Presentation:
 * Classic triad: fever, headache, neck stiffness. Note only 45% of bacterial meningitis patients actually present with all of these.
 * More often encountered are __2 of these 4__: fever, headache, neck stiffness, and altered mental status.
 * Median patient age currently is 25 (as of 1986, was 18 months-- in between you had the enterobacter vaccine).
 * Management:
 * Immediately start antibiotics (within 60 minutes of arrival to ED).
 * Give corticosteroids (dexamethasone) with first dose of antibiotics-- but __only continue administration if organism is pneumococcus__.
 * Get an LP immediately unless you see signs of increased intracranial pressure (altered mental status, etc). If you do see signs of increase ICP, wait for imaging on the LP but still start antibiotics immediately.
 * Pathogenesis:
 * Infection of the subarachnoid space, usually from the blood, but can also be from nearby intracranial infections (sinus infections, otitis, mastoiditis) or congenital/traumatic defects in the skull or spinal column.
 * Inflammation (due to cytokine activation) increases permeability of BBB; results in vasogenic edema and increased ICP.
 * Can cause infarcts and hydrocephalus thanks to occlusion of vessels or ventricle pathways.
 * Agents:
 * Neonates:
 * About 50% of cases: Streptococcus agalactiae (Group B strep)
 * About 30%: E. coli and Enterobacter
 * 7% and 5%: Listeria monocytogenes and Staphylococcus aureus
 * 1 month to 30 years:
 * 50-60%: Neisseria meningitidis
 * 25-30%: Streptococcus pneumoniae ("pneumococcus")
 * [others]
 * Over 30 years:
 * 50-70%: Pneumococcus
 * 10-25%: Neisseria meningitidis
 * 5-10%, or 20-25 over 60 years: Listeria monocytogenes
 * [others]
 * CSF features:
 * White cell number and type: 100-10,000, predominantly neutrophils
 * Protein: Elevated (100-500)
 * Glucose: Low (< 40)
 * Use Gram stain to differentiate organism
 * If no response to antibiotics in 48 hours, repeat LP
 * Know the clinical features, most common organisms, basic CSF profile, and key diagnostic tests for viral meningitis and encephalitis.
 * Presentation of both: acute, febrile illnesses with headache. Stiff neck is generally meningitis, mental status/seizures/focal neurological deficits is generally encephalitis.
 * Note viral meningitis frequently recurs after clearing.
 * Causative organism:
 * __Meningitis__: vast majority are enteroviruses (fecal-to-oral transmission), a small number are herpes simplex (mainly HSV-2).
 * __Encephalitis__: 10% of herpes simplex (mainly HSV-1), 20% other identified (including West Nile virus), 70% unknown etiology.
 * [Note West Nile virus causes both meningitis and encephalitis.]
 * CSF profile:
 * White cell number and type: 10-2,000, mainly lymphocytes
 * Glucose: Normal
 * Protein: Normal or elevated
 * Send for PCR to differentiate organism
 * Tests:
 * **PCR** of viral genomic material is extremely useful (both sensitive and specific); also **CT/MRI** to look at patterns of encephalic inflammation (especially in HSV-caused encephalitis, where you see inflammation in the temporal lobe and areas of the limbic system).
 * Note that with neuroinvasive West Nile virus, the virus has mainly cleared by the time a patient presents; therefore you look for IgM in the CSF against WNV instead.
 * (can use IV acyclovir to treat HSV-caused encephalitis, sometimes works and sometimes doesn't in HSV meningitis)
 * [Arboviruses: mainly mosquito-borne; notably West Nile.]
 * Know the basic clinical features, diagnostic tests, and initial antimicrobial therapy for patients with a focal suppurative CNS infection (e.g. brain abscess, empyema).
 * [Definitions:]
 * Brain abscess: focal infection in brain tissue. Usually arises by direct extension from nearby intracranial infections, infection from bloodstream (particularly from infectious endocarditis or dental abscesses), or introduction of organisms through trauma.
 * Subdural empyemas: infections between the arachnoid and the dura.
 * Epidural abscess: infections between the dura and bone.
 * Note distinction between empyemas and abscesses: the former exist in a natural cavity, the latter create the cavity they exist in.
 * Presentation of abscesses (evidently as representative of this category, as he didn't go into empyemas or epidural abscesses):
 * Headache, drowsiness, stupor, confused, fever. As with any patient with altered mental status, don't get an LP before MRI/CT imaging (increased ICP).
 * Diagnostic tests: MRI seems to be the best diagnostic: better at visualizing posterior fossa and cerebellum and can distinguish abscess from capsule from edema better (also picks up sinusitis, otitis, mastoiditis).
 * Organisms: most frequently Streptococci, but also Staphylococcus aureus, Bacterioides, E. coli, and Pseudomonas. Obviously where the infection is coming from determines the spectrum of likely organisms.
 * Treatment: Antimicrobial treatment: start with ceftriaxone and metronidazole and then move on to specific agents once organism is identified.
 * Can avoid surgical intervention in small abscesses or in areas that are highly vascularized

=Inflammatory Disease in the CNS=
 * Describe the basic subtypes of MS.
 * Relapsing-remitting (85% present like this): Sporadic episodes of new, worsening symptoms over 2-10 days; variable improvement afterwards for 1-6 months before the next relapse.
 * Primary progressive (15% present like this): No real relapses; disease steadily progressive.
 * Secondary Progressive: starts as relapsing-remitting, converts to progressive (no relapse, steady progression). Note that 50% of relapsing-remitting patients will do this.
 * Describe the basic epidemiology of MS.
 * 75% of patients present between 15 and 45 years old; about 5% are under 18.
 * Two-thirds of patients are women; most are Caucasian; incidence increases the farther you get from the equator.
 * 10,000 new cases per day in US; 400,000-500,000 cases extant in US. About 1/700 prevalence in Colorado.
 * Most common cause of neurological disability in US women.
 * Most common CNS inflammatory disease.
 * Note that better outcomes are associated with being young, non-smoking, Caucasian, and female, with low relapse rates, and minimal changes on MRI.
 * Describe the typical clinical symptoms, neurologic abnormalities and laboratory study abnormalities seen in MS.
 * [Various genes linked to risk.]
 * Neuropathology:
 * Sharply defined edges of demyelination. Note that there's also significant axonal disruption and transection as well as just demyelination. Note also that there can also be gray matter loss in addition to the classic white matter loss. There can be other immune-mediated damage as well.
 * Look for 'axon bulbs' (also known as 'onion bulb lesions') on axons-- progressive waves of demyelination of axons leaves multiple 'skins of myelin remnant around the axon.
 * Clinical symptoms:
 * Early: Numbness and tingling, loss of vision in one eye, gait problems, weakness, double vision, numbness/tingling down the spine when the patient bends their neck, urinary urgency, constipation.
 * Late: All of the above, plus fatigue, sexual/cognitive dysfunction, depression, pain, loss of appetite; sometimes seizures and hearing loss.
 * Clinical diagnosis:
 * Look for CNS abnormalities that locate in at least 2 different places and that either come and go for 24+ hours 30 days apart (for relapsing/remitting MS) or that progress steadily for 12 months (progressive MS). Note symptoms are often asymmetric.
 * Neurological abnormalities on exam:
 * Asymmetric neuro exam; upper motor neuron damage; eye and eye movement abnormalities; sensory loss; cerebellar dysfunctional; cognitive dysfunction.
 * Lab tests:
 * Use MRI studies-- look for brain atrophy, lesions progressing out into the cortex on midline sagittal images, round/ovoid lesions near the ventricle.
 * CSF analysis: protein always less than 110, glucose always normal, white blood cells almost always less than 40.
 * Most important thing is that there's elevated IgG in the CSF. Look for oligoclonal bands on electrophoresis of CSF that aren't in the serum; Ig's made in the CNS and not in the periphery.
 * Measurement of evoked potential to measure conduction speed: good test for demyelination. Note can get complete conduction block.
 * Get blood tests to rule out serum-based inflammatory disorders.
 * Know the basic approaches to therapy in MS and what to expect from immunotherapy in MS.
 * Symptomatic:
 * Physical/occupational/speech/psychological therapy.
 * Use pharmacotherapy to treat fatigue, spasticity from UMN lesions, urinary dysfunction, sexual dysfunction, pain, depression.
 * Treatments of acute attacks:
 * High-dose corticosteroids; plasma exchange only for severe demyelination that's unresponsive to steroids. Note that it only works for a subtype (type II) of MS.
 * Immunotherapy:
 * For relapse-remitting MS: use generally interferon beta or 'glatiramer acetate.'
 * Tend to reduce new attacks by a third and can slow progression of disability and lesions.
 * For secondary progressive MS: use the same drugs, but less effective.
 * For primary progressive MS: no proven effective treatment.
 * Note that these treatments are expensive ($20,000/year) and have significant side effects.

=Clinical-Pathological Correlations II+III= PML (Progressive Multifocal Leukoencephalopathy) is caused by a virus that infects oligodendrocytes in immunosuppressed patients, causing brain necrosis and leading to pro-oncogenic effects. Note difference between this and multiple sclerosis, which mostly affects the myelin rather than the oligodendrocytes, doesn't have an infectious basis, and isn't oncogenic. Pathology: HIV-leukoencephalopathy and PML show up as diffuse white matter lesions Brain abscesses turn up as unifocal lesions Toxoplasmosis and primary CNS lymphoma tend to have multifocal enhancing lesions. Radiation/chemotherapy damage (particularly with methotrexate) to brain: can damage vascular endothelial cells and oligodendrocytes (radiation-induced leukoencephalopathy).
 * CPC III, 9/5/08:** Your guess is as good as mine. CT/MRI basics (T1, liquid dark; T2, liquid bright; T2 with FLAIR, liquid dark but better resolution of structures). He did mention that once you can see an infarct on CT, the tissue is already dead/irreversibly damaged.

=Nutritional Disorders of the Nervous System=
 * [Brain is a fine instrument, and like all fine instruments, little things upset it.]
 * Describe the effects of alcohol on the CNS both acutely and chronically.
 * Chronically: Cerebral atrophy: neuronal loss from frontal cortex (shrinkage of cell body, retraction of dendrites, increased lipid bodies). Note also specific vulnerability of the superior vermis in the cerebellum (granule and Purkinje cell loss: cause of ataxia).
 * Acutely: Massive cerebral edema. Death from cardiorespiratory paralysis > 450-500 mg/dL in the blood.
 * Describe the clinical, radiographic, and pathologic findings in Wernicke's encephalopathy and Korsakoff's psychosis. Understand the treatment of these conditions.
 * Etiology: both Wernicke's and Korsakoff's are caused by thiamine (B1) deficiency. Robbins indicates that acute Wernicke's can progress to Korsakoff's if untreated, and that the syndrome is thus often named "Wernicke-Korsakoff syndrome." Note that although alcoholism is linked to thiamine deficiency, it's the thiamine deficiency and not the alcoholism that is the direct agent of damage in these syndromes.
 * Pathology: damage is focused in the mammary bodies, periaqeuductal gray, medial thalamus, floor of the fourth ventricle, rest of hypothalamus. Some focus on white matter as well.
 * Clinical:
 * Wernicke's encephalopathy:
 * Classic triad: Ataxia (incoordination), nystagmus (back-and-forth eye movements), and confusion. All of these may not always be present in all Wernicke's patients.
 * Korsakoff's psychosis:
 * Confabulation (confusion of imagination with memory), amnesia, apathy. Seems to particularly result from the thalamic lesions.
 * Radiographic: MRI can pick up disruption of the BBB, evidently.
 * __Thiamine deficiency can be lethal__ due to hypothalamic damage; dilated capillaries and petechial hemorrhage with necrosis and disruption of BBB. Correct with IV thiamine.
 * A deficiency in thiamine causes a problem in glucose metabolism (the pentose pathway shunt for people with more biochem background than I have). With B1 deficiency plus a high-glucose diet, patient can get worse.
 * If you're not getting B1 in your diet, don't go slam that 12-pack of Dew.
 * More to the point, if you miss the B1 diagnosis and give a patient a glucose drip, you're going to acutely worsen the symptoms.
 * Thiamine deficiency is generally caused by poor diet and excess alcohol consumption, or both.
 * Understand the etiology, treatment, clinical, and pathologic findings associated with Cobalamin [B12] deficiency.
 * Etiology: generally not diet-related; tends to be a dysfunction of cobalamin absorption in the ileum.
 * Treatment is, unsurprisingly, IV B12 (can reverse progress of disease) and figuring out what the underlying problem is.
 * Clinical: Tingling, numbness, spastic weakness of the extremities.
 * Pathology: See patchy/spongy changes (swelling of myelin and degeneration of axons) in the white matter of the spinal cord (lateral and/or posterior columns) thus causing motor/sensory problems. Brain examination shows only edema.
 * Describe the etiology and pathogenesis of hepatic encephalopathy and Wilson's disease.
 * Etiology: here, most commonly chronic alcohol abuse.
 * Clinically: look for tremor, confusion, forgetfulness, drowsiness; eventually coma.
 * Pathogenesis: Ammonium is the current favorite culprit. But in general, failure to detoxify substances can result in those substances getting to the brain and mucking around.
 * Astrocytic nuclei in hepatic encephalopathy become __swollen__.
 * Near glutamate-releasing presynaptic membranes, astrocytes pick up glutamate, add an ammonium molecule to convert it to glutamine, and give the glutamine back to the presynaptic neuron. If too much ammonium is present, the astrocyte becomes irreversibly damaged in its attempts to detoxify/use up the ammonium through this pathway and degenerates.
 * The lack of functional astrocytes leads to a lot of problems, since the astrocytes regulate pH, electrolytes, neurotransmitters, etc.
 * __Wilson's disease__: disorder of copper metabolism, leading to high copper levels. This will damage the liver in a fashion similar to alcohol abuse, except at a young age (patients tend to present around 12 years of age).
 * High copper levels accumulate in the putamen/globus pallidus (ie. in the lenticulate nucleus) and cause their degeneration, leading to uncoordinated, spastic movements and executive function degradation.
 * Astrocytes become swollen here as well due to liver damage.
 * Note that you can correct the high copper levels with chelating agents.
 * Describe the etiology and pathogenesis of Central Pontine Myelinolysis (CPM).
 * Etiology: too-quick correction of hyponatremia causes CPM.
 * Pathogenesis: triangular areas of demyelination on the ventral pons (pons evidently principally targeted due to its dense mix of gray and white matter). Seems to be caused by osmotic imbalances opening up the BBB in the pons, leading to edema. Can result in quadriplegia (most common clinical presentation according to Robbins), pseudobulbar palsy, and pseudocoma.

=Sensory Receptors=
 * Understand that the basis for the receptor (generator) potential is the opening or closing of different ion channels. What is a transduction channel, and how does it differ from voltage-dependent ion channels? Why are action potentials necessary to transmit information in long sensory receptors?
 * Transduction channels: ion channels that open, not in response to voltage, but in response to a sensory stimulus (light, odor, stretch, etc). They're called transduction channels because they're taking a non-electrical stimulus (light, heat, etc) and transducing it into an electrical signal (ie. a change in the membrane potential of the cell).
 * "Special systems:"
 * Visual system: detects EM radiation.
 * Auditory system: detects changing air pressure.
 * Taste/olfaction: detect chemical signals.
 * Somatosensory system:
 * Touch, vibration, proprioception: exteroception (see next lecture)
 * Pain, irritating chemicals, temperature (nociception, see lecture after that)
 * Note that sensory receptors cells need specialized proteins (sensory receptor proteins) to detect whatever type of stimulus they're designed to detect.
 * Another note: sensory receptor cells that receive the initial stimulus are called the __primary__ sensory cells; the next cells to which they transmit their information are called the __secondary__ or __second-order__ neurons.
 * How this works:
 * (1) Stimulus comes in and is detected by sensory receptor proteins.
 * (2) [Optional element in long receptors] stimulus is transduced into an AP and taken down a sensory process (ie. a dendrite) to the cell body. In short receptors, the membrane potential produced by the stimulus just sort of diffuses over to the cell body.
 * (3) The signal gets to the cell body.
 * (4) [Optional element in long receptors] The signal is transmitted as an AP along an axon. If not, the membrane potential produced by the stimulus, again, diffuses over in the direction of the synapse.
 * (5) The signal reaches the synapse. Generally it releases __glutamate__.
 * [Quick vignette on long vs short sensory receptors: some sensory receptor cells are really long (eg. the ones that sense stuff in your foot and send it up to your ipsilateral medulla). Some are really short (the photoreceptors in your eye are only a tiny space away from the synapse).]
 * You need APs in __long sensory receptors__ (like touch sensory neurons in your foot) for the same reasons you need APs for anything else-- the signal will deteriorate too quickly to reach the synapse otherwise. On the other hand, if the receptor cell is pretty short and the synapse is right next to the sensory proteins, there's not much point in making an AP-- simple diffusion will do fine since the signal won't deteriorate before it hits the synapse.
 * See next LO regarding the contrast with stretch (long) vs light (short) detection.
 * In general, __somatosensory__ cells pretty much all need APs (they're all long, or long enough to need the help with signal transmission). Special-sense systems are a mixed bag.
 * Understand how light hyperpolarizes photoreceptors and how stretch depolarizes mechanoreceptors.
 * How stretch **depolarizes** mechanoreceptor cells (long receptor cells):
 * The changed pressure alters the configuration of mechanoreceptor proteins (special non-selective cation channels) on the sensory cell membrane. The change in configuration causes the channels to open and cations to go through.
 * The membrane depolarizes due to sodium influx, generating an AP that travels up the sensory process/dendrite, past the cell body (in the dorsal root ganglion) and out the axon to synapse onto the second-order neuron.
 * How light **hyperpolarizes** photoreceptors:
 * Light comes in and hits in and around a seven-times membrane-spanning G receptor protein in the primary sensory cell called **rhodopsin**.
 * Now rhodopsin has a molecule called **retinal** attached to it. Retinal, without light stimulus, has a kink in it (it's //cis//). Once the retinal is hit by the light stimulus, it changes conformation to become straight (all-//trans//).
 * (note the primary receptor protein of the photoreceptor is retinal, not rhodopsin.)
 * This conformational change of retinal causes rhodopsin to undergo a conformational change, activating a G protein called __transducin__.
 * (Note that vitamin A is required to regenerate //cis//-retinal from all-//trans// retinal; no vitamin A, no vision.)
 * Once transducin is activated, one of its subunits goes and activates another membrane protein, phosphodiesterase (PDE). PDE decreases the level of intracellular cGMP.
 * The decreasing cGMP **closes** a __cGMP-dependent non-specific cation channel__.
 * Note that photoreceptor cells, without stimulus (ie. in the dark) have this NSC channel open; thus __the resting membrane potential of photoreceptor cells in the dark is closer to the reversal potential of NSC-open states and thus depolarized relative to normal cells, around -40 mV__.
 * The closure of this NSC channel results in the cell membrane __hyperpolarizing__ relative to its resting state. The __degree__ to which this hyperpolarization occurs depends on the __intensity__ of the light stimulus involved.
 * Note that the presynaptic membrane at the other end of the photoreceptor cell works about the same as most other presynaptic membranes-- its NTs are released in response to a depolarized membrane. When it gets relatively hyperpolarized, the NT transmission stops.
 * Note this is kind of backwards from how we're used to thinking about it. We're used to a stimulus producing a depolarization, causing the presence of NT in the synaptic cleft. This (photoreception) involves a stimulus producing a hyperpolarization and __de__creasing the presence of NT in the synaptic cleft.
 * The important thing to understand, I think, is that the functional efficacy of sensory mechanisms relies on the fact that the CNS has a way to detect the difference between stimulus and nonstimulus, whatever the state during nonstimulus and the state produced during stimulus. It's like drawing a black line on a white board vs. drawing a white line on a black board. Either way you can tell there's a line there.
 * Understand that mutations in genes that encode for proteins involved in phototransduction often lead to retinitis pigmentosa (Box B of Chapter 10 in Purves).
 * Genetic mutations in rhodopsin, and the opsin family in general, can result in degeneration of the photoreceptor cells, leading to night blindness, tunnel vision, and complete blindness over decades. The mechanism may have something to do with misfolding (which would maybe lead to membrane instability?).
 * Understand the concept of labeled lines: How do we perceive the modality of a stimulus? What is the route generally taken by sensory information that will become conscious?
 * Basic concept here: all sensory systems convey __four aspects__ of a stimulus:
 * Modality (smell? sight? taste? pain?)
 * Intensity (how much?)
 * Duration (for how long?)
 * Location (where is it on/in the body?)
 * (note there's another aspect in his notes, namely "Quality," which I think is a subset of modality-- within the vision modality there are distinct subsets of red, blue, etc.)
 * __Labeled lines__: This is how the modality of a given stimulus is kept distinct from the modality of a different stimulus (vision nerves vs auditory nerves). I think the idea is that the 'lines' (nerve fibers) connecting, say, the optic fibers to the thalamus go to a different place within the thalamus than the 'lines' connecting the auditory fibers to the thalamus. This way a stimulus doesn't get mistaken for a different kind of stimulus.
 * Note the exception to the sensory labeled line to the thalamus thing: the olfactory system doesn't go through the thalamus. More on this, presumably, later.
 * Note also that it doesn't just apply to the thalamus, but to any synaptic location. C fibers synapse and A-delta fibers, though they're both part of the same anterolateral system, carry different modalities of sense and hence synapse onto different parts of the dorsal horn in the spinal cord. See "Nociception."
 * Route: Not all sensory experience makes it to conscious awareness (like the million emails from the Deans that mysteriously end up in my deleted folder without my conscious awareness of having put them there). The ones that do, usually go through the thalamus to the cortex.
 * Explain how stimulus intensity is encoded by sensory receptors. How is encoding of stimulus intensity different between short and long receptors?
 * In long receptor cells: an increase in stimulus intensity is encoded by __an increase in AP firing frequency__ (ie. an increase in depolarization frequency).
 * In short receptor cells: an increase in stimulus intensity is encoded by an __increase in hyperpolarization__. (note possible exception with auditory nerves, see p. 5 subsection c.)
 * How are peripheral nerves classified in terms of conduction velocity and size? What is the relationship between size/myelination and conduction velocity? What kind of information do different size peripheral nerves carry?
 * Large-diameter fibers conduct faster than small-diameter fibers (due to less relative loss of signal to nonconducting extracellular environment, see Betz's AP notes). Myelinated fibers generally conduct faster than nonmyelinated fibers due to the myelin insulation.
 * A-alphas are bigger than A-betas and A-gammas, which are bigger than A-deltas, which are bigger than C fibers.
 * A fibers: myelinated, larger than C fibers.
 * Subdivided by types of stimulus and size:
 * alpha = muscle spindle/stretch receptors, proprioception; biggest.
 * beta = mechanoreceptors of skin, secondary muscle spindle receptors; next biggest.
 * delta = sharp pain and hot-pain (also cool temperature); 3rd biggest and only lightly myelinated.
 * C fibers: unmyelinated, smaller than A fibers.
 * These carry warm temperature, cold-pain, itch, and crude touch. Smallest.
 * Note alpha/beta carry DCML tract info and delta/C fibers carry spinothalamic info. This becomes significant.

=Exteroception=
 * Understand the classification of sensory receptors of the skin in terms of adaptation properties and receptive field. Which of these receptors detect vibration? Which sense steady touch? What is understood by receptive field? How are sensory receptors of skin classified in terms of receptive field?
 * Here we're really discussing the dorsal column medial lemniscus system and its associated senses (fine touch, proprioception, vibration, lumped together under the unfortunate name of **exteroception**). Pain, temperature, and crude touch show up in the next lecture under **nociception**.
 * All of the nerve fibers carrying exteroceptive information are heavily myelinated (class A alpha/beta fibers).
 * **A-alpha: proprioception**
 * **A-beta: fine touch, vibration** (stretch or mechano-receptors)
 * As mentioned, both of these go into the posterior column medial lemniscal system (see next LO).
 * Modality: (fine) touch. Note that although Dr. Restrepo described this as just "touch," Dr. Ojemann's earlier lectures (and Dr. Restrepo's notes, pg. 1) differentiate between fine touch (which would fall under exteroception, thus A-alpha or A-beta fibers in the posterior column) and coarse touch (which would fall under nociception, ascending in unmyelinated C fibers in the anterolateral column, see next lecture).
 * Submodalities: vibration (both low and high), steady touch, patterned touch (think Braille).
 * DCML system sensory receptors are classified according to __how quickly they adapt to stimuli__ (rapid-adapting vs slow-adapting), and also by the __size of their receptive field__ (how large an area on the skin they respond to).
 * Note that adaptation means how quickly the receptor stops firing APs in response to a given stimuli. Fast-adapting receptors will fire a couple APs in response to a new stimulus and then stop until the stimulus is removed (at which point it'll fire a couple more, since it's 'used to' the stimulus being there by that point), while slow-adapting receptors will fire APs throughout the duration of a stimulus and stop when the stimulus is removed (they haven't 'gotten used to' the stimulus).
 * How I think of it: this has to do with what 'normal' is. Assume receptors will fire every time they sense that their situation isn't normal (which is, after all, a concept fundamental to sensation). Fast adapting receptors get used to 'normal' being the stimulus very quickly (which is why they think it's not normal, and fire APs, when the stimulus is removed). Slow adapting receptors don't get used to resetting their 'normal' states very quickly, and will keep firing APs in the face of a continued stimulus and stop when it's removed because their 'normal' hasn't budged from where it was at the beginning.
 * One can also think of fast-adapting receptors as goldfish and slow-adapting receptors as like elephants. The goldfish forget almost instantly that anything ever changed and regard the new situation as normal. The elephant is going to remember, and be constantly aware of, the fact that the new situation is not normal.
 * Note also that fast-adapting receptors are better at picking up rapid changes in stimulus/not-stimulus-- which is why they're used for detecting **vibration**.
 * How this whole thing works on a molecular level depends on the shape, configuration, and encapsulation of the receptor in question.
 * Sensory receptor types:
 * Unencapsulated:
 * Free nerve ending: discussed in next lecture. Used for nociception (next lecture).
 * Encapsulated:
 * **Merkel's disk**: Slow-adapting, small receptive fields.
 * **Meissner's corpuscle**: Fast-adapting, small receptive fields.
 * **Raffini endings**: Slow-adapting, large receptive fields.
 * **Pacinian corpuscle**: Fast-adapting, large receptive fields.
 * __Fast-adapting receptors__: used for vibration detection. **Pacinian** corpuscles: better for __high frequencies__ (200 Hz); **Meissner's**: better for __low frequencies__ (60 Hz).
 * __Slow-adapting receptors__: used for steady touch (**Merkel's**: small receptive fields, used for patterned-touch discrimination; **Raffini** endings, with larger receptive fields, are used for grip sensation).
 * Understand the flow of information (anatomical pathway) along the medial lemniscal and trigeminal lemniscal system.
 * Medial lemniscal system:
 * Recall that fine-touch sensations from the body ascend up the __ipsilateral posterior column__, either in the gracile or cuneate fasciculus, and still in the primary axon.
 * Once it reaches the medulla, the axon synapses (still ipsilaterally) on either the nucleus gracilis (lower limbs) or the nucleus cuneatus (upper limbs).
 * The second-order sensory axons from the body decussate from the medulla, going up to the contralateral thalamus in the __medial lemniscus__, and go to the __ventral posterior lateral nucleus__ of the thalamus.
 * They synapse there and their third-order neurons go to the __primary somatosensory cortex__ in the postcentral gyrus (Brodmann 3/1/2).
 * Note that the second-order fine-touch sensory axons from the __face__ do something completely different. This is the **trigeminal lemniscal system**.
 * Fine-touch/proprioception/vibration signals from the face (primary neurons) go into the __ipsilateral trigeminal ganglion__ and transmit their signals to synapse in the __pons__ on the __ipsilateral principal nucleus of the trigeminal complex__.
 * From there, the second-order neurons decussate in the pons and ascend in the __trigeminothalamic tract__ or __trigeminal lemniscus__ through the midbrain all the way to the __ventral posterior medial nucleus__ in the __thalamus__.
 * After the synapse there, the third-order neurons head over to the primary somatosensory cortex (3/1/2) like the body-fine-touch neurons do.
 * What is somatotopy? Why are some regions (e.g. mouth and hands) enlarged compared to others in the somatotopic map in primary somatosensory cortex? Understand that there are parallel somatotopic maps in different Brodmann's areas in somatosensory cortex.
 * See "Introduction" for somatotopy and homunculus explanations.
 * The concept that's new here is that in different Brodmann's areas (and different sub-areas (3a vs. 3b) you feel different modalities of sensation. Ie. in 3a you get proprioception, in 1 you get direction and orientation, in 2 you get direction, orientation, and shape, etc.
 * Note that there's also cross-talk both between different somatosensory regions but also between motor and somatosensory regions. This is significant for integrating a bunch of information and being able to respond to complex stimuli.
 * [Note further that the primary somatosensory cortex (S-I) is assisted by the secondary somatosensory cortex (S-II), which stores very short-term sensory memories to maintain a sense of sensory continuity, and the parietal/frontal tertiary cortices, which are involved with understanding certain sensations as coming from "self" and others are being "extrinsic to self."]
 * For each sensory modality (thus each Brodmann's area) in the somatosensory cortex, there is an individual, parallel homunculus. They are slightly different from modality to modality, but not drastically so.
 * What are cortical barrels or columns?
 * If you cut through the cortex from top to bottom, you see 6 different layers. Each layer contains nerve fibers that go to a particular part of the brain-- ie, layer 4 contains nerves coming from the thalamus, layer 6 contains nerves going to the thalamus, etc.
 * For each somatotopic region (fingers, toes, bellybutton, etc) there are these 6 layers that are distinct to that particular region-- each finger has its own 6 layers, each toe likewise, etc. These are further grouped into rapidly-adapting 6-layered regions of a given toe that are distinct from the slow-adapting 6-layered regions of that toe.
 * Ok. There are three spatial dimensions in the somatosensory cortex (and everything else that we know of). Imagine that you're pinpointing a location on the outside of that cortex. Now imagine moving the pointer in each of the three spatial axes individually, while remaining still in the other two:
 * When you move your pointer superiorly or inferiorly on the outside of the gyrus, you're changing the **location of the body** that the cells under your pointer correspond to.
 * When you move your pointer ventrally or dorsally along the outside of the gyrus, you're changing the **sensory modality** that the cells under your pointer correspond to.
 * When you move your point deep (into the 6 layers of the cortex), you're changing the **axonal destination** of the cells under your pointer.
 * As far as I can tell, the cortical barrel concept means that each functional unit of the body correlates to a discrete, three-dimensional area of the brain. That is, there's a particular, cohesive chunk of cortex that corresponds to all sensory modalities and all six layers of cortex relating to your big toe. There's another one corresponding to all sensory modalities and all six layers of cortex relating to your next toe. And so on.
 * What kind of stimulation do cells in different Brodmann's areas of primary somatosensory cortex respond to?
 * 3a: proprioception
 * 3b: cutaneous receptors
 * 1 and 2: direction and orientation
 * Note above note about complexity and neuronal cross-talk.

=Nociception I, II, & III= [Notice that we're focusing more or less exclusively on the non-facial input here.] [This is a very concept-heavy section. Good to pay attention here, I think.] Geek haiku of the day. Lonely tylenol a palindrome but useless for my pounding head
 * Know the pathways for processing of pain and temperature information. Where are pain and temperature information first detected? Where does information first enter the central nervous system? How does the information get to the brain?
 * Pain and temperature are carried by A-delta fibers (myelinated) and C fibers (unmyelinated).
 * (recall, by contrast, that fine touch and vibration/proprioception are carried by A-alpha and A-beta fibers. A-delta and C fibers in the anterolateral system, A-alpha and A-beta fibers in the DCML system.)
 * Pain and temperature are first detected by unencapsulated **free nerve endings** in the skin.
 * How they enter the CNS: recall that pain and temperature are transmitted to the brain by the __anterolateral system__: go to the dorsal root ganglion, go up through Lissauer's fasciculus, and synapse ipsilaterally in the substantia gelatinosa; the second-order neurons go over through the anterior white commissure and then up contralaterally.
 * How it gets to the brain: there are three destinations and thus three subdivisions within the ascending (secondary) anterolateral neurons:
 * __Thalamus__ (from spinothalamic tract)
 * __Midbrain__ (from spinomesencephalic tract)
 * __Reticular system__ (in the medulla) (from spinoreticular tract)
 * [Note differences here between anterolateral and dorsal column medial lemniscus system:]
 * **Sensory modality**: AL has temp/pain, DCML has touch/proprioception/vibration.
 * **Receptive terminals**: AL's are free nerve endings (unencapsulated), DCML's are encapsulated.
 * **Primary sensory neurons**: AL's are A-delta and C, DCML are A-beta and A-alpha.
 * **First synapse**: ALs it's in the spinal cord, DCML it's in the medulla. Note that in both cases it's ipsilateral.
 * **Ascending side in spinal cord**: AL it's contralateral, DCML it's ipsilateral.
 * Know the type of receptors that detect temperature information.
 * As mentioned, free nerve endings (unencapsulated, no corpuscles). Specifically, thermal receptors in free nerve endings.
 * Know how temperature receptors code their information.
 * Warm receptors (30-48 degrees Celsius): their rate of firing increases as temperature increases.
 * Cool receptors (10-37 degrees Celsius): their rate of firing increases as temperature decreases.
 * Note that here we're talking about a limited temperature range of 10-48 degrees Celsius. Anything above or below that, it's pain, not temperature. This is presumably why they call these receptors "warm" and "cool" instead of "hot" and "cold."
 * Note also that you have about 10 times as many cold receptors as warm receptors.
 * Note further that what you seem to be detecting as 'temperature' is the **difference** between the firing rate at one ambient temperature and the firing rate at another.
 * Why this is: although there is a change in the rate of firing at absolute higher or lower temperatures for either of these receptors, there's a more expressive cluster of firing (or not-firing if the change is in the opposite direction of the receptor) in a given receptor when the temperature actually changes significantly. So we can, subtly, detect the absolute temperature by how often a receptor is firing, but it's much easier to detect the big burst of firing (or burst of absence-of-firing) at the moment when the temperature actually changes.
 * Bottom line: this means we detect **changes** in temperature better than absolute temperature; the transient sensation of changing temperature is stronger than the sustained sensation of absolute temperature.
 * Know the types of manipulations that distinguish first pain from second pain.
 * **First pain**: "whoa": pain is immediate, well-localized, and well-tolerated.
 * **Second pain**: "ow": pain is delayed, poorly localized, and poorly tolerated.
 * Two different fiber types underlie these two responses:
 * __A-delta fibers carry first pain__.
 * __C fibers carry second pain__.
 * Note that different manipulations will selectively block, or activate, different types of pain:
 * **Pressure** applied to site of injury selectively blocks __first__ pain and leaves __second__ pain intact (you block A-betas and -alphas, then A-deltas, then Cs with increasing pressure-- effectively blocks from biggest to smallest).
 * **Local anesthetics** block __second__ pain and leave __first__ pain intact (low concentrations selectively target the smallest fibers, C fibers). See next lecture for why this is.
 * **Electrical stimulation** activates A-beta and -alpha fibers first (touch, vibration, and proprioception), then A-delta fibers (first pain), then finally C fibers (second pain) with increasing intensity of the electrical stimulus (like pressure, goes from biggest to smallest, but activates rather than blocks fibers).
 * [Types of pain receptors, or **nociceptors**, and the fibers that carry their information:]
 * Thermal nociceptors: Very-hot pain = A-deltas, very-cold pain = C.
 * Pressure (mechanical) nociceptors: A-delta fibers.
 * Polymodal nociceptors: C fibers.
 * Thermal and mechanical are fairly self-explanatory and are limited to only responding to their given stimulus (extreme heat, extreme cold, someone hitting you). Polymodal nociceptors respond to a variety of types of __high-intensity__ painful stimuli, whether they be mechanical, thermal, or chemical (eating hot peppers).
 * Note that this means that high-intensity stimuli tend to be carried by C fibers (which is presumably why second pain is on C fibers).
 * Know the stimuli that activate polymodal receptors.
 * As mentioned, mechanical, thermal, chemical.
 * How chemical sensing works: chemical stimuli hit the **VR-1** (capsaicin, temperature, protons), **ASIC** (protons), and **P2X** (ATP) receptors within polymodal receptors. Each class of receptor, as indicated, senses a particular kind of stimulus.
 * Know the stimuli that activate the VR-1 receptor. Where is the VR-1 receptor located?
 * Stimuli for VR-1: Capsaicin, temperature, acid.
 * VR-1 receptors are located in the free nerve terminals in the periphery. (also, beyond the scope of the class, in the CNS.)
 * Know the identities of chemicals that act as pain activators and sensitizers [see next LO for more in-depth description of the sensitization process]
 * Activators: here, mainly __bradykinin__; tangentially, potassium, acid, and serotonin.
 * (bradykinin is the active, cleaved form of its proform, which is cleaved by substances released during cell damage. It directly stimulates firing of the primary nociceptor neurons of A-delta and C fibers.)
 * Sensitizers: __prostaglandins__ (note inhibition of this pathway is the basis for NSAID analgesia), __substance P__, __ATP__, __ACh__; sometimes serotonin as well.
 * Note **serotonin** can act as either an activator or a sensitizer in the periphery (or, in the central system in the periaqueductal grey, an analgesic-- see below).
 * Know the basis for peripheral sensitization.
 * Sensitizing agents lower the threshold for activation of the primary nociceptor neurons. Specifics on Substance P effects are below under "Know the basis for central sensitization."
 * Note that C fibers release substance P when repeatedly stimulated.
 * Note also that there are two grades of sensitization: **hyperalgesia**, in which normally painful stimuli become even more painful, and **allodynia**, in which normally non-painful stimuli evoke a pain response. Evidently this depends on just how much sensitization you're talking about.
 * Know the basis for the analgesic action of aspirin.
 * As mentioned, they stop prostaglandin synthesis by inhibiting cyclooxygenases. Prostaglandins are sensitizers; thus their inhibition de-sensitizes nociceptors.
 * Know the basis for the triple response.
 * Triple response: reddening, wheal, and flare.
 * All of these are, directly or indirectly, caused by bradykinin activated by enzymes released during cellular damage.
 * __Reddening__: bradykinin is a vasodilator (increased blood flow).
 * __Wheal__ (edema): bradykinin is a vasodilator and a loosener of the capillaries (increased capillary leakage).
 * __Flare__: bradykinin activates local C fiber nociceptors that go into the peripheral skin; the activation of C fibers releases Substance P, which also causes vasodilation, but less so than bradykinin (which is why the flare is less red than the central reddening).
 * This causes allodynia due to the release of Substance P (which, recall, is a sensitizer of the nociceptor terminals in the area of the flare).
 * Know the location of action and the effects of Substance P.
 * Location of action: Substance P is kind of an odd duck:
 * It's contained in vesicles and released like a neurotransmitter where the first-order neuron synapses in the dorsal root ganglion onto the second-order neuron.
 * BUT it's also contained near the primary sensory receptors themselves, in the receptor terminals.
 * So when a C fiber gets activated a lot, you get Substance P release both at the originating site (cutaneous) and also in the dorsal horn of the spinal cord.
 * Effects: as mentioned, sensitization of pain-nerve membranes, both at the incoming sensory terminal and in the dorsal horn. The way this works, as will be gotten into a bit more below, is that substance P binds to NK1 receptors and closes potassium channels, slightly depolarizing the membrane potential closer to threshold.
 * Know what type of pain information is carried by C fiber afferents.
 * **C fibers: Second pain (dull, delocalized, intolerable); very-cold pain; warm temperature sense; crude touch information; itch; chemical signals like increased H+ or increased ATP.** Note that all polymodal receptors (sense high intensity stimuli of various kinds) are carried by C fibers.
 * [Recall referred pain lecture from anatomy-- sometimes visceral inputs from internal organs and inputs from cutaneous sites synapse on the same second-order neuron in the dorsal horn; since the cutaneous neurons dominate, the pain is perceived as coming from various areas on the body.]
 * Know the location of the first synapse in the pain pathway. Which neurotransmitters operate at this synapse?
 * Here, we're talking mainly about C fibers. Note that different pain/temperature fibers synapse on different areas in the dorsal horn in the spinal cord. C fibers are the ones we're primarily interested in here, and they synapse in the substantia gelatinosa (Rexed's lamina 2). A-delta fibers evidently synapse in Rexed lamina 1. Note that this is normally a fairly sharp division (A-delta fibers don't synapse onto RL 2 areas) for obvious reasons-- you don't want one type of stimulus to synapse onto the pathway that tells the brain it's a different kind of stimulus. Back to labeled lines. Note that in chronic neuropathy these lines can get crossed (see last LO).
 * In any event, the first synapse for C fibers is in the substantia gelatinosa (Rexed's 2).
 * **C fibers release __glutamate__**; they also, as mentioned, release **__Substance P__** when they're stimulated repetitively.
 * There are AMPA and NMDA receptors on the postsynaptic membrane. See next LO.
 * Actually there are NK1 receptors there too. See the LO after that.
 * Know the differences between and the properties of AMPA and NMDA receptors at the dorsal horn synapse.
 * AMPA: pretty simple; it's a ligand-gated ion channel (glutamate binds, gate opens, membrane depolarizes. Generally this is non-specific cation territory.
 * NMDA: as described earlier ("Molecules to Memory"), requires both glutamate and postsynaptic depolarization in order to activate; when it does activate, it allows calcium into the cell, further depolarizing the membrane.
 * When NMDA receptor is activated a lot, the receptor itself becomes phosphorylated such that it doesn't need to have the membrane depolarized as a prerequisite for firing anymore. This produces sensitization; see next LO.
 * Know the basis for central sensitization (e.g., at the dorsal horn synapse).
 * Substance P sensitization: note a third type of receptor on the postsynaptic membrane: __NK1__ receptors, or neurokinin 1 receptors. These bind substance P; when activated, they close K channels and depolarize the membrane slightly (ie., they make it easier for a small amount of glutamate to depolarize postsynaptic membrane to AP). This is the mechanism for substance P sensitization in the dorsal horn.
 * NMDA sensitization: when the NMDA receptors are activated a lot (C fibers firing repeatedly enough to stimulate the second-order dorsal horn neuron), as mentioned, they change to stop acting like NMDA receptors and start acting like plain old AMPA receptors (they start behaving like simple ligand-gated, depolarizing ion channels). This effectively increases the number of AMPA receptors on the postsynaptic membrane, which strengthens the ability of the first-order axon to stimulate the second-order membrane to AP. This is the mechanism for NMDA sensitization in the dorsal horn; it's also called **wind-up**.
 * [Note why you rub a body part you've just hit on something to ease the pain (this seems like a digression but winds up being extremely important so read it):]
 * A-beta fibers (carrying the rubbing sensation) send out inhibitory fibers to Rexed's lamina 2; when they're activated a lot, __they inhibit the ability of C fibers to transmit pain information__ at the dorsal horn synapse.
 * How they do this: the inhibitory fibers synapse on an inhibitory neuron that's right next to the C fiber synapse in the dorsal horn. This inhibitory neuron, when stimulated by the glutamate released from the A-beta fibers, releases **enkephalin**, an endogenous opioid. The enkephalin inhibits both the presynaptic and postsynaptic transmission from the C fiber to the second-order neuron.
 * How __that__ works:
 * (1) __Presynaptically__: it blocks calcium channels on the presynaptic membrane, preventing release of vesicles (like a NT-based version of Lambert-Eaton syndrome).
 * (2) __Postsynaptically__: It binds to opioid receptors on the postsynaptic membrane and hyperpolarizes it by opening its potassium channels.
 * Of course, you can also achieve this effect by shooting opioids into the spinal column, as in epidural morphine.
 * Note that, as you might think, only the A-beta fibers at the site of injury actually exert an inhibitory effect on C fiber synapses coming from that site; you can't rub your ear to make your toe feel better. Unless you have some kind of freaky ear thing going on, in which case good for you but I don't want to know about it.
 * Note also that you normally have some degree of inhibition through the A-beta pathway going on at all times. Thus if the A-beta fibers deteriorate, as in late-phase syphilis, you lose the inhibitory tone of those fibers on the C fibers, which means you wind up having a lot of excruciating pain all the time. This is called //tabes dorsalis//.
 * Note this also means that you can use electrical stimulation at a low intensity (recall that low intensity electricity only activates A-alpha/beta fibers) to prevent pain.
 * This concept, where you have a synapse between the first- and second-order neurons in the pain pathway that can be influenced both by excitatory and inhibitory neurotransmitters, is called the **gate control theory**: the synapse is the gate, which is being either opened (by the first-order C fibers, glutamate, and substance P) or shut (by endogenous or exogenous opioids).
 * Know the role of the PAG in modulation of pain.
 * PAG: the **periaqueductal gray** area. It's a powerful analgesic system pre-built into the wiring.
 * How it works:
 * The PAG projects to a region in the medulla called the __nucleus raphe__. Neurons from there project to a tract down the spinal cord called the dorsal lateral funiculus and synapse onto those C fiber synapses, just like the A-beta fibers we were talking about a moment ago.
 * __The PAG fibers release **serotonin**__, which activate the A-beta inhibitory projecting fibers, releasing enkephalin and profoundly depressing the ability of the pain synapse to transmit APs.
 * PAG: to medulla, down to dorsal horn, releases serotonin, causes release of enkephalin, suppresses C fiber transmission.
 * (this is why we mentioned earlier that serotonin, centrally, can be an analgesic agent, and why SSRIs often address body pain-- which may have arisen in the first place due to a lack of serotonin, causing a lack of normal analgesia in the dorsal horn.)
 * Note that the PAG is really pretty central in most of endogenous pain management so it's worth grokking this.
 * When you take systemic morphine, it acts directly on the PAG, inhibiting the normal inhibitors that keep the PAG from firing more.
 * Of course, systemic morphine is also going to act all throughout the brain and cause all brands of nastiness. It's largely avoided by giving morphine as an epidural.
 * Note also that the basis for being distracted from pain by focusing on something else is in the PAG (at least by fMRI).
 * Know the bases for the placebo effect and stress-induced analgesia.
 * Both of these seem to work through the PAG mechanism described above.
 * Before we get into it, let's mention **nalaxone**, a synthetic compound that __blocks opioid receptors__. (Dr. Goljan mentions that it's one of the compounds you give semi-comatose patients in the ED, just in case it's an overdose situation. The other two, if you're interested, are glucose for hypoglycemia and thiamine for Wernicke's and Korsakoff's.)
 * Germane to our discussion, what this does is block the effects of A-beta/PAG/morphine inhibition of C fiber transmissions (since they all rely on encephalin or encephalin-like substances binding to opioid receptors to open potassium channels and hyperpolarize the postsynaptic pain membrane). Note A-beta fibers use glutamate and PAG fibers use serotonin, but they both activate the inhibitory neurons that uses the opioids.
 * Again, germane to the concept at hand, giving nalaxone should block any analgesia coming from the PAG.
 * __Stress-induced analgesia__: evidently, the limbic system, through the amygdala and hypothalamus, can activate the PAG to varying degrees.
 * __Giving nalaxone blunts, but doesn't entirely erase, stress-induced analgesia__, implying that there are analgesic mechanisms aside from the PAG at work.
 * [Note also that long-term stress potentiates pain.]
 * __Placebo effect__: We're not really sure of the pathway here, but the PAG seems to be involved, since __giving nalaxone eliminates the analgesic benefit derived from placebos__.
 * Know mechanisms underlying neuropathic pain.
 * Neuropathic pain: persistent pain syndromes, arising from either a lack of discernible stimulus or stimuli that are normally not painful.
 * Dr. Ribera: "Understand that the nervous system has changed and is abnormal in neuropathic pain syndromes."
 * __Peripheral mechanisms of neuropathic pain__: involve **sodium channels**. When primary nociceptor sensory afferents are damaged and regrow, the sodium channels can rearrange such that there are neuromas (thickenings of nervous tissue) that contain a very high density of sodium channels. With such a high density of channels, the C fiber can fire a pain signal with a very small stimulus, or even __spontaneously__.
 * Note that there may be a genetic basis for this; the genes encoding certain sodium channel proteins may play a part in determining inflammatory pain thresholds.
 * __Central mechanisms of neuropathic pain__:
 * (1) Although we haven't talked about it much, there are inhibitory GABA neurons that, like encephalins, inhibit the 'gate' in the dorsal horn. When the nervous system is damaged, for unclear reasons, its GABA content goes down, and decreases normal pain inhibition at the gate.
 * Note also that __GABA can flip from being an inhibitory influence to an excitatory influence__ (bad news if it's at the pain synapse).
 * The way this works: recall that GABA tends to open __chloride__ channels. But this only works because the level of chloride in the cells are very low, keeping ECl below depolarization threshold. During and after damage, __the chloride levels in the cell can rise__ such that ECl can be above threshold for depolarization.
 * How __that__ works: microglia, the macrophage-like cells, can release some messed-up junk when the nervous system gets damaged. One of them is a neurotrophin that changes the chloride content of cells, causing the GABA flip mentioned above.
 * (2) After C fiber injury, a lot of nerve growth and development occurs. This can result in some problems as nerve fibers synapse onto neurons they shouldn't be synapsing onto. Think of it of the labeled-lines Dr. Restrepo described getting mixed up with each other.
 * The example that's given here is that A-beta fibers can send out projections that synapse directly onto the second-order pain neurons instead of onto the inhibitory neuron. This can cause pain sensation from simple mechanoreceptor activation on the skin.
 * [By the way: recall that we said there were three different tracts running up the spinal cord; other than the spinothalamic tract going to the ventral posterior lateral nuclei, the other two go to the midbrain and the reticular system in the medulla. These latter two lines are involved in behavioral and emotional responses to pain-- which can involve sending signals to the PAG to stimulate inhibition of first-to-second-neuron pain transmission in the dorsal horn. So pain can beget emotional reaction to pain can beget an adaption of pain transmission.]

=Local Anesthetics=
 * Describe the general structure of local anesthetics, and key chemical properties of the structures.
 * 3 components:
 * (1) lipophilic aromatic portion
 * (2) alkyl chain with either an amide group or an ester group
 * (3) hydrophilic amine portion
 * The changes in action depend largely on whether you have an ester or an amide group on the alkyl chain in the middle.
 * __Useful note__: Note that __amide__-containing alkyl group compounds have __two__ "i"s in the name (lidocaine) while __ester__-containing alkyl group compounds only have __one__ "i" in the name (cocaine, procaine).
 * Don't know if it helps, but the names with more "i"s correspond to the name of the group with more vowels (2 "i"s = amides, 1 "i" = esters).
 * Target of local anesthetics: voltage-gated sodium channels in peripheral axons that conduct APs.
 * [Note the side effects: vast majority is by blocking sodium channels in the wrong tissue. Need to avoid applying them in a way that supplies a large amount of the drug to the brain or heart, unless that's why you're applying them in the first place (see "Antiarrhythmics" in CVPR, especially lidocaine in class IB).]
 * Note that almost all local anesthetics end in "-caine".
 * Note that the local anesthetics generally don't share cocaine's effect of inhibiting catecholamine reuptake, which is why people aren't breaking into clinics and shooting up lidocaine, other than the fact that it would presumably stop their hearts.
 * Describe the structural and chemical differences between amide and ester local anesthetics.
 * Structural: well, one has an amide group and one has an ester group. Not rocket science.
 * Chemical: Amide-containing compounds generally have lower pKas and are more lipid-soluble and ester-containing compounds generally have higher pKas and are less lipid-soluble. See 3 LO's down for more info.
 * Describe the role of pH in determining the effectiveness of local anesthetics.
 * Note that at any given pH, a dose of local anesthetic contains a mix of positively charged and neutral amine groups at any given point in time. The exact proportion depends both on local pH and the pKa of the drug in question.
 * The point, I think, is that the charged form can't cross membranes, which means that the pH of the environment determines how much of a dose of local anesthetic is going to be able to get through the skin's lipid barrier. If the pH goes down, more of the drug is going to be positively charged, meaning that the drug dose will need to be increased in order to have enough drug penetrate that barrier to have the desired effect.
 * Note that it gets more complicated than this on account of the fact that it's the cationic form that actually binds to the site of action. More about this in the next LO.
 * Describe the molecular target and structure-based mechanism of action of local anesthetics.
 * Molecular target: as mentioned, voltage-gated sodium channels. These channels, recall, have two gates, one for activation (at rest, it's closed) and one for inactivation (at rest, it's open). The first gate opens very quickly with depolarization to threshold; the second gate closes more slowly with the depolarization caused by opening the first gate. As far as I can tell within this context, we're only really talking about the activation gate here.
 * How it works: the drug binds to the inside of the sodium ion channel and plugs it up. But it can't get inside the channel from the extracellular space, the channel's extracellular opening is too narrow. So it has to diffuse across the cellular membrane and get into the channel from the intracellular side of it. Dig?
 * Now I'm going to very slightly rock the world that Dr. Betz built: the activation gates for sodium are actually on the __intracellular__ side of the channel. So when those gates are closed, even if the anesthetic is on the intracellular side where the pore is large enough to enter, it's still blocked from binding unless the activation gate opens.
 * Important here is the point that **local anesthetics do not enter, or affect, closed sodium channels**. The reason for this is that the binding site for local anesthetics are __inside__ the channel itself and the only way for the drug to get to them is through an open activation gate on the intracellular side of the membrane. The activation gates need to be open for the blocking agent to enter the channel and plug it up.
 * The result is that __local anesthetic preferentially affects nerves that are frequently firing__. The nerves that are firing faster are opening up more sodium channels to allow the drug to bind them up; the nerves firing slower have sodium channels that are less frequently open and are therefore affected less.
 * This is called '**use dependence**'-- the more a nerve is used, the more it's blocked by local anesthetics. This is one reason the injections of lidocaine at the dentist's doesn't particularly affect your mouth's motor functions: you're not using the motor neurons much.
 * Note the corollary of this concept: in order for the anesthetic to wear off again, the activation gates need to open to allow the drug to be released from the channel. If a blocked channel is never stimulated to open, the drug is going to hang around in that pore forever and a day.
 * Yes, yes, there's a mention in the notes that there's very slow diffusion into (and out of) the pore binding site without the gate opening. Simplify, simplify.
 * As alluded to, the cationic form of the anesthetic is the form that binds well to the inside of the pore. This brings up a problem: how is the charged form of the anesthetic supposed to get through the cellular membrane to come at the channel from the correct side? The answer lies in the fact that the drug is constantly fluctuating between cationic and neutral forms at physiologic pHs depending on whether its amine group is charged or not. When it's neutral, it can cross the lipid barriers in the skin and the plasma membrane; afterwards it can convert to its charged form and diffuse throughout the intracellular compartment to bind in the pore. So you need the cationic form to bind once you're inside the cell, but you need the neutral form to get inside the cell (to say nothing of getting past the skin's lipid barrier) to begin with.
 * Important other point: __local anesthetics act differently on myelinated vs nonmyelinated axons__. **They affect myelinated axons less**, mainly partly because (a) those have high densities of sodium channels at nodes of Ranvier (high safety factor) and (b) they're open for a shorter period, which doesn't allow the drug as much time to act. The unmyelinated axons, by contrast, have a smaller safety factor and their APs tend to be of longer duration (thus allowing the drug a greater opportunity to bind inside the channels while they're opening and closing). Note that local anesthetics **affect smaller myelinated axons more than they affect larger myelinated axons** because the distance from node to node is smaller in smaller-diameter axons (thus less sodium channel clustering at those nodes and longer APs).
 * Note what these two things imply: C fibers (unmyelinated) and A-delta fibers (thin and myelinated) are preferentially affected by local anesthetics. Coincidentally, these are also the types of fibers that carry pain information. Ann, meet aesthetic.
 * Describe physicochemical properties of local anesthetics that determine potency, onset, and duration of drug action.
 * Two important ones are __pKa__ (related to **onset**) and __lipid solubility__ (related to **potency**).
 * Low pKa leads to a faster onset, while high pKa leads to a slower onset.
 * High lipid solubility leads to higher potency, while low lipid solubility leads to lower potency.
 * Stuff that generally goes with amide compounds: low pKa, high lipid solubility.
 * Thus amide compounds are generally fast-acting and highly potent.
 * Stuff that generally goes with ester compounds: high pKa, low lipid solubility.
 * Thus ester compounds are generally slow-acting and less potent.
 * **Duration of drug action**: determined by other junk as below:
 * Amide compounds get bound to proteins in the plasma, protecting them from degradation in the liver. Thus amide-containing local anesthetics have a longer duration of action.
 * Ester compounds are not protected by plasma proteins and are in fact broken down even before they get to the liver by plasma esterases. Thus ester-containing local anesthetics have a shorter duration of action.
 * Describe methods of local anesthetic application.
 * Topically
 * IM (inject nearby nerve bundles)
 * Epidural
 * Note you often apply local anesthetics along with a vasoconstrictor to avoid getting the anesthetic into the circulation.
 * Describe how local anesthetics differ in action from tetrodotoxin and saxitoxin.
 * Tetrodotoxin: produced by pufferfish.
 * Saxitoxin: produced by red algae in red tides, which are eaten by shellfish (making said shellfish toxic to humans).
 * These are extraordinarily selective for nerve and muscle sodium channels (1000x more than for cardiac channels). They work differently from local anesthetics also in that (1) they can enter the extracellular entrance of the sodium channel and (2) their binding to their active site is not use-dependent (doesn't depend on the activation gate being open).
 * These kill you by paralyzing your respiratory muscles, which is a reasonably significant difference from local anesthetics.

=Clinical Assessment of the Spine and Spinal Cord= [There was a disturbance in the Oje. Be warned.]
 * Understand the meaning of the following terms:
 * Paresthesia: abnormal sensation in an area.
 * Dysesthesia: dense loss of sensation in an area.
 * Paresis: weakness.
 * Dermatome: all skin innervated by a given sensory root.
 * Myotome: all muscles innervated by a given motor root.
 * Radiculopathy: impingement of a given spinal root.
 * Myelopathy: a spinal cord disorder resulting in loss of nerve function.
 * Understand the functions of the __3 major spinal tracts__ and know where they cross:
 * Spinothalamic tract (pain and temperature): second-order neurons decussate in the anterior white commissure in the spinal cord.
 * Posterior columns (vibration and position): second-order neurons decussate in the medial lemniscus, which runs between the medulla and thalamus.
 * (technically they decussate in the internal arcuate fibers in the medulla, which go on to form the medial lemniscus; see "Intro to the Brainstem I + II" for next unit.)
 * Corticospinal tract (motor): first-order neurons decussate below the pyramids of the medulla on their way down to the lateral tract (or don't at all on their way down to the ventral tract).
 * Know where the __nerve roots exit__ (e.g. C6 root exits between C5-//C6//; T2 between T2-//T3//).
 * In cervical spine: each nerve root comes out **above** its similarly numbered vertebral body (C8 comes out over T1).
 * Thus in the cervical spine, for a root to be impinged on, it takes a herniation of the disc between the similarly numbered vertebral body and the vertebral body **above** it.
 * Below this, each nerve root comes out **below** its similarly numbered vertebral body.
 * Thus below the cervical spine, for a root to be impinged on, it generally takes a herniation of the disc between the similarly numbered vertebral body and the vertebral body **below** it.
 * Note there are some exceptions to this once you get down into the lumbo-sacral area; see 5 LO's down under the cauda equina syndrome.
 * Know the spinal __cord level that each vertebral body overlies__ (C6 bone overlies C7 cord.)
 * This is more complicated.
 * In the upper cervical spine, the number of the vertebral body corresponds with the number of the underlying spinal cord level.
 * In the lower cervical spine, the number of the vertebral body corresponds with the number of the underlying spinal cord level __plus one__.
 * In the upper thoracic spine, the number of the vertebral body corresponds with the number of the underlying spinal cord level __plus two__.
 * In the lower thoracic and lumbar spine, the number of the vertebral body corresponds with the number of the underlying spinal cord level __plus two or three__.
 * Note that in adults, **the lower edge of the L1 vertebral body is generally right over the conus medullaris** (containing the last 3 or 4 sacral roots).
 * Note that this also indicates the inexactitude of saying which vertebral body is over which cord level, since the cord levels really compress at the end there under the last few thoracic levels and the first lumbar vertebra.
 * Recognize the symptoms of a __radiculopathy__ and understand __Lhermitte's__ symptom.
 * **Lhermitte's symptom**: results from neck flexion; feels like a shock down the back, sometimes into arms. Arises from posterior column disease.
 * **Radiculopathy**: shooting, burning pain or tingling/numbness along one or more dermatomes, and/or weakness and diminished reflexes in one or more myotomes.
 * Know the neurologic signs used to distinguish lesions affecting the __lower motor neurons__ versus those affecting the __upper motor neurons__.
 * Lower motor neurons: fasciculations, flaccid weakness (hypotonia), absent reflexes
 * Upper motor neurons: no fasciculations, hypertonic weakness, hyperreflexia or abnormal reflexes like Babinski's sign or Hoffman's sign.
 * Know the major tract deficits associated with __10 spinal cord syndromes.__
 * **Complete cord transection**: affects all tracts, ascending and descending, on both sides of the cord. Deficits in all sensory and motor levels below lesion. Results in spinal shock (flaccid paralysis below transection), followed by upper motor neuron lesion signs. Can show root signs (LMN deficits at the level of the injury).
 * **Central lesion** (eg. **syringomyelia**): at least at first, involves the anterior white commissure and the pain/temperature fibers within it that are in the act of decussating after synapsing in the substantia gelatinosa. Central lesions, therefore, show up with pain/temperature deficit more or less at the level of the lesion (maybe a little below, due to Lissauer's fasciculus?) but intact proprioception.
 * **Posterior column syndrome**: involves the entire posterior column; bilateral loss of position and vibration sense below lesion. Note: look for Lhermitte's sign.
 * **Combined anterior horn-pyramidal tract syndrome** (eg. **ALS**): involves all motor neuron fibers (corticospinal tract, lower motor neurons); bilateral weakness with both upper and lower motor neuron deficit signs.
 * **Brown-Sequard (hemi-section) syndrome**: involves one side of the spinothalamic tract (already decussated from its origin), corticospinal tract (already decussated from its origin), and posterior column (not yet decussated from its origin); look for ipsilateral weakness and vibe/position deficit, contralateral pain/temp deficit.
 * **Posterolateral column syndrome** (eg. **cobalamin deficiency**): involves both sides of the posterior column and lateral corticospinal tract; bilateral vibe/position deficit and weakness.
 * **Anterior horn cell syndrome** (eg. **polio**): involves lower motor neuron bodies only; bilateral loss of strength with lower motor neuron deficit signs.
 * **Anterior spinal artery occlusion**: involves the anterior two-thirds of the spinal cord (everything but the posterior column); bilateral loss of pain/temp and muscle strength, sparing vibe/position.
 * **Pyramidal tract syndrome**: involves both sides of the corticospinal tract; involves bilateral upper motor neuron failure with weakness and upper motor neuron deficit signs. Note a complete sparing of all sensory tracts and bladder function (no sympathetic/parasympathetic nerves affected).
 * Oje: Although there are somatic nerves innervating the external sphincter of the bladder (2 LOs down), they travel in a somewhat distinct pathway from the corticospinal tract and are thus unaffected. No loss of bladder function whatsoever in pyramidal tract syndrome.
 * **Myelopathy with radiculopathy** (eg. **cervical spinal stenosis**): can involve any or all of the tracts, particularly the corticospinal tract; often shows up as bilateral upper motor neuron deficit syndrome with root signs and possible bladder dysfunction.
 * Know how to distinguish __conus medullaris syndrome__ from __cauda equina syndrome__.
 * [__Extramedullary__ tumors: arise from outside the spinal cord and compress it (as meningioma). Pain arises early (nociceptors in leptomeninges).]
 * [__Intramedullary__ tumors: arise from inside the spinal cord (as in Schwannomas). Pain arises late (no nociceptors in cord itself).]
 * Note that at lumbar and sacral levels, the nerve roots descend fairly steeply and one (or many) can be impinged on by other herniated discs than the one that is directly near its egress point.
 * Note that sacral nerve roots tend to be thin and easily impinged upon; they're also the ones (S2-4) that control a lot of somatic/parasympathetic bladder and sphincter function (see next LO), so you often get incontinence with their impingement.
 * **Conus medullaris syndrome**: involves damage to the tip of the cord inside the conus, involving the S3-S5 roots. Does not involve the lumbar roots. Frequently caused by intramedullary tumors (compressing the conus roots but not disturbing the lumbosacral fibers outside the conus itself).
 * Late development of pain, but early bladder/bowel/sexual dysfunction.
 * Weakness of __pelvic floor muscles__.
 * __Symmetric__ anesthesia.
 * **Cauda equina syndrome**: compression of the cauda equina; involves all the roots therein, from __L1 to S5.__ Note that this is (spatially) __below__ where you'd find causes of the conus medullaris syndrome, even though it affects __higher__ nerve roots. Frequently caused by extramedullary tumors compressing the lumbosacral roots.
 * Early development of pain, but late bladder/bowel/sexual dysfunction
 * Weakness of __leg muscles__ with decreased deep tendon reflexes
 * __Asymmetric__ anesthesia
 * Understand the basic neural pathways involved in the control of micturition, and the difference between upper motor neuron and lower motor neuron lesions affecting bladder function.
 * For micturition:
 * **Voluntary** sphincter has to open (somatic, S2-4)
 * **Involuntary** sphincter has to open (sympathetic, T11-L1)
 * **Detrusor** has to contract (parasympathetic, S2-4)
 * S2-4 lesions: the bladder can't contract, and the voluntary sphincter can't empty; get overflow incontinence where it leaks.
 * T11-L1 lesions: upper motor neuron syndrome involving sphincter muscles: initially flaccid muscles, evolving into a spastic sphincter (can cause reflex into kidneys if the involuntary sphincter contracts at the same time that the detrusor is contracting).
 * Understand the sensory territory, unique motor territory, and reflex components of the C5,C6,C7 and L4,L5,S1 nerve roots, as presented in this lecture.
 * Sensory:
 * C5: shoulder and upper arm
 * C6: thumb and first finger
 * C7: middle finger
 * L4: knee and medial thigh
 * L5: dorsum of foot, hallux
 * S1: lateral foot, little toe, sole of foot.
 * Motor:
 * C5: deltoid, infraspinatus, biceps
 * C6: wrist extensors, biceps
 * C7: triceps
 * L4: psoas, quadriceps
 * L5: foot dorsiflexion/eversion, big toe extension
 * S1: foot plantarflexion
 * Reflex:
 * C5: biceps
 * C6: biceps, brachioradialis
 * C7: triceps
 * L4: patellar
 * L5: none
 * S1: Achilles
 * Know the thoracic dermatomes that typically cover the nipple line, xyphoid, and umbilicus.
 * T4: nipple line
 * T6: xyphoid
 * T10: umbilicus
 * Understand ALL of the material presented in neuroexam.com under “reflexes” (except the material on “reflexes tested in special situations").
 * Go to it.
 * Retain the learning objectives from the spinal cord powerpoint exercise from last exam.
 * Right. Notice that there are somatic divisions in the lateral corticospinal tract and the spinothalamic tract that invert the DCML system of lower-body medially, upper-body laterally. This means that, at least in principle, compression from one side will affect motor control and pain/temperature sensation in the bottom of the body first and ascend, but will affect fine touch and proprioception in the top of the body first and descend.
 * [Note slide on difference between neurogenic and vascular causes of claudication.]

=Opioids I + II= [God only knows how much of this he actually wants us to know. Use your best judgment.] >> =bad. **SSRIs**= >> good.
 * Know the medical circumstances in which opioids are indicated and contraindicated
 * General indications:
 * Pain associated with malignancy
 * Painful diagnostic procedures (w/ local anesthetics and/or sedatives)
 * Postoperative pain
 * Obstetrical anesthesia (epidural route; note possible respiratory depression effect in newborn)
 * Patient-controlled analgesia
 * At lower doses, can be used for __cough suppression__.
 * Post-myocardial infarction for pain and to reduce cardiac load (unknown mechanism)
 * Can __alleviate pulmonary edema__ through an unknown mechanism. Note that this is the only exception to the rule that you don't give opioids to patients with respiratory disorders (see next point)
 * To repeat: **pain, cough suppression, treatment of pulmonary edema**.
 * Contraindications:
 * Never use in head injury due to increased intracranial pressure (see below).
 * Never use in patients with respiratory patients due to respiratory depression (note exception above).
 * Don't use in hypotension (as in shock)-- opioids lower blood pressure and can trigger some histamine release, further decreasing it.
 * For the same histamine reasons, don't use in anaphylactic patients.
 * Don't use in patients with hypothyroidism (not sure why).
 * Don't use in patients with impaired hepatic function (can't clear toxic metabolites).
 * To repeat (mainly): **head injury, respiratory patients, hypotension**.
 * [Note that opioids don't treat fever.]
 * Know the potential adverse interactions of opioids with other drugs
 * Barbiturates + opioids: profound additive CNS depression, can increase metabolism rate of opioids.
 * Antipsychotics (phenothiazines) + opioids: generally increase respiratory depressive and hypotensive effects of opioids.
 * MAOIs/tricyclic antidepressants + opioids: increase respiratory depression, can induce CNS excitation and seizures.
 * (on the other hand, note that SSRIs + opioids can facilitate descending PAG activation)
 * To repeat: **barbiturates, phenothiazines, MAOIs/tricyclics**
 * Know the life-threatening side effects of opioid drugs, and the appropriate means to avoid/treat these actions
 * Mainly **respiratory depression** via activation of opioid mu receptors.
 * Primary cause of opioid-induced death; even at analgesic doses you still get some depression of respiration.
 * How this works: decreases sensitivity of CO2 receptors in brain, so the signals to the diaphragm to work harder to clear CO2 don't go through
 * Also: CO2 builds up in the blood, leading to cerebral vasodilation, increasing intracranial pressure.
 * Note that you can avoid most respiratory depression effects by injecting opioids through an epidural.
 * Type II __anaphylactic reactions__ to opioids are rare but do occur.
 * Opioids cause **increased smooth muscle tone**: this results in __constipation__, __increased biliary pressure__, and __increased urinary retention__.
 * Note you can also get hallucinations via kappa activation at high doses.
 * Generally they act as sedatives. If you see **behavioral excitation** (over-stimulated activity), it's a sign of __acute toxicity__-- the toxic opioid metabolites start to build up and react with things they oughtn't. This is why you can't use high doses of codeine.
 * Note that you get **pupillary constriction** as well-- often a sign that someone's been using. Note also that during withdrawal from opioids the pupils dilate like crazy.
 * Understand the mechanism by which opioids act upon the central and peripheral nervous systems
 * They bind to receptors:
 * Three major classes of opioid receptors: mu, delta, and kappa. All are G-protein coupled receptors. They're barrel-shaped, seven-times membrane-spanning proteins with a kind of pocket in the middle.
 * Most clinically useful drugs act through the mu receptors; mu receptors produce analgesia and respiratory depression. Delta receptors and kappa receptors can produce analgesia without respiratory depression, but are not yet used widely as clinical targets.
 * All opioid receptors are coupled to either Gi or Go proteins (no Gs). Thus they tend to be inhibitory receptors.
 * Specifically, they __inhibit presynaptic calcium channels__, decreased neurotransmitter release. They also __open potassium channels__, hyperpolarizing membranes on the postsynaptic membrane [possibly also the presynaptic membrane, though I haven't been able to find corroboration yet]. Finally the Gi subunit-utilizing receptors can __inhibit adenylyl cyclase__, decreasing cAMP synthesis and decreasing neuronal excitability.
 * So, as discussed yesterday, they __directly__ inhibit pain transmission between the primary C fiber and the second-order fiber in the dorsal horn in the anterolateral system.
 * They also activate the descending periaqueductal grey pathway, causing the PAG to release serotonin onto the inhibitory neurons onto that same first synapse in the pain pathway, causing it to release endogenous opioids as well. (note that exogenous opioids, which are generally inhibitory, do this by inhibiting the inhibition on the PAG.)
 * Note this is all involved with C fibers (second pain)-- it's not going to do a lot about first pain.
 * However, they also reduce the subjective response to pain; they induce tranquility and euphoria by acting in the limbic system.
 * This effect tends to correlate with how readily an opioid crosses the BBB and is activated by mu receptors. Obviously this means that highly lipid-soluble opioids are more susceptible to being abused.
 * How it works: they activate dopaminergic reward pathways in brain (more about this later).
 * Understand the definitions of tolerance and dependence, and the degree to which these phenomena develop in various opioid-sensitive systems
 * Tolerance: decreased response to a drug as a result of previous exposure. This develops based on frequency and duration of usage and the level of the dose.
 * Significant levels of tolerance are not commonly seen over 2-3 weeks of normal therapeutic use.
 * Notice that you **don't develop tolerance for constipation and pupillary constriction**.
 * Dependence: On a physical level: the required continued use of a drug to maintain a normal physiological state and prevent withdrawal. On a psychological level, a constant desire or craving for a drug.
 * Physical dependence is rare with short-term therapeutic opioid use. With long-term therapeutic use, dependence usually develops, but gradual withdrawal avoids epic problems with coming off the drug.
 * [Withdrawal symptoms for opioids:]
 * Opioid withdrawal symptoms are more or less the opposite of normal opioid actions: dilated pupils, insomnia and restlessness, diarrhea. Also look for "flu-like" symptoms: nausea, vomiting, cramps, chills, sweating.
 * To prevent withdrawal symptoms, can use smaller doses of opioids or can use __clonidine__ (agonist for alpha-2 receptors to increase reuptake of catecholamines) to treat over-sympathetic tone.
 * Note that __opioid withdrawal isn't generally life-threatening__ (no seizure danger like that associated with ethanol or barbiturate withdrawal).
 * Know the sites of opioid action in the CNS and periphery
 * CNS: synapse at first-second pain transmission from C fibers, PAG, limbic system.
 * Periphery: smooth muscle in GI/biliary tract/bladder, maybe something in the lungs and heart?
 * Know that in the case of chronic pain associated with terminal malignancy the responsibility of the physician is to ensure that the patient is pain-free and comfortable
 * You mean you don't break his legs and call him names?
 * Know the different classes of endogenous opioids, and representatives of each class
 * Enkephalins (neurotransmitters; rapidly broken down so they only act at the synapse; found in CNS neurons)
 * Examples: Methionine-enkephalin and leucine-enkephalin
 * Endorphins (neurotransmitters but also neurohormones, so can be released into the bloodstream; larger than enkephalins; found in hypothalamus and pituitary, where they're linked with the stress axis)
 * Note beta-endorphin has a methionine-enkephalin motif at one end.
 * Beta-endorphin is the most active endorphin.
 * Dynorphin (unclear physiological role)
 * Most biologically active: dynorphin A (has a selectivity for kappa receptors)
 * Endomorphins (new family, selectivity for mu receptors)
 * Learn the names and uses of opioid agonists from each classification
 * Opioid phenanthrene agonists (full mu receptor agonists):
 * Morphine: IV/IM, post-operatively and acute trauma. For chronic pain can use a oral sustained-release form (MS Contin).
 * Heroin: not approved; more potent than morphine. More lipophilic = higher abuse potential.
 * Codeine: most common opioid analgesic; note that codeine is metabolized to active morphine through CYP450 pathway and that different populations have varying levels of efficacy of CYP metabolism-- so doesn't work in everyone.
 * With acetominophen: tylenol 3.
 * High oral bioavilability.
 * Less potent than morphine.
 * Oxycodone: about the same strength as morphine, better oral availability; available in sustained-release form.
 * Hydrocodone (with acetominophen, Vicodin): similar to codeine.
 * Tramadol: blocks monoamine uptake to potentiate descending pain pathway through serotonin buildup.
 * Phenylpiperidines (also full mu receptor agonists but different pathway?):
 * Meperidine (Demerol): Faster onset/clearance than morphine, decreased problems with smooth muscle contraction, not an antitussive. Slower onset of tolerance, but faster buildup of toxic metabolites means it's used only for acute analgesia.
 * Loperamide (Imodium): stay in GI tract, activate mu receptors there to induce constipation.
 * Fentanyl: way, way more potent than morphine; used in operative setting, very short-acting (1 hour duration). Triggers severe respiratory depression, so at high doses requires mechanical ventilation. Can be used chronically in slow-release form.
 * Methadone: full mu receptor agonists but doesn't produce much euphoria; suppresses withdrawal symptoms.
 * Partial mu receptor agonists: there are some. They tend to be milder and can antagonize the effects of morphine.
 * [Note opioid antagonists that are clinically important: **naloxone** (short-acting, no oral availability) and **naltrexone** (longer-acting, orally active).]

=Headache= [This was just a clinical mess of a lecture and the notes seem to be written by a schizophrenic. I'm not sure what to make of it all. Best guess follows.]
 * Describe these potentially dangerous conditions often presenting with a headache
 * __subarachnoid hemorrhage__: Blinding, "worst pain in my life," "thunderclap" headaches. Can see nausea, vomiting, loss of consciousness. An acute life-threatening situation.
 * SAH is often preceded by a lesser, 'sentinel' headache.
 * __meningitis__: steady, deep pain, generalized location. Often shows up with fever and/or stiff neck.
 * __giant cell arteritis__: generally over 65 years old, generally women, in the temporal region (this disorder is also called temporal arteritis). A throbbing, persistent, aching pain. Note __can cause permanent blindness__ (50% in two weeks) so don't miss it.
 * __idiopathic intracranial hypertension__: symptoms and signs of increased intracranial pressure (bilateral persistent headache, nausea, papilledema, visual field abnormalities) in the absence of focal neurological/neurodiagnostic findings.
 * Know the common headache syndromes
 * common migraine (without focal neurological symptoms, or 'aura'):
 * At least 5 headache attacks lasting 4 to 72 hours
 * No 'organic' disease
 * At least 2 of:
 * __Unilateral__ location
 * Pulsating quality
 * moderate to severe intensity
 * Aggravated by routine physical activity
 * At least 1 of:
 * Nausea/vomiting
 * Photophobia/phonophobia
 * classic migraine (with focal neurological symptoms, or 'aura'):
 * This seems to be a "common" migraine headache with new exciting features.
 * Most of the 'aura' is visual (99%): tend to be new features in vision rather than vision features disappearing.
 * Aura is typically abrupt in onset, builds over 20-30 minutes, and then goes away with the beginning of the headache.
 * Types of visual aura:
 * Sparkled or colored lights
 * Jagged lines in visual field ("fortifications"): tend to start in the middle and proceed outwards.
 * Hallucinations
 * (may be due to a spreading cortical depression wave originating at the occipital pole?)
 * cluster headache:
 * nocturnal, __unilateral__, seen in middle-aged men who drink alcohol or take vasodilators
 * associated with tearing eyes and runny nose, agitation, and miosis (pupillary constiction).
 * come in regular clusters (thus the name); can be one every other day, can be 8 per day.
 * it may be weeks or years between clustered episodes
 * tension headache:
 * 10 episodes, lasting 30 minutes to 7 days; tends to worsen as the day goes on.
 * 2 of the following:
 * pressure/tightening sensation ('a band around the head')
 * mild to moderate pain
 * __bilateral__, not aggravated by physical activity
 * No nausea or vomiting
 * No more than one of photosensitivity or phonosensitivity
 * Describe migraine in detail
 * categories
 * Common (no aura)
 * Classic (aura)
 * Ophthalmoplegic (ocular paresis)
 * Retinal (vision loss)
 * Complicated (prolonged neurological symptoms)
 * Equivalents (aura without headache)
 * epidemiology: more often in women, onset usually in late teens; associated with a positive family history. Tend to improve over time.
 * clinical features: generally broken down into (a) prodrome, in which you get alterations of mood/alertness/appetite before the migraine; (b) aura, as described above; (c) headache, as described above; and (d) post-event lethargy and exhaustion.
 * food and drink irritants: red wine or other alcohol, caffeine, dairy products, chocolate, meats, MSG, citrus or canned fruit, certain vegetables.
 * abortive and prophylactic therapies:
 * Abortives:
 * Migraine-specific agents: serotonin agonists (triptans)
 * Non-specifics: aspirin, NSAIDs, caffeine (trying to counteract vasodilation), dopamine agonists, 'ergot compounds' (oh, yeah, ERGOT compounds!).
 * CGRP-specific antagonists in development.
 * Prophylactics (when headaches are very severe or very frequent, or when the abortive therapies don't work):
 * Beta-blockers
 * Calcium-channel blockers
 * Tricyclic antidepressants
 * Anti-seizure meds

=Intro to the Brainstem I + II=
 * [Principle to keep in mind: motor nuclei ventral, sensory nuclei dorsal.]
 * Locate and identify the attachment points of all the brainstem cranial nerves (CNIII - CNXII) {Fig. 2-18 to Fig. 2-22}
 * I don't have much to add. See Haines.
 * Note that the notes say a good indication of a brainstem lesion is ipsilateral cranial nerve deficit and contralateral long tract deficits (motor/sensory).
 * Nice organizing principle: if a nucleus has to do with visceral/autonomic control, it's closer to the sulcus limitans; if it has to do with somatic control, it's farther away from the sulcus limitans.
 * Another nice organizing principle: pure motor nerves exit the brainstem more ventrally; pure sensory nerves exit the brainstem more dorsally; mixed nerves tend to be in the middle.
 * Locate and identify the following features on the intact brainstem: approximate dividing lines between medulla, pons and midbrain; optic chiasm, mammillary body, superior and inferior colliculi; crus cerebri (cerebral peduncle), basal pons, superior, middle and inferior cerebellar peduncles, pyramid and olive. {Figs. 2-18, 2-20, 2-21; 2-32; 2-34}
 * Again, see Haines.
 * For each of the following structures listed on the handout, be able to locate them on a representative section, identify in what region of the brainstem they occur (medulla, pons or midbrain), describe what functional role they play, and what they are connected to, both in terms of input and output: MEDULLA {5-9 to 5-11}, PONS {5-16 to 5-19}, MIDBRAIN {5-22 to 5-24} 
 * I'm not even going to come near that one. Go look at Dr. Ojemann's corrected handout for the complete list (didn't import into Blackboard).
 * Starting at the receptor endorgan and ending in cortex, identify the components of and trace the pathways taken by systems serving somatosensory functions for the body and head, including: I) pain & temperature for the body, II) pain and temperature for the face, III) touch and vibration sensation for the arms and for the legs, and IV) touch and vibration sensation for the face (Figs. 7-4 to 7-7}
 * __Pain and temperature for the body (anterolateral system)__:
 * (1) End organ to DRG up Lissauer's tract to the ipsilateral substantia gelatinosa
 * **synapse in ipsilateral substantia gelatinosa**
 * (2) Decussates in ventral white commissure and ascends in spinothalamic tract to the VPL in the thalamus (upper body in medial part, lower body in lateral part).
 * **synapse in contralateral VPL**
 * (3) Runs up to same-sided cortex to synapse in post-central SS cortex.
 * **synapse in contralateral SS cortex**
 * __Fine touch and vibration for the body (dorsal column medial lemniscus system)__:
 * (1) End organ to DRG up ipsilateral dorsal column in either the fasciculus gracilis (lower body, medial tract) or fasciculus cuneatus (upper body, lateral tract) to the nucleus gracilis or cuneatus, respectively.
 * **synapse in ipsilateral nucleus gracilis/cuneatus**
 * (2) Decussates in interior arcuate fibers and forms the medial lemniscus on the contralateral side; medial lemniscus migrates laterally to run to the VPL in the thalamus.
 * **synapse in contralateral VPL**
 * (3) Runs up to same-sided cortex to synapse in post-central SS cortex.
 * **synapse in contralateral SS cortex**
 * Note the second-order neurons of both the spinothalamic tract and the dorsal column-medial lemniscus system synapse in the ventral posterior lateral nucleus in the thalamus.
 * Recall that while the DCML system has a medial-lower-body, lateral-upper-body orientation, the anterolateral and corticospinal systems have a medial-upper-body, lateral-lower body orientation.
 * The medial lemniscus is always on the contralateral side from the source of the sensation. The fibers leaving the cuneate/gracile nuclei actually decussate immediately in the internal arcuate fibers before being called the medial lemniscus. Unnecessary verbiage? Probably. But whenever you see the medial lemniscus on a path slice, it contains fibers that originated contralaterally.
 * Keep in mind that although the medial lemniscus does actually start in the medial part of the brainstem, it has to go lateral in order to get to its destination (the ventral posterior lateral nucleus). It starts to do this in the pons and keeps doing it through the midbrain til it gets to the VPL nucleus in the thalamus.
 * __Pain and temperature for the face (spinal/descending trigeminal system)__:
 * Enters the mid-pons with the trigeminal nerve (cell body in trigeminal ganglion); runs caudally in the __spinal trigeminal tract__ to reach the __spinal trigeminal nucleus__ in the medulla.
 * **synapse in the ipsilateral spinal trigeminal nucleus**
 * Decussates and runs rostrally in the contralateral __ventral trigeminothalamic tract__ up to the VPM of the thalamus.
 * **synapse in the contralateral VPM**
 * (3) Runs up to same-sided cortex to synapse in post-central SS cortex.
 * **synapse in contralateral SS cortex**
 * __Fine touch and vibration for the face (principal trigeminal system)__:
 * Enters the mid-pons with the trigeminal nerve (cell body in trigeminal ganglion) and goes directly to the primary trigeminal nucleus in the pons.
 * **synapse in ipsilateral principal trigeminal nucleus**
 * Decussates and runs rostrally in the contralateral ventral trigeminothalamic tract up to the VPM of the thalamus.
 * **synapse in the contralateral VPM**
 * (3) Runs up to same-sided cortex to synapse in post-central SS cortex.
 * **synapse in contralateral SS cortex**
 * Note also you get a __mesencephalic ganglion__ on each side that seems to be spinal/ganglionic nerve matter. It's largely sensorily redundant but seems to be significant for boards. It's up in the midbrain, no surprise.
 * Starting from auditory receptors and ending in cortex, identify the components of and trace the pathways taken by the auditory system including: cochlear nuclei, superior olive, trapezoid nuc., lateral lemniscus, inferior colliculus, medial geniculate and auditory cortex {Fig. 7-29}. You do not yet have to be able to identify any thalamic nuclei on the brain sections (this comes later in the course) but you should know the names of these relay nuclei
 * (1) Auditory receptors to the auditory nerve to the cochlear nucleus (actually three different cochlear nuclei, one dorsal and two ventrals). **synapse at the ipsilateral cochlear nuclei**
 * (2) Some fibers decussate (through the middle of the medial lemniscus in the __trapezoid body__; some fibers evidently branch off to each __trapezoid nuclei__) to run to the contralateral side; the fibers that remain on the ipsilateral side are likewise joined by contralateral fibers. These combined fibers ascend as the __lateral lemniscus__ and go into the ipsilateral __superior olive__. **Both sides synapse at each superior olive**
 * (3) The lateral lemniscus fibers ascend from there to the __inferior colliculus__. **Both sides synapse at each inferior colliculus**
 * (4) Fibers ascend from there to the __medial geniculate nucleus__ in the thalamus. **Both sides synapse at each medial geniculate nucleus**
 * (5) Fibers go from there to the auditory cortex. **synapse at the auditory cortex**
 * Describe the role of the MLF in the circuitry of the vestibuloocular reflex
 * Vestibulo-ocular reflex: makes sure you don't lose sight of the suspicious thing you're looking at while you're turning your head away from it to call your buddy over-- essentially responsible for the fact that your eyes don't automatically turn along with your head. The eighth nerve conveys info about how you're moving your head to cranial nerves VI and III (and, presumably, IV as well). So the following example presupposes that you're turning your head laterally but want to keep your eyes on something-- that means one eye has to turn laterally in your head and one has to turn medially (think about this for a second if it doesn't make sense). This has to happen at the exact same time and to the exact same degree. There's a tract called the medial longitudinal fasciculus that makes sure all the ocular motor nuclei are synched.
 * The command for lateral eye movement comes out of the vestibular nucleus and goes to the abducens nucleus. This command is then relayed up to the oculomotor nucleus via the medial longitudinal fasciculus (MLF), which runs through the brainstem, to be able to track the other eye in a medial direction to the exact same degree that the first eye is tracking laterally.
 * Notice that the MLF is large and heavily myelinated (needs to react very quickly, with sudden movement); as such, it's one of the first targets of demyelinating diseases like MS. The eyes can move laterally and can move medially, but when one goes lateral the other can't track well.
 * Name the cranial nerve nuclei that give rise to preganglionic parasympathetic fibers and give their function {Fig. 7-15 and 7-16}
 * From Haines 8-23 and 8-21:
 * __Superior salivatory nucleus__: goes to the lacrimal and submandibular glands via the pterygopalatine and submandibular ganglia, respectively.
 * __Inferior salivatory nucleus__: goes to the parotid gland via the otic ganglion.
 * __Dorsal motor nucleus of the vagus__: goes to the thoracic and abdominal viscera, smooth muscle, cardiac muscle, and a host of glandular epithelium, mainly through terminal or intramural ganglia in the target organs.
 * __Edinger-Westphal nucleus__: goes to the ciliary muscles via the ciliary ganglion.
 * Define Corticonuclear (corticobulbar) fiber systems and describe how their distribution to ipsilateral and contralateral motoneurons is different for the upper and lower parts of the face {Fig. 7-11}
 * Corticobulbar fibers: motor fibers from the cortex to the various motor nuclei in the brainstem controlling motion in the face.
 * The point here is that the corticobulbar fibers controlling the upper parts of the face go to motor neurons on __both__ sides of the brainstem, while those controlling the lower parts of the face go only to motor neurons on the __contralateral__ side of the brainstem.
 * The practical effect of this is that, with a lesion in one corticobulbar tract, you'll lose movement in the contralateral lower face, but the movement in the contralateral upper face will remain intact due to co-innervation from the other corticobulbar tract.
 * Trace corticospinal fibers through all levels of the brainstem and identify whether they arise from ipsilateral or contralateral motor cortex for all levels of the brainstem and spinal cord {Fig. 7-10}
 * Recall that they enter the brainstem via the internal capsule; in the midbrain they're ventral in the cerebral peduncles/crus cerebri; in the pons they get kind of lost in all the pontine nuclei but are still ventral in the basus pontus; in the medulla they form pyramids that decussate at the bottom.
 * At the bottom of the pyramids they're about 80% decussated (lateral tract) and about 20% undecussated (ventral tract) from their origin in the cortex.
 * Trace the pathways and identify key components of the pupillary light reflex {Fig. 7-25}
 * (1) Light is shone into one eye.
 * (2) The corresponding visual information is carried down that optic nerve and synapses directly in the __pretectal nuclei__ in the midbrain.
 * (3) Fibers from each pretectal nucleus synapse onto __both__ Edinger-Westphal nuclei.
 * (4) The Edinger-Westphal nuclei send out parasympathetic fibers that run with the oculomotor nerve to the ciliary ganglia in the eye.
 * (5) The ciliary ganglion passes on the parasympathetic effect to the iris constriction muscles, causing the iris to constrict, causing the pupil to seem smaller.
 * To sum: II to pretectal nucleus to E-W nucleus to both III's to the iris.
 * Trace the arterial blood supply from the vertebral arteries to the Circle of Willis including the major brainstem branches: Posterior Inferior Cerebellar A. (PICA), Anterior Inferior Cereballar A. (AICA), Superior Cerebellar A. (SCA) and Posterior Cerebral Artery {Fig. 2-36}
 * This was done in the first week of class. Note all the arteries named above come off the **vertebral and basilar** arteries.
 * Note that on the medulla, the vertebral arteries are still distinct, while on the pons they've merged into the basilar artery.
 * For each level of the brainstem, indicate the approximate territory served by median vs. lateral vessels (e.g. vertebral vs. PICA) and identify the major fiber systems passing through each of these territories with special attention to: corticospinal tract, dorsal column/medial lemniscus, anterolateral system (incl. spinothalamic tr. and trigeminothalamic tr.), spinal trigeminal tr. {Fig. 5-14, 5-21; 5-27}
 * You know, this just seems silly to me. It's on Haines, 6-14, 6-21, and 6-27. Good clinical information but the sort of thing we're going to forget in five minutes (as opposed to most of the rest of this, which we're going to forget in five days). As you might expect, the more medially/anteriorly-located structures are supplied by the more medial arteries. For my money, a more useful diagram is the drawing of the vessels on the brainstem on 2-21; if you know where the vessels are anatomically you have a better shot of knowing what areas they supply than trying to memorize all the rest of it.

=Auditory I, II, & III= [Dr. Tollin was extraordinarily cool about this and went through and vetted the entire thing--so this should be more or less accurate. Kudos to him.]
 * Understand the physical nature of sound, including concepts of intensity (dB SPL) and frequency (Hz).
 * Sound: fast changes in atmospheric pressure. It has intensity (amplitude of wave, or loudness), measured in decibels of sound pressure level (dB SPL, on a modified log10 scale where every increase of 20 decibels = a 10-fold increase in intensity), and frequency (ie. pitch), measured in hertz (Hz) or cycles per second.
 * Note that over about 120 decibels you start doing permanent damage to the auditory cells.
 * What is auditory threshold, how is it measured in the audiogram?
 * Auditory threshold: the lowest-intensity (ie. softest) sound a subject can detect.
 * __0 decibels__ is defined as the auditory threshold for most human hearing.
 * [Note that there's a threshold, on both low and high sides, for frequency too: humans can hear generally between 20 and 1600 hertz.]
 * [Note you preferentially lose higher-frequency hearing capacity as you age.]
 * Understand the concept of acoustic impedance mismatch and the role of the middle ear in overcoming impedance mismatch between the air-filled middle ear and fluid-filled inner ear.
 * Here's the thing. Air is comparatively easy to vibrate. Fluid is much denser and more difficult to vibrate. This distinction is called the **acoustic impedance mismatch**. Vibrations in the air lose a lot of energy very quickly when they go into fluid (which is why it's hard to hear your parents telling you to get your ass out of the pool when you're underwater, which in turn is probably why you stayed underwater as long as possible); about 99.9% of the energy in the air vibration is reflected back from the surface (winds up being about 30 decibels). So when you're wanting to translate vibration in the air (sounds in the middle ear) into vibration in the fluid (sounds in the inner ear), you have to figure out a way to compensate for the fact that you're losing all that energy.
 * Enter the middle ear bones (malleus, incus, stapes) and the tympanic membrane. The function of these bones and the membrane is to **amplify** the signal from the middle ear so that it can continue to have significant energy in the inner ear. They do this by two mechanisms:
 * One, they reduce the area upon which the air pressure is acting (tympanic membrane, which is relatively large, is acting on the stapes footplate, which is about 1/20th the size. Since pressure is proportional to force over area, by decreasing the area, you increase the force on the inner ear.
 * Two, they act as a lever arm system: it pivots about a point between the malleus and the incus, increasing the force by a further ~1.3-fold.
 * Together this means there's a roughly (1.3*20 =) 26-fold increase in pressure, which is enough (20*log10[26] = about 28 decibels) to compensate for most of the acoustic impedance mismatch.
 * [Note that people with calculators and too much time, and who weren't paying attention in lecture, will note that with the decibel formula I gave above, there should still be a decibel mismatch of 32 decibels. There's not; you use a different formula for decibel levels resulting in pressure change and decibel levels resulting in intensity change. There's a factor of 2 involved, all that jazz. It's really not important.]
 * Understand the difference between sensorineural and conductive hearing loss.
 * Essentially it's a question of neurological/cellular vs. mechanical problems:
 * __Sensorineural hearing loss__: when the inner ear itself is damaged, specifically the damaging or loss of auditory hair cells and/or nerve fibers. Generally caused by excessive loudness, ototoxic drugs (aminoglycosides, diuretics, aspirin, chemotherapy), or age.
 * __Conductive hearing loss__: problems with the middle or external ear; occurs when the mechanical transmission of sounds through the middle ear and the ossicles is degraded. Basically this is when you either have something like fluid or masses obstructing the flow of air (and vibrations in the air) through the middle ear, or when you damage the tympanic membrane or middle ear bones.
 * How does sound elicit movement of the BM? What is the tonotopic map? Why do hair cells located along the length of the BM respond maximally to different frequencies?
 * BM = the basilar membrane, a ridiculously important structure in the cochlea.
 * If you unroll the cochlea into a long tube and cut through it, you'd find three areas inside: the scala vestibuli, scala media, and scala tympani. These are separated by two membranes, Ressner's membrane between the vestibuli and media and the basilar membrane between the media and the tympani. Germane to this lecture, the basilar one is the one we care about.
 * Note that to simplify it's generally convenient to compress this down into a long tube containing the scala vestibuli on top and the scala tympani on bottom, separated by the basilar membrane.
 * The **oval window** (to which the stapes footplate is attached) is on the scala vestibuli (on one end of our long unrolled tube). On the same end, but attached to the scala tympani beneath, is the **round window**. At the opposite end of the tube there's a hole between the two scalae allowing fluid to pass between them.
 * A note on these windows (mostly written by Dr. Tollin): Neither is an actual aperture that allows fluid out. Instead they are thin membranes in the otherwise rigid structure of the cochlea. By having these membranes, you allow pressure waves in the fluid within the cochlea (since the cochlear walls are effectively incompressible). The pressure waves travel along the length of the cochlea much in the same way waves in the ocean or sound pressure waves in air propagate; the molecules of the fluid or air do not really move much and as a consequence the pressure propagates forward. As an analogy, imagine holding a rope somewhat taught with one end tied securely to a wall. If you now snap your wrist a “wave” of movement travels along the length of the rope towards the wall. Note that the “wave” moves from one end of the rope to the other even though the rope itself does not move. This is the concept of the “traveling wave” of pressure in the fluids of the cochlea. The resulting pressures of the fluid inside the cochlea is what sets up the up and down movement in the basilar membrane, which consequently is responsible for translating it into the chemical stimuli that will become auditory nerve signals.
 * Note a couple real important things about the basilar membrane:
 * One is that the basilar membrane starts thin and gets wider as it goes away from the oval window down the tube.
 * The other is that the basilar membrane near the oval window is very stiff, while the membrane at the other end is relatively flexible.
 * __What this means__: Vibrations of given frequencies trigger large oscillations only in particular segments of the basilar membrane. That is, if you cut the basilar membrane into strips, a given strip will respond maximally to a given sound frequency.
 * __High frequencies are represented near the oval window__ (at the __base__ of the cochlea), while __low frequencies are represented at the other end__ (at the __apex__ of the cochlea).
 * **Organ of Corti**: sits on top of the basilar membrane, in the scala media, and contains hair cells (both inner and outer hair cells, not to be confused with the inner and outer regions of the ear). The outer hair cells on the Organ of Corti are firmly connected to a membrane sitting atop them called the **tectorial membrane**; the inner hair cells are not so connected.
 * Note there's a specialized epithelial region called the //stria vascularis//, which pumps potassium into the fluid in the scala media (called the **endolymph**) and out of the fluid surrounding the hair cells (called the **perilymph**).
 * This gradient (low K+ in the perilymph, high K+ in the endolymph) becomes important in the transduction of sound into membrane potential. More on this later.
 * More on hair cells in the next 2 LOs.
 * How does the IHC respond to bending of the sterocilia? What are the properties of the transduction channels located at the tips of the sterocilia? What is the role of the endocochlear potential in auditory transduction?
 * The hair cells sit at the intersection between the scala media and the scala tympani (on the basilar membrane). This means, since the endolymph in the scala media is very high in potassium and the perilymph surrounding the basilar end of the hair cells is very low in potassium, that there's a pretty big electrochemical gradient sitting there waiting for the cell to utilize it.
 * Specifics from Dr. Tollin: there is also a large electrochemical gradient for K+ between scala media and the inside of the hair cell. Thus, upon opening the K+ channels by deflecting the hair bundle, K+ rushes into the hair cell down this gradient thereby depolarizing the hair cell. K+ on the basal end of the hair cell allow K+ to exit into scala tympani. Ultimately there is an ~130 mV driving force for K+ from scala media through the hair cell into scala tympani.
 * Inner hair cells have stereociliary bundles (little 'hairs') on the side of the cell inside the scala media. These cilia are linked to each other and also to potassium channels in the membrane.
 * When the cilia move in one direction, the channels open and potassium rushes into the cell, __depolarizing__ it, causing calcium channels to open, allowing the release of NT-containing vesicles. The NTs hit nerve projections of the vestibulocochlear nerve and go on.
 * Note that if the ciliary bundles are then deflected in the opposite direction, the ion channels close again and __hyperpolarize__ the cell-- so when a vibration is set up in the cochlea (ie, when you hear a sound), the cilia are being deflected in one direction and then another very quickly, and the depolarization/hyperpolarization pattern on the nerve is going to mimic the peaks and troughs of the vibration signal almost exactly. Pretty cool.
 * What this means: you're effectively transducing sound (vibration) into electrical impulses and feeding them to the nerves. Note that at high frequencies the cell membrane can't keep up with the vibration rate.
 * Note the ciliary mechanism is amplitude-sensitive-- more deflection of ciliary bundles, more ion channels opening (hence stronger signal to nerve); less deflection, less ion channels open (hence weaker signal to nerve).
 * How the cilia move in the first place: recall that the inner hair cells are NOT attached to the tectorial membrane. As it turns out, the tectorial membrane doesn't move in quite the same fashion as the basilar membrane. As the basilar membrane goes up and down, the shearing force between the tectorial membrane and the fluids surrounding the cilia of the inner hair cells cause the cilia to be pushed either in one direction (depolarizing the cell) or the other (hyperpolarizing the cell).
 * What is understood by the "cochlear amplifier"? Understand the role of the OHCs in the cochlear amplifier. Know that OHCs are of clinical significance because of their susceptibility to damage by ototoxic antibiotics and prolonged exposure to loud sounds.
 * Note that although the inner hair cells are the ones that provide the afferent inputs to the auditory system, the __outer hair cells are more numerous__, and most hearing loss is caused by damage to them rather than damage to the inner hair cells.
 * What the outer hair cells do: allow us to amplify and discriminate sounds.
 * Outer hair cells, like inner hair cells, have stereocilia. But unlike inner hair cells, they respond to changes in their membrane potentials by **changing their lengths**.
 * They also release neurotransmitter onto the Type II auditory nerve fibers, but it's unknown what function those fibers actually serve.
 * The reason this is key is that the outer hair cells are firmly attached to the tectorial membrane at one end and the basal membrane at the other. This means they can act, as they contract and lengthen while they transduce vibrations in the endolymph, as amplifiers: they push and pull on the basilar membranes to increase or decrease the amplitude of its oscillation at their particular location.
 * This is what's called the **cochlear amplifier**.
 * As mentioned, most hearing loss is due to loss of outer hair cells (they're particularly susceptible to ototoxic drugs, which block their transduction channels, and loud noise). However, note that since the outer hair cells are voltage-sensitive, this is a great place to put an electrical stimulus to help correct the problem.
 * Note that although outer hair cells don't transmit signals by afferent pathways, they are still innervated-- there's a kind of fine-tuning system whereby the signals from the inner hair cells provide a feedback loop to the outer hair cells, telling them where the frequency peak of the sound is. The outer hair cells can then amplify that particular frequency and dampen the frequencies around it, allowing a very specific identification of frequency. Pretty damn amazing.
 * Understand the response of spiral ganglion cells to sounds of different frequencies. Understand that information on frequency for high frequency sound is determined by which spiral ganglion cells respond maximally, while for low frequency sounds (below 1.5 kHz) it is determined by the temporal pattern of action potential firing.
 * Two general types of auditory nerve fibers:
 * Type I: myelinated, by far more numerous; innervate the inner hair cells. Note that since the inner hair cells are much less numerous than the outer hair cells but they receive way more innervation, __many different type I nerve fibers innervate a specific inner hair cell__.
 * Function: carry information from inner hair cells to brain (see pathways in next LO), as well as feedback information to outer hair cells to allow 'sensitivity' of the cochlea as mediated by the outer hair cells.
 * Type II: unmyelinated, much less common; innervate the outer hair cell. By contrast, __each type II nerve fiber innervates several outer hair cells__.
 * Function: uncertain (I presume it has something to do with the feedback mechanism described above).
 * Spiral ganglion: a pet name for the auditory portion of cranial nerve VIII, which transmits auditory signals from the inner hair cells to the brain. Called "spiral" since it spirals along with the cochlea.
 * Ok. If you're designing an auditory system, there are two basic types of information you need to be able to convey about a sound: (1) its frequency, and (2) its intensity. What you have to work with is a bundle of nerves that carry APs. The next couple of points have to do with how these two things are encoded in it.
 * How frequency is encoded:
 * __At low frequencies__ (below 1.5 kHz), the dominant mechanism is **phase locking**:
 * Recall that the structure of the inner hair cells and the properties of the basilar/tectorial membranes causes the ciliary bundles to be deflected back and forth; recall that this occurs optimally (to the greatest extent) at a particular frequency.
 * __Phase locking__ refers to the tendency of hair cells to align their own patterns of depolarizing and hyperpolarizing with the frequency of the vibration itself when the frequency of the vibration is within the hair cell's frequency field.
 * The brain seems to decode the tempo of phase-locked APs from the auditory nerve to reconstruct the frequency of the sound stimulus that created them.
 * __This only works at low frequencies__.
 * __At high frequencies__ (above 1.5 kHz), the hair cell can't depolarize and hyperpolarize fast enough to keep pace (phase lock) with the signal, so instead it just stays depolarized, with the amount of depolarization being determined by the amplitude of the stimulus. In this range, the cells that respond maximally (depolarize the most, generally because they're at the right spot on the basilar membrane to do so) will determine the frequency as decoded by the brain. Note that since each bundle of type I nerve fibers only innervates one hair cell, and that hair cell tends to maximally depolarize at a given frequency range as determined by its position on the basilar membrane, each given bundle of nerves in the spiral ganglion is encoding a particular range of frequency.
 * How intensity is encoded:
 * It's encoded by **rate coding**: that is, by how many total hair cells are responding to the stimulus. This determines, in turn, how many APs are sent through the spiral ganglion.
 * Note the distinction: frequency is encoded partially by degree of response/position on the basilar membrane and partially by the frequency of the APs, while intensity is encoded by the number of total hair cells responding.
 * Describe the anatomical pathway for the auditory system in the brainstem, diencephalon, and cerebral cortex. Where do axons decussate in this pathway? What is the clinical significance for decussation of axons in the brainstem in the auditory pathway?
 * Auditory nerve: goes into the ipsilateral cochlear nucleus in the medulla. Note that there are three different subdivisions of the cochlear nucleus - dorsal, posteroventral, and anteroventral - depending on the frequency of the sound input in question. There's a structure in the dorsal cochlear nucleus that allows superior-inferior localization of stimuli.
 * After the cochlear nucleus, some auditory fibers decussate in the 'trapezoid body fibers' in the pons (they split the medial lemniscus) to join their counterparts on the other side; some don't. The combined (decussated and non-decussated) fibers on either side of the midline ascend in the **lateral lemniscus** to a variety of locations.
 * The first of these stops is the **superior olivary complex**, in both its lateral and medial nuclei. The fact that the lateral lemniscus contains both decussated and non-decussated fiber means that each side of the superior olive receives input from both ipsilateral and contralateral ears and allows __horizontal localization of sound__, as detailed below:
 * **Medial** superior olive: receives __excitatory__ inputs from both ipsilateral and contralateral auditory nerves: integrates differential AP-frequency information to determine the difference in __timing__ of a sound arriving at both ears. This allows horizontal localization of the sound stimulus (see (1) in next LO).
 * This is mainly used for horizontal localization of __low-frequency__ stimuli.
 * **Lateral** superior olive: __excitatory__ input from ipsilateral auditory nerve, but __inhibitory__ input from contralateral auditory nerve. Allows comparison of the __intensity__ of sounds from both ears, also allowing horizontal localization (see (2) in next LO).
 * This is only used for horizontal localization of __high-frequency__ stimuli.
 * After the superior olive, the lateral lemniscus runs into the midbrain into the **inferior colliculus**; this seems to be where auditory information is fully integrated in space (horizontal localizations join vertical localizations). Note that since each lateral lemniscus carries ipsilateral/contralateral information, a lesion on one side of the inferior colliculus doesn't result in unilateral deafness.
 * After this, the fibers run up into the **medial geniculate nucleus** in the thalamus; after this, the fibers run to the **primary auditory cortex** in the **temporal lobe**.
 * Understand the two main mechanisms involved in sound localization. When is a difference in intensity used by the auditory system to localize sound? When is time of arrival used? Where and how are these cues encoded in the ascending auditory pathway?
 * For left-to-right localizations:
 * (1) Since the ears are located at two different points in space, a sound stimulus from the left will arrive at the left ear before it gets to the right ear, and vice versa for a stimulus at the right. This timing distinction between what sounds get to which ears first allow a general localization of sound.
 * __Horizontal localizations that depend on timing are done in the medial superior olive__.
 * See Figure 11 in his notes for a diagram on how this works.
 * (2) Also, particularly for high-frequency sounds, much of the sound energy is being deflected by the head itself, meaning that the sound energy that reaches the opposite ear is diminished. Figuring out which sound intensity is higher in which ear can also allow horizontal localization.
 * __Horizontal localizations that depend on intensity are done in the lateral superior olive__.
 * See Figure 12 in his notes for a diagram on how this works.
 * For localization in elevation or AP dimensions: "Spectral cues." The shape of the pinna in the external ear tends to funnel anteriorly- and superiorly-located sounds differently than sounds located posteriorly and inferiorly. This distinction allows localization in the other two dimensions.
 * AP and elevation localizations are evidently done in the dorsal cochlear nucleus, but it doesn't seem to be a point heavily emphasized here.
 * What is the role for the auditory cortex? Understand that auditory cortex is arranged in a tonotopic map.
 * Unknown extent of role. Wernicke's area: deals with speech __comprehension__. Note Broca's area on the other side of the primary auditory cortex (other side of the sylvian fissure) deals with speech __production__. More on this in the next lecture.
 * Tonotopy: neurons carrying lower frequencies are more anterior, while those carrying higher frequencies are more posterior.

=Speech and Aphasia=
 * Appreciate the importance of a comprehensive and systematic mental status examination
 * Whoa. That is SO important. Can I just tell you?
 * Ok, seriously, if you track down the exact deficit you can frequently localize the problem in the brain. It's sort of like doing deep tendon reflexes to localize the radiculopathy. See the last LO, below, for good examples.
 * Specifically, the localization of speech disorders is one of the best-correlated patterns in the brain; although there are always more complicated distributed networks responsible for various higher functions, the connection of specific speech deficits to specific brain areas is pretty good.
 * Recognize the distinction between aphasia and amnesia
 * **Aphasia**: an acquired disorder of language resulting from damage to brain areas that serve a linguistic function.
 * **Amnesia**: impaired local memory with deficient ability to learn new information.
 * These really have little to do with each other. My guess is it's a dumb-third-year-clerkship-mistake-you-don't-want-to-make kind of deal.
 * Know the relationship between handedness and cerebral language dominance
 * Cerebral language dominance: language is lateralized; in most people it's on the left.
 * Note this corresponds __poorly__ with handedness: although 10% of the population is left-handed, about two-thirds of them are left-handed for language (along with 99% of the right-handed people). Take-home is that **if you have a patient with aphasia, look for problems in the left hemisphere.**
 * Note, by contrast, stuff that comes mainly from the __right__ hemisphere:
 * Automatic speech - expletives, angry outbursts etc.
 * Prosody (the inflection of speech with emotion)
 * Singing ability
 * Humor and metaphor
 * The right hemisphere also frequently takes over the function of a damaged left hemisphere.
 * Define the syndrome of aphasia
 * Defined above.
 * Note language is the capacity to communicate using verbal symbols.
 * Note consequently that aphasia - that is, disorders of language - implies nothing about an individual's ability to form thoughts, only to convey them or understand their communication from others using those verbal symbols.
 * Understand the neuroanatomy of Broca's, Wernicke's, conduction, and global aphasia
 * **Broca's aphasia**: lesions are, surprisingly, located in Broca's area (on the frontal cortex above the sylvian fissure). Results in an inability to produce speech, but with good comprehension of speech.
 * **Wernicke's aphasia**: lesions are, shockingly, located in Wernicke's area (on the temporal/parietal cortex right at the end of the sylvian fissure). Results in an inability to comprehend speech, but with an intact ability to produce it (although the speech that is produced is frequently irrelevant or unconnected).
 * **Conduction aphasia**: lesions are located in the arcuate fasciculus (note that Wiki says recent work has also implicated the extreme capsule), a white matter tract that connects Wernicke's to Broca's areas. Results in an odd condition in which speech is both understood and able to be produced, but the ability to repeat or react appropriately to what's heard is impaired.
 * **Global aphasia**: lesions are located both in Wernicke's and Broca's areas, and usually also the fibers that connect them. Results in an inability to either comprehend or produce speech.
 * [Aphasia exam: check for fluent (unlabored and > 6-word phrases) spontaneous speech, auditory comprehension, accurate repetitions (repeat "no ifs, ands, or buts"), and naming common and less common objects. This breaks down the above aphasias fairly well. Note there's a table on the last page of the notes from this lecture with this breakdown.]

=Hearing Loss and Disorders of the Ear=
 * Recognize conductive versus sensory hearing loss on an audiogram.
 * Audiogram: graph of sound intensity vs. frequency. Note that the sound intensity (on the y-axis) is inverted, with low decibels at the top and high decibels at the bottom.
 * The graph charts the ability of first one ear, and then the other, to detect sounds of various frequencies at various intensities. Note you test both conductive hearing and direct vibrational hearing (see next LO).
 * How to tell conductive vs. sensory hearing loss: present a sound through the air (test conduction of the sound through the air in the ear canal), then present the same sound through vibration in the skull (test the ability of vibration in the cochlea to detect the sound).
 * If the ability to sense air-conducted and vibration-conducted sounds are both decreased, that's **sensory** hearing loss.
 * If air-conducted is decreased but vibration-conducted is normal, that's **conductive** hearing loss.
 * Understand the most common causes of conductive, sensory and neural hearing loss.
 * Conductive hearing loss:
 * Otitis media
 * Tympanic membrane perforation
 * Aural atresia (born without ear canal)
 * Otosclerosis (localized bone remodeling disorder)
 * Sensory (cochlea) hearing loss:
 * Presbycusis (age-related hearing loss)
 * Noise trauma
 * Ototoxicity (mainly aminoglycosides)
 * Disease-related (diabetes, hypertension, etc)
 * Genetic factors
 * Neural (8th nerve/central pathway) hearing loss:
 * 8th nerve tumors (recall common is Schwannoma, if bilateral look for NF-2)
 * Multiple sclerosis
 * Neural sarcoidosis
 * Auditory neuropathy
 * Describe the common types of pathology underlying sensory hearing loss.
 * Hair cell loss: presbycusis, noise trauma, ototoxicity, genetic factors.
 * Keep in mind that hair cells are never replaced-- so once they're gone, they're gone.
 * Also keep in mind that sensory hearing loss generally relates to the cochlear amplifier (ie. the outer hair cells).
 * Presbycusis: __symmetrical__, gradual, progressive hearing loss, particularly in higher frequencies. Auditory threshold gets higher and higher; also harder to understand even speech that you can hear. Note that the auditory processing pathways don't age well either (harder to focus on one sound with a lot of other sounds going on).
 * Noise trauma: acute/chronic exposure; causes a 'notch' in the audiogram around 4000 Hz (evidently this is where heard sound is most amplified, thus where the most damage occurs).
 * __Endolymphatic hydrops__: pathological finding in which the endolymph in the cochlea (recall, high K+, low Na+) is abnormal and causes swelling, distorting the normal endolymph compartment. Caused by a wide variety of processes: infections, blocked drainage, inflammatory syndromes, dietary deficiencies, allergies, etc.
 * Causes Meniere's Disease: the ear feels plugged and swollen, patients get spells of severe vertigo and hearing loss: Meniere's Disease.
 * Characteristic audiogram on Meniere's disease: low-frequency loss that comes and goes. But notice that over time it can evolve into other audiogram patterns as well.
 * Impaired inner homeostasis:
 * Basically the stria vascularis is out of whack. And when it is, the potassium gradient that allows the depolarizations that conduct sound (recall "Auditory I, II, & III") is also out of whack.
 * This tends to result in an across-the-board loss (lowered flat audiogram).
 * [Note that asymmetrical hearing loss is most frequently a result of a Schwannoma on the eighth nerve.]

=Vestibular System=
 * Recognize and name the components of the vestibular system.
 * Three semicircular canals (anterior, posterior, horizontal) detect head rotation or angular acceleration.
 * Two otolith organs, the utricle and the saccule, detect linear position/acceleration and the direction of gravity.
 * Note that hair cells transduce vibration into APs in the vestibular system just as they transduce vibration into APs in the auditory system.
 * The fluid that surrounds the organs in the vestibular system: perilymph. Fluid inside the organs: endolymph. (These are described, to some extent, in "Auditory I, II, & III.") The same potassium gradient that keeps the hair cells depolarizing and hyperpolarizing in the cochlea is responsible for them doing the same thing in the vestibular system.
 * The nerves that innervate the hair cells exit into two main nerve branches that feed into the vestibular part of the eighth nerve, which joins up with the auditory part of the eighth nerve and together go into the pons along with the facial nerve.
 * Describe the hair cell and its physiology.
 * Again, partly described in "Auditory I, II, & III". She emphasizes the tapering nature of the stereociliary bundle; there's a structure called the kinocilium on the tallest side of the bundle that dictates the "on" (ie. opened K channels) direction.
 * As in hair cells in the cochlea: movement stretches the K channels open, K flows into the cell, the membrane depolarizes, voltage-gated calcium channels open, calcium enters the cell, and neurotransmitters are released to the nerve underneath.
 * Understand how the vestibular sensors communicate motion information.
 * __Otolith stuff__ (translational position/acceleration):
 * "Otolith:" "ear stone". That about sums it up.
 * Crystals of calcium carbonate (otochonia, effectively a fancy plural of otolith) lie on a membrane called a **macula** in each of the two otolith organs in your head: the shifting of the crystals on the membrane translates into the direction of gravity or linear position/acceleration. Note that the two otolith organs are set up in different orientations (see below) to detect different axes.
 * Note that every hair cell in a given region of a macula have the same polarity-- they're all depolarized by the same direction of motion.
 * However, there's a more complicated pattern of polarity on each organ as a whole. I don't think it's tremendously important but it's on the bottom of the third page in her notes if you're interested.
 * The __utricle__ is shaped like the seat of a chair, lies on the floor of the vestibule, and detects **horizontal and AP** acceleration/position.
 * The __saccule__ is shaped like the back of a chair, hangs on the lateral surface of the vestibule, and detects **superior/inferior** (ie., normally, gravity) acceleration and position.
 * Notice that when you lie down, the utricle picks up gravity and the saccule picks up lateral motion (axes shift). This doesn't disturb your brain at all, which is pretty cool.
 * __Semicircular stuff__ (rotational acceleration):
 * If your head regularly undergoes rotational motion (as ours do) you need a way to tell you're doing it. That's the semicircular canals.
 * There's three perceptible spatial dimensions; we have one canal in each dimension to sense rotation in that plane. Note that they're positioned in a particular orientation in the head (if you tipped your chin down 30 degrees and tilted your head to the side 45 degrees, the canals would roughly correspond to AP, horizontal, and vertical directions).
 * __Ampulla__: swelling at one end of each canal.
 * __Crista__: specialized ridge of epithelium inside an ampulla that contains hair cells.
 * __Cupulla__: membrane-covered clump of hair cells growing out from the crista and dividing the ampulla. As fluid pushes on it, the cupulla and the hair cells (which all have the same polarity of motion) go in one direction or another.
 * Notice that the fluid is pretty inertial and doesn't really move quickly; the bones move around it. For all practical intents and purposes, however, it's the same thing.
 * Note that this system detects __acceleration__-- that is, changes in velocity. It does not detect absolute velocity or position, so if you turn around a couple times, you'll sense the acceleration in your inner ear as you begin to turn but the sustained velocity as you continue to turn isn't sensed there.
 * Notice, however, that your brain generally extrapolates the velocity from the acceleration information.
 * So, how this all works: the vestibular systems on one side oppose the vestibular systems on the other side. The frequency of the firing of the hair cells in a given semicircular canal on one side __relative to__ the firing of the hair cells in the same kind of semicircular canal on the other side determines the sense of angular acceleration as detected by the brain.
 * Head motion towards a given side increases the firing (depolarization) rate of the hair cells on that side.
 * Note that the hair cells on both sides are always firing at a basal rate, which is either decreased or increased depending on the direction of the rotational acceleration.
 * Notice that this means that if the vestibular hair cells on one side of your head stop firing, your brain will interpret this discrepancy in the firing rate between one side and the other as rotation, thus causing **vertigo**.
 * Note further that another response to that sense of rotation is **nystagmus** (eyes beating **away** from the damaged side).
 * I think this actually makes sense if you integrate a few things. Recall that the response to (say) turning your head to the right is that your eyes both smoothly shift left to keep an object in view. Now if your left vestibular nucleus (say) is damaged, your brain is going to think that the preponderance of signals coming from the right sided vestibular nucleus means you're turning your head to the right. This sets off the MLF cascade, which rotates your left eye laterally (to the left, via the abducens nucleus) and your right eye medially (also to the left, via the oculomotor nucleus). Thus you see an eye 'drift' towards the left, with quick saccades (see "Eye Movements I + II") back to the right (and away from the damaged side). Pretty cool.
 * [She didn't discuss it extensively in class but here's the general pathways for all you gunners out there:]
 * The utricles project to the lateral vestibular nucleus and head down from there to the limbs and postural reflexes.
 * The semicircular canals project to the medial and superior vestibular nuclei, which give rise to the MLF running to the nuclei of the ocular muscles.
 * The utricles, saccules, and semicircular canals all project to the inferior vestibular nucleus, which projects to the vermal cerebellum.
 * Discuss the three vestibular motor reflexes.
 * **Vestibulo-ocular reflex**:
 * As described here, a three-neuron arc (keep in mind that elsewhere it's described as having an obligate stop in the abducens nucleus; at press time, I hadn't heard from Dr. Foster): from the hair cells in the vestibular system, a neuron goes to the vestibular nucleus, where it synapses onto another neuron that goes to the oculomotor nucleus; that neuron synapses onto another neuron that goes to the actual oculomotor muscles.
 * (This does beg the question of why the third neuron is there at all (the efferent neuron from the vestibular nucleus could just synapse right onto the oculomotor muscle). The reason seems to be that the third neuron is there is so that the eye can send feedback to the oculomotor nucleus to adjust the motion if it's imperfect. As discussed in the next lectures, two-neuron reflexes are vanishingly rare in the body, presumably for this reason.)
 * It keeps the gaze steady during head movement, as by now extensively discussed.
 * The vestibulo-ocular reflex is the shortest reflex arc in the body (needs to be quick and precise).
 * __Vestibulo-colic reflex__: causes the head to be maintained in balance on the top of the head when you're moving.
 * __Vestibulo-spinal reflexes__: involve all muscles in limbs: keep stable/upright, balance.

=Motor Systems I, II, & V= [Note that Motor Systems I, II, and V are taught by Dr. Caldwell (whose LOs for all three lectures are below), while Motor Systems III and IV are taught by Dr. Ojemann (whose LOs follow in the next section).] __Notes__
 * [Note that (recall from "Neurogenesis, Migration, and Postnatal Development") during development, muscle fibers start out innervated by more than one neuron; these neurons 'compete' for the connection to the muscle fiber, and the most successful competitor (the one that can most successfully cause the muscle fiber to depolarize with one AP signal) is kept at that muscle fiber.]
 * [Note that if a motor neuron's connection to a muscle fiber is damaged, the adjacent motor neurons sprout connections to replace them.]
 * [Note that there's a somatotopic body map within the lower motor neurons in a given ventral horn region; arms are in a different place than shoulders, flexors are in a different place than extensors.]

**__LMNs and Spinal Cord Integration__**

 * Describe the key elements of the stretch reflex. Include the sensory ending, the sensory neuron, and the motor neuron. In addition to the motor neurons innervating the muscle in which the spindle resides (homonymous motor neurons), name two other sets of neurons innervated by the afferent endings.
 * Stretch reflex: a two-neuron, monosynaptic reflex.
 * Afferent from muscle spindle (sensory ending) to dorsal root ganglion (sensory neuron) to dorsal horn: __A-alpha__ nerve fiber (also called, here, Ia afferents).
 * This synapses in the dorsal horn on dendrites from the motor neuron (an **alpha motor neuron**, the largest variety, with a cell body in the ventral horn), which then sends the appropriate contractile motor signals out back to the muscle from which the stretch signal was received (the name for the muscle from which the sensory input was received is the **homonymous** muscle).
 * Note that the stretch reflex is the only example of a two-neuron (monosynaptic) reflex in the body. Pretty much everything else has some kind of interneuron in its arc.
 * Note also that a muscle spindle (stretch) signal from a spindle in a given muscle will trigger a contractile response in __every__ motor neuron that innervates that muscle, which magnifies the physical response immensely.
 * He went on about this at some length, and it's actually pretty interesting: each stretch-carrying A-alpha fiber is going to synapse about 9 times on each of the 300 motor neurons that innervate the muscle in question.
 * In addition, you can get it synapsing on all of the motor neurons that innervate the synergistic muscles nearby that muscle, __and__ also all the inhibitory interneurons that inhibit the __opposing__ muscle's motion.
 * So in addition to stimulating the motor neurons in the homonymous muscle, A-alpha fibers from stretch receptors also stimulate the motor neurons in the supporting muscle and stimulate inhibitory interneurons that inhibit the opposing muscle.
 * Additionally, the A-alpha fibers run up the dorsal column medial lemniscus system to the nucleus gracilis or cuneatus.
 * Finally, they also run over to a spinal nucleus (**Clark's nucleus**) that in turn projects the __spinocerebellar tract__ up to the __inferior cerebellar peduncle__ to coordinate movement and position.
 * To sum up: one A-alpha fiber synapses tens of thousands of times on multiple systems (at least 5 that we've described here: excitation of homonymous motor neurons, excitation of nearby supportive motor neurons, inhibition of nearby antagonistic motor neurons, dorsal column tract, and Clark's/spinocerebellar tract).
 * Note that, as you might expect, interneurons in the motor control system can be both excitatory or inhibitory; this has as its corollary that all movements involve excitation of synergistic muscles and inhibition of antagonistic muscles.
 * Another take-home message from Dr. Caldwell on all this: the same proprioceptive signals used in the reflex system serve as input for a variety of complex computational processes and are used in complex behavior.
 * What is the function of gamma motor neurons?
 * Discussed in the next LO.
 * Compare and contrast muscle spindles and Golgi tendon organs. Include parallel versus series arrangement, the type of information they transmit (force vs. length), and the type of innervation they make on motoneurons.
 * __Muscle spindle__: small structures, randomly distributed throughout the muscle and oriented __parallel__ to the large muscle fibers. They're covered by connective tissue sheaths and contain small muscle fibers of their own that run from one end of the spindle to the other. The motor neurons that activate these muscle fibers - called **gamma** **motor neurons** - synapse onto each end (not the middle) of the fibers. An A-alpha afferent comes into the spindle and wraps itself around the center of one of the fibers to send stretch info out.
 * The spindle has a __fusiform__ shape (wide in the middle, narrow at the ends)-- thus the muscle fibers inside the spindle are called "intrafusal fibers," while the muscle fibers outside the spindle ('traditional' muscle fibers that contract bones towards each other) are called "extrafusal fibers."
 * The intrafusal fibers are, as mentioned, set up in __parallel__ with the extrafusal muscle fibers.
 * When the extrafusal muscle is stretched, the intrafusal muscles are stretched with it. This opens the stretch receptors wrapped around them, which in turn send APs up the A-alpha neuron innervating them.
 * The gamma motor neurons function to keep the intrafusal muscles taut when the extrafusal muscles contract; if the extrafusal muscle is contracted around the spindle, the spindle deforms and shortens, and the intrafusal muscles - rather than going slack - contract to maintain themselves taut.
 * The gamma and alpha motor neurons (innervating intrafusal and extrafusal muscles respectively) have some degree of interplay (called the alpha-gamma coactivation): when you go to do a movement, you predict the appropriate degree of contraction and send signals to the gamma motor neurons to contract the spindles to the appropriate length, as well as signals to the alpha motor neurons to contract to an appropriate degree. When the spindles are contracted to some greater or lesser extent than this length (ie., the initial assumption was wrong and the extrafusal fibers contract more or less than expected, deforming the intrafusal fibers from their preset lengths), the stretch feedback can inform the motor centers in your brain to correct the initial assumption before you use too much or too little strength.
 * Example from Dr. Caldwell: you go to pick up a glass mug of beer for a swig. As it turns out, it's really a lightweight plastic mug of beer. You contract your muscle spindles to a degree that would be appropriate for the contraction necessary for lifting the weight of a glass mug. You start to exert a fair amount of force in the surrounding muscles, which contract to a greater extent than they would if the mug was actually glass. This deforms the muscle spindles from their preformed positions, telling the brain that the degree of muscle contraction that you thought was necessary is way too large. This allows you to modulate, on the fly, the degree of alpha motor contraction that you're using (and to reset the spindles to a different degree of stretch) to avoid spilling beer all over yourself.
 * Essentially: the A-alpha fibers from muscle spindles transmit information about how long a given muscle is, and how that stacks up with how long it was expected to be. Various sites in the brain can then figure out if they want to change the degree of force to correct the movement or not.
 * Golgi tendon organs: Found in the tendon itself at the site of its attachment to bone.
 * These are found in __series__, not parallel to fibers. What this means: they're not deformed along with the muscle, since they're not embedded within the muscle.
 * These respond to either active (muscle is contracting) or passive (non-contracting muscle is being extended by another contracting muscle) stretch.
 * Note the contrast here: while muscle spindles send more signals when the muscle's tensed and less when it's extended (according to how much the intrafusal fibers have to shorten to maintain their tautness), Golgi tendon organs send more signals whether the muscle is tensed or extended (either way, force is being extended towards the middle on the tendons).
 * The nervous impulse from Golgi tendon organs is carried to the dorsal root ganglia by a different species of **A-alpha** afferents (here, also called the Ib neurons). In response to stretch, the A-alpha afferents fire, synapsing on inhibitory interneurons in the spinal cord that inhibit the motor neurons of its homonymous muscle.
 * That is: stretch/activation of Golgi tendon organs sends inhibitory signals to the muscle whose tendon they're on. Note that this is much less complicated than the interplay of the muscle spindle with its homonymous muscle, and that the direction is also reversed-- while the stretch reflex in the muscle spindles prompts an excitatory response in its muscle, stretching the Golgi tendon organs prompts an inhibitory response.
 * This serves a couple of functions: one seems to be to protect the tendons from over-contraction of muscle. The more important one, however, is detecting relative position and tension in muscle and being able to stop a muscle contraction at a specific point.
 * Dr. Carry's thought on this: Imagine you want to hold a double-edged razor blade between your fingers (sharp edges face the finger pads). You need to be able to modulate exactly the degree of contraction you're exerting and inhibit that contraction at a specific amount of tension.
 * Note that muscle spindle reflexes are a two-neuron excitatory arc and golgi tendon organ reflexes are a three-neuron inhibitory arc.
 * What is the “size principle” for recruitment of motor neurons and what is the functional significance of this? Give examples of the problems that would arise if the size principle did not apply for very low force exerted and very high force exerted.
 * Note that a "motor unit" is one motor neuron and all the muscle fibers that it innervates; the motor unit size is the number of muscle fibers it innervates. Note that each muscle fiber, as mentioned several times by this point, is innervated by only one motor neuron. Note also that the variety of motor unit sizes in muscles spans from very few to very large; when you're sending the signals to contract a muscle, you start by recruiting the small-size motor neurons and work up to the big-size motor neurons. This allows you to stop at the desired level of contraction (ie., to approximate a graded response) and is called the __size recruitment principle__.
 * If you didn't have this, you wouldn't be able to do small or gentle movements with a small degree of contraction signal; presumably, it would also mean that at the higher levels of contraction signals, you couldn't be assured of getting a big response with that extra level of contraction.
 * Specify the signaling that is involved in the flexor withdrawal reflex and the crossed extensor reflex (consider only the spinal cord and the periphery, not higher centers).
 * Flexor withdrawal/crossed extensor reflex: when one leg gets flexed reflexively, the other leg has to be extended at the same time (think what happens in your legs when you step on a tack-- the one that's hurt flexes up, the other extends to support your weight).
 * Signaling: nociceptive fibers run into interneurons in the spinal cord: these excite the flexors and inhibit the extenders in the damaged leg, and excite the extenders and inhibit the flexors in the opposite leg. See figure 8 in the handout.

**__II: Locomotion__**

 * What is the “hierarchical” organization of the motor system?
 * Higher motor centers (in the cortex and brainstem) send signals to central pattern generators (in the spinal cord, see below), which send signals to the effector organs (muscles), which affect the environment.
 * In practice, it's not really all that hierarchical because there's so many feedback mechanisms built into the system. The proprioceptive feedback from the muscles affect the central pattern generators; the feedback from the environment affect the CPGs and also the higher centers; the CPGs affect higher center control. When you can cut the spinal cord and still stimulate CPG generation in the limbs below that point with sensory input alone, that's not a traditional hierarchy (the upper levels aren't even involved).
 * But note that even with all the sensory elements in the legs taken away, the signals for muscle movement can still arise from the top down.
 * What are central pattern generators and where are they located?
 * CPGs control rhythms of regular, repetitive muscle contractions and relaxations. Walking is a good example; so is breathing.
 * For walking: what you're looking at is flex-extend, flex-extend alternation in the legs.
 * CPGs: they're in the spinal cord. They seem to largely consist in coordinating the interplay between flexor and extensor regions in motor neurons in different parts of the ventral horn. The flexor neurons are going to inhibit the extensor neurons and vice versa. The setup whereby the flexor neurons and extensor neurons swap activity back and forth, and inhibit whichever one isn't active, is the guts of the CPG machinery.
 * What are the consequences of lesions of the spinal cord and brainstem on locomotion in experiments in cats? What is the midbrain locomotor center? Describe the experiment in which this center was stimulated in a cat on a treadmill. In general, what is the role of sensory input in the performance of rhythmic, automatic motor behavior such as walking?
 * If you transect the brainstem between the superior and inferior colliculi at the front of the midbrain, the cat __can still walk__ if the neurons in a particular area of the midbrain (the midbrain locomotor region) are stimulated. Greater intensity of the stimulus leads to different gaits (walk, trot, gallop).
 * Note that sensory inputs have an enormous amount of influence on this CPG regulation as well-- a cat whose spinal column is transected at the thoracic levels will still walk with its hind legs when it's placed on a moving treadmill, and a cat whose spinal column is transected at the high cervical levels can still walk with all four legs when it's placed on the same treadmill.
 * Along the same lines, sensory input is continually controlling locomotion-- if the top of your foot encounters an obstacle while it's swinging to the front while walking, you will automatically raise your leg and alter your gait to get over it.
 * What are the implications of understanding central pattern generators for the future treatment of spinal cord injury?
 * As I see it, there are two main take-homes here. One is that CPGs can arise directly from the locomotor system in the midbrain; the other is that CPGs can also arise directly as a consequence of sensory input. Either one has possible therapeutic consequences.
 * In principle you could stimulate the fibers from the mesencephalic locomotor system to control the CPGs and generate movement. In addition, paraplegics with only partially severed spinal cords are sometimes able to be retrained to walk to some extent if you put them in harnesses and place them on a treadmill-- this seems to retrain the inhibitory interneurons in the CPGs in the spinal cord to rewire themselves around the injured area.
 * What brainstem nuclei contribute to the ventromedial descending control of spinal motor neurons?
 * Vestibular nuclei (vestibulospinal tract, controlling axial musculature)
 * Pontine/medullary reticular formation (reticulospinal tract, also controlling axial musculature)
 * Superior colliculus (colliculospinal tract, controlling head and eye movement).
 * Note that medial tracts tend to control medial musculature.
 * What is the function of the rubrospinal tract?
 * Movement of distal limb musculature, particularly the **digits**.
 * Note also that the corticospinal tract (the other main lateral descending tract) and the rubrospinal tract seem to function as backups of each other-- damage to one will impair function for a while, but eventually the other one will partially take over and restore some function.
 * Describe the somatotopic organization of the primary motor cortex. What areas of motor cortex are there in addition to primary motor cortex and what functions do they serve?
 * As in the somatosensory cortex, there's a body map in the motor cortex; it's similarly shaped (more motor control in the face, hands, and tongue, just like there's more sensory input from those areas as well).
 * However, note that the very specific somatotopic organization in the SS cortex (one contiguous area of the cortex senses one contiguous area of the body) isn't preserved with as much fidelity in the motor cortex. There are disparate areas within the hand section, for example, that activate the same muscle, and stimulation of a single area doesn't just stimulate a single muscle either. Similarly, going deep through the cortical layers contacts the axons of multiple muscles as well. All of this to say that the concept of "barrels" doesn't quite hold for the motor cortex to the same degree that it does in the SS cortex.
 * Instead, it's organized around __functional areas__-- the muscles that create movement utilizing a single joint, for example, are all in the same area, but within that area they aren't neatly separated into individual muscle regions in the motor cortex.
 * Non-primary motor cortex: the **premotor cortex** (Brodmann 6, anterior to the primary motor cortex:
 * Two areas: ventral/lateral premotor cortex and supplemental premotor cortex (more dorsal/medial).
 * Both of these have their own body maps.
 * In general, they control more complex movements:
 * Ventral/lateral premotor cortex:
 * (1) Responds to external cues (green light means hit the gas and ease off the clutch, red light means hit the brake and downshift).
 * (2) Controls the process of conforming hands to grip objects.
 * Supplementary premotor cortex:
 * More involved in __planning and rehearsing__ motor tasks. Note that as the task becomes learned and routine, the activity in this cortex subsides.
 * What is the evidence that the cortical somatosensory and motor representation of the body is dynamic rather than static?
 * If you partially denervate a hand muscle, there ceases to be activity in that particular part of the motor/sensory cortices. However, after a few weeks, nearby regions of the cortex controlling parts that are still active will begin to invade or take over the portion of the cortex that used to sense/control the denervated muscle.
 * (if you recall that synapses' continued existence are dependent on neurotrophin talk back and forth between the pre-synaptic terminal and the post-synaptic membrane, and that after an axon disconnects from a muscle, another nearby axon takes over and innervates that muscle, this whole process makes more sense. At least it seems likely to me.)
 * Note that Dr. Caldwell said that long-range axonal growth to take over these regions doesn't seem to happen; instead, previously hidden and dormant connections become activated. Looks like most things innervate most nearby things-- they just aren't used until they're needed.
 * Experiments in monkeys: cut dorsal roots to denervate the entire arm and hand regions; the region controlling muscles of the head and face takes over the regions of arm and hand. Note that it's only the face, never the shoulder (on the opposite side of the hand region)-- it's unclear why the specificity.
 * ..So this makes you wonder if the old saw about heightening other senses when you lose your vision or hearing or what have you is actually partially true; maybe the areas of the SS cortex that control vision are taken over by the regions that control hearing, touch, etc, and make those senses more capable? Probably not, but it's an interesting idea.
 * More evidence: after the face areas of the SS cortex took over the arm regions in an amputee, different areas of the patient's face sensed different areas of the missing arm- a body map of the missing limb had been created on the facial area that grew in to take its place.
 * More evidence: using mirror boxes, when a patient with phantom limb pain looked at the reflection of their remaining hand as if it was their lost hand, by unclenching the intact hand, they were able to relieve the phantom pain in the missing hand.
 * More on plasticity: adults who have gone blind and learned Braille have an increased amount of the motor cortex dedicated to their fingers. If they use two fingers to read Braille, the lines distinguishing the two parts of the SS cortex devoted to those fingers begins to get blurry.
 * Stroke: "C-I therapy" (constrained-induced):
 * (1) Constrain the limb with intact motor ability so that it can't be used.
 * (2) Use the limb with non-intact motor ability to do repetitive tasks throughout the day for 6 hours.
 * This results in a lot of improvement in post-stroke capacity.
 * Take-home here: lots of evidence for plasticity in the adult human cortex:
 * With atrophy, nearby cortical regions invade and take over;
 * With use, cortical regions expand (bulge outwards, don't invade other areas);
 * After damage (stroke), function can regenerate through use.
 * Where in the pathway from the periphery to the cortex could these dynamic changes take place?
 * Point here: there's somatotopic organization in the thalamus and spinal cord. Dynamic changes that we think of as occurring solely in the cortex can also occur here.

=Motor System III: Cerebellum= [Lots and lots of deep dark material here. Proceed with caution.] [Middle cerebellar peduncles: Incoming connection from pons to cerebellum.] [Inferior cerebellar peduncles: Incoming connection from medulla to cerebellum. ] [Superior cerebellar peduncles: Outgoing connection from cerebellum to midbrain.]
 * Describe the functional organization of the cerebellum. Include a listing of the efferent and afferent connections of the various zones and regions.
 * Zones:
 * Spinocerebellum (aka paleocerebellum):
 * Vermis:
 * __Input__: Spinal, vestibular, visual afferents (mossy fiber input); also from the contralateral olive (climbing fiber input); both via the inferior cerebellar peduncle.
 * __Output__: Purkinje output to the fastigial nucleus; from there it goes to the **medial descending tracts** (reticulospinal tract, vestibulospinal tract, colliculospinal tract; see "Motor System V") on both sides (note, however, that Dr. Ojemann also said that the ipsilateral cerebellum tended to control ipsilateral motion, and that gait/axial control weren't well-localized).
 * __Function__: Posture, locomotion, and gaze (axial control of movement).
 * Paravermis:
 * __Input__: Spinal afferents only (mossy fiber input) via the dorsal spinocerebellar tract that arises from Clark's nucleus and the cuneocerebellar tract, both through the inferior cerebellar peduncle. Also input from the contralateral olive (climbing fiber input), going up into the inferior cerebellar peduncle as well.
 * __Output__: Purkinje output to the interposed nucleus; from there it goes out the superior cerebellar peduncle to the contralateral red nucleus; from there the fibers decussate again down the **lateral descending tracts** (rubrospinal tract).
 * __Function__: Fractionated control of movement of the extremities (fine motor control of the digits) on the ipsilateral side.
 * Corticocerebellum (aka neocerebellum or lateral zones):
 * Input: Corticopontine fibers, mostly from the visual and motor cortex, come down through the internal capsule to synapse in the ipsilateral pontine nucleus; pontocerebellar fibers arise from there and decussate, coming through the middle cerebellar peduncle to form mossy fiber input to the contralateral corticocerebellar region.
 * Output: out to the __dentate nucleus__; from there out and decussating in the superior cerebellar peduncle, then through the red nucleus to the contralateral VA/VL thalamus. The thalamus, in turn, sends fibers to the same-sided motor cortical regions, which in turn send decussating fibers back down to the original side of the cerebellum.
 * Function: Planning and initiation of movement.
 * Vestibulocerebellum (paleocerebellum, flocculonodular lobe):
 * Input: Axons from the vestibular nuclei; also some fibers direct from the eighth cranial nerve itself.
 * Output: Purkinje cells go directly to the ipsilateral vestibular nucleus (no synapses in deep cerebellar nuclei)
 * Function: Also helps control axial motor control, as well as the vestibulo-ocular reflex.
 * What is the general functional role of the flocculo-nodular lobe?
 * The __FN lobe__ integrates vestibular information into axial motor functions dealing with equilibrium and balance, and also controls the vestibular reflex (constancy of visual field during head movements).
 * What is the general functional role of the vermal and paravermal regions?
 * The __vermal region__ controls axial motor functions dealing with the coordination of posture, locomotion, and gaze, while the __paravermal region__ controls coordination of distal motor functions.
 * What is the general functional role of the neocerebellum (the large lateral hemispheres)?
 * The __lateral hemispheres__ control initiation, planning, and timing of movement (coordinating with the motor cortex).
 * Describe the connections of the cerebellar deep nuclei.
 * **Dentate nucleus**: corticocerebellum outputs fibers that go into the dentate nucleus. From there, they output to the superior cerebellar peduncle and the contralateral VA/VL nucleus of the thalamus.
 * **Interposed nucleus**: paravermis outputs fibers that go into the interposed nucleus. From there, they go up in the superior cerebellar peduncle to the contralateral red nucleus, then come down again in the lateral descending tracts to control fine motor movement.
 * **Fastigial nucleus**: vermis outputs fibers that go into the fastigial nucleus. From there, they go to the medial descending tracts to control gaze, posture, and locomotion.
 * Note all deep nuclei afferents, as presented here, are ipsilateral.
 * What types of deficits arise from cerebellar damage?
 * Problems with synergy (ie ataxia or uncoordinated movement), equilibrium, and tone.
 * Features:
 * (1) No weakness, no sensory damage.
 * (2) Small lesions in the cerebellar cortex generally have little effect- need to lesion large portions of the cortex or the deep cerebellar nuclei to produce large detriments.
 * (3) **Cerebellar defects always produce ipsilateral symptoms**.
 * Mnemonic for symptoms of cerebellar lesions: __HANDS Tremor__
 * **H**ypotonia
 * **A**taxia
 * **N**ystagmus
 * **D**ysarthria
 * **S**tance/gait
 * **Tremor** (when initiating and sustaining movement)
 * What are the cellular constituents of the cerebellar cortex?
 * __Molecular__ layer (outermost, relatively few cell bodies; made up mainly of dendrites from the Purkinje cell layer and axons from the granule cell layer)
 * __Purkinje cell__ layer (next deepest, sends extensive dendritic branches up into the molecular layer)
 * Purkinje cell: big cell body with a really broad but thin dendritic tree that's oriented perpendicularly to the length of a given folium of the cerebellum; the dendritic trees from many Purkinje cells stack like a deck of cards down the folium's length. Note that the axons from Purkinje fibers are the only cerebellar axons that leave the cerebellum (all cerebellar output is carried on Purkinje fibers).
 * __Granule cell__ layer (next deepest; recall that these migrate deep from being on the external surface layer after ~ 2 years of life)
 * Granule cells: cell body sends out an axon that runs parallel to the length of the folium, intersecting lots of Purkinje cells, but only having contact with a given Purjinke cell at one point). Tons and tons of these.
 * Below that: white matter.
 * Below that: deep cerebellar nuclei.
 * Which cells of the cerebellar cortex have inhibitory actions?
 * The __Purkinje fibers act to inhibit efferent nerve fibers arising from the deep nuclei__. Note that these nuclei are getting excitatory direct innervation from climbing fibers and mossy fibers; the Purkinje fibers are acting as a kind of delay loop.
 * Note also that stellate cells and basket cells (not discussed in class), when activated by the parallel fibers, inhibit nearby Purkinje cells. This has the effect of inhibiting an inhibition and thus promoting deep nucleus activity.
 * What inputs to the cerebellum are carried by climbing fibers?
 * 2 types of input nerves to the cerebellum: climbing fibers and mossy fibers.
 * Climbing fiber input: come from the **contralateral inferior olivary nucleus**, ascend in the inferior cerebellar peduncle, innervating all three function zones.
 * What they do: they each make lots of contacts with a given few Purkinje cells. One AP up a climbing fiber will generate __lots and lots__ of depolarization in its Purkinje cells (a complex spike).
 * This seems to be an **error signal**.
 * Note that this means that if an input to the cerebellum doesn't come from the inferior olive, it's a mossy fiber-carried signal and not a climbing fiber-carried one.
 * [Note the mossy fiber input, by contrast, does not come from the olivary nucleus but arises from several different sources depending on the functional zone they innervate:]
 * Vestibular input: goes to vestibulocerebellum
 * Spinal input: goes to spinocerebellum
 * Pontine input: goes to corticocerebellum
 * [Mossy fibers: synapse to excite granule cells. A given granule cell will synapse to excite each Purkinje cell it innervates __just once__ (only one point of contact, as opposed to climbing fiber input), generated a simple spike.]
 * Describe the role of the climbing fiber input in motor learning. Explain the sequence of events that occurs in the cerebellar cortex during visual-motor learning (like that demonstrated in class).
 * Something similar to long-term potentiation occurs when there's simultaneous activation of both climbing and mossy fiber input, except it's more like long-term depression.
 * When you're making an errant movement, the climbing fibers send signals that, in combination with mossy fiber depolarizations, will weaken synapses responsible for those movements relative to other synapses.
 * Visual-motor learning: the cerebellum adjusts quickly to the visual feedback of an unsuccessful movement via the inferior olivary complex and recalibrates the motion via the climbing (in) and Purkinje (out) fibers. If that movement is in turn unsuccessful, the cerebellum re-adjusts. In an individual with a cerebellar lesion, no adapting to a failed motion is observed. The visual part of this entails putting glasses on the subject that cause their vision to be skewed off, allowing them to correct for it, and then removing the glasses (causing the previously corrected movement to be inaccurate) and allowing the cerebellum to adjust the motion again back to its original configuration.
 * Rather like the muscle spindles being pre-set to a given length in anticipation of how much force will be required, the cerebellum seems to set itself for an anticipated motor coordination and sends signals to correct the motion if the anticipated coordination doesn't come off right.

=Motor System IV: Basal Ganglia=
 * Give a general description of the role of the basal ganglia in motor control.
 * Planning and initiating movement; the notes mention that virtually all non-traumatic metabolic disruption of motor control involves a problem in the basal ganglia.
 * [Note that, unlike in the cerebellum, lesions in the basal ganglia (like those in Huntington's chorea, Parkinson's, and hemiballismus) result in contralateral symptoms-- they're involved with the ipsilateral thalamus and cortex, which in turn are involved with contralateral sensation and motion.]
 * What is the major source of input to the basal ganglia?
 * Frontal cortical areas, coming into the striatum.
 * [Note that the two parts of the striatum receive distinct types of innervation. The putamen gets its afferent signals from the __sensory/motor cortices__ and affects mainly the VA/VL region of the thalamus. The caudate nucleus gets its afferent signals from the __frontal association cortex__ (we don't really know what this is yet) and affects mainly the dorso-medial thalamus.]
 * Is the output of the basal ganglia inhibitory or excitatory?
 * Recall that the dorsoventral patterning in the prosencephalon gives rise to distinct regions of neurotransmitter-oriented neurons (eg. the output neurons of the diencephalon and cortex are, generally, glutamatergic).
 * The output neurons that arise in the basal ganglia are GABA-ergic and inhibitory, thus the functional output of the basal ganglia is inhibitory.
 * More specifically, the globus pallidus internus fibers - the output of the basal ganglia - inhibit the thalamus.
 * Note that the interneurons __inside__ the basal ganglia are still mainly inhibitory but can be excitatory as well (see __subthalamic nucleus__, below).
 * [Four parts of the basal ganglia:]
 * **Caudate nucleus/putamen** (the **striatum**) (generally GABA-ergic)
 * **Globus pallidus** (generally GABA-ergic)
 * **Substantia nigra** (generally dopaminergic)
 * **Subthalamic nucleus** (generally glutamatergic)
 * Describe the “direct path” from the cortex to basal ganglia and eventually back to cortex (which synapses are excitatory and which are inhibitory).
 * I think we need to go more into detail than that to understand what's going on. There seem to be two main pathways by which the cortex influences activity in the basal ganglia, the direct (D1) and indirect (D2) pathways.
 * The basal ganglia, as you might expect since they're GABA-ergic, serve primarily an inhibitory function. Specifically, the internal globus pallidus is the major output nucleus, sending inhibitory fibers to the thalamus to inhibit signals to the cortex to promote movement (also inhibits cognitive/associational thalamic signals).
 * To reiterate: the tonic state of the globus pallidus internus (and thus the tonic output state of the basal ganglia) seems to be inhibition of thalamic pathways involved in movement initiation and cognitive association.
 * To modify this tonic state, the cortex sends signals to the caudate and putamen (the striatum); these signals are then passed on to the globus pallidus internus through one of a couple of pathways to either promote the GPI's inhibitory activity or to inhibit it (and thereby promote the generation of signals from the thalamus to the cortex).
 * The "__direct path__" mentioned above involves the following:
 * (1) The cortex sends excitatory, glutamatergic signals to the striatum.
 * (2) The striatum sends inhibitory, GABA-ergic signals to the globus pallidus internus. (note that it also inhibits the subthalamic nucleus, which is promoting globus pallidus internus activity.)
 * (3) These signals inhibit the GPI's tonic inhibition of the thalamus.
 * (4) The thalamus now is free to send excitatory, glutamatergic signals to the cortex.
 * Note that the direct-pathway neurons have D1 dopamine receptors.
 * [The other, "indirect," pro-thalamic-inhibition pathway looks like this:]
 * (1) Cortex sends excitatory signal to striatum
 * (2) Striatum sends inhibitory signals to the __globus pallidus externus__, which is normally sending inhibitory signals to the __sub-thalamic nucleus__, which in turn is normally sending excitatory signals to the globus pallidus internus (which is sending inhibitory signals to the thalamus).
 * So the cortex promotes an inhibitor (striatum) of an inhibitor (GPE) of a promoter (STN) of an inhibitor (GPI) of the thalamus.
 * Decoded, you're __promoting thalamic inhibition__ (reducing the thalamus's ability to send excitatory, glutamatergic signals to the brain).
 * Note that the indirect-pathway neurons have D2 dopamine receptors.
 * [The idea behind dopaminergic switching is that you have two pathways as just described, one D1-activated, pro-movement/thalamic signals, and one D2-activated, anti-movement/thalamic signals. Dopamine excites D1 receptor-carrying neurons and inhibits D2 receptor-carrying neurons. By varying the level of dopamine produced by the substantia nigra, the basal ganglia can flip between either the pro-thalamic input or anti-thalamic input quickly. This becomes particularly important when the system goes wrong, as in Parkinson's Disease, below.]
 * Note that dopamine seems to be involved with encoding an error about your prediction of reward. Unexpected reward = dopamine release, reinforcing the action that produced the reward.
 * [Note also that the physical junction between the caudate and the putamen (where the internal capsule doesn't separate them) is called the **nucleus accumbens** and receives afferent innervation from the limbic system. This seems to be heavily involved with addiction and reward processing. We'll talk about it more later.]
 * Why does a stroke in the subthalamic nucleus cause hemiballismus? What type of stimulus (depolarizing or hyperpolarizing) would you predict would be used for the “deep stimulation” treatment of Parkinson patients?
 * Hemiballismus: one half of the limbs are flying around in involuntary, large-amplitude movements.
 * Recall that the subthalamic nucleus promotes activity of the GPI, which in turn inhibits movement. A stroke in the subthalamic nucleus would cause a lack of excitation to the GPI, causing a relative decrease in GPI inhibition of motion on one side of the brain, allowing random motion to occur without inhibition.
 * Notes from Dr. Ojemann on Parkinson tremors:
 * Stimulation, it turns out, works mainly by exciting the myelinated fibers in the vicinity. Myelinated fibers in the vicinity of the STN are the gaba-ergic afferents from the GPe. In the GPI, the afferents from the striatum (Gabaergic) apparently have a greater "weight" than the glutamatergic input from STN, so that when stimulation stimulates them to release their transmitter, the net effect is inhibition of the neuronal somas that project from the nucleus to targets. In the end, the result is much like if you created a lesion in the nucleus: less output from GPi to thalamus, or STN to GPi. As I said in lecture, a better name might be "Deep Brain Inhibition"....hasn't caught on yet.
 * Describe the character and probable cause of Parkinson's disease.
 * Resting tremor, bradykinesia, rigidity; difficulty initiating movements and tremulous speech patterns.
 * Etiology: loss of dopaminergic neurons in the substantia nigra.
 * Recall that dopamine promotes the D1 (direct) pathway that encourages movement signals from the thalamus and inhibits the D2 (indirect) pathway that inhibits those movement signals. If you eliminate dopamine, more emphasis goes to the indirect (inhibitory) pathway, inhibiting movement.
 * Note that giving dopamine at the wrong dosage can create the opposite problem (dyskinesia).
 * What is the genetic cause of Huntington’s Disease and what areas of the basal ganglia are affected?
 * Huntington's, as mentioned a couple times by now, is an autosomal dominant disease mediated by CAG repeats on chromosome 4.
 * Notes from Dr. Ojemann on areas affected:
 * Huntington's does seem to preferentially decrease the activity of the D2 receptor pathway that goes from striatum to GPe to STN to GPi to thalamus. The chemistry of each means this is less inhibition of thalamus by GPi, and hence, chorea. It may be the principal neuron affected is the cholinergic interneuron in the striatum that has the opposite effect of dopamine: it normally EXCITEs the indirect pathway neurons (those also possessed of D2 receptors) and INHIBITS the direct (D1 receptor, movement promoting pathway). The overall result in any event is hyperkinesia: too much movement.

=Eye Movements I + II= [High visual acuity only occurs in the central 5 degrees of our vision: the fovea.] [Conjugate movement: eyes move in the same direction, to the same extent, at the same time.]
 * What are the four types of eye movements?
 * (1) Tracking/smooth pursuit (keeping an object on the fovea).
 * This involves the visual cortex and the cerebellum.
 * The maximal rate of smooth tracking is about __50 degrees__ of vision per second.
 * (2) __Saccades__ (bring an object onto the fovea); rapid, ballistic eye movements. Involved in acquisition of a target.
 * This involves the visual cortex and the superior colliculus (organizing maps of visual space relative to where you are).
 * Note you can also use it to "track," sort of, an object moving too fast to track smoothly. The maximal rate of "tracking" (actually just moving the eyes in the predicted pattern of motion of the target) is 700 degrees per second.
 * (rapid small eye movements, called microsaccades, have to do with the fact that the eyes are continually jumping around, to a very small extent, all the time. This is actually extremely important; if an image stays exactly still on the retina, it disappears. The jumping allows an image to stay more or less put.)
 * (3) __Optokinetic nystagmus__ and the __vestibulo-ocular reflex__:
 * OKN: smooth, slow tracking of one target, then rapid saccadic acquisition of another.
 * Note that the direction of rapid acquisition is what dictates the nomenclature of the nystagmus-- if the eyes drift right to follow one object and then snap left to acquire another, it's called __left-beating__ nystagmus. Note nystagmus refers to both a normal reflex and a pathological phenomenon.
 * VOR: as mentioned previously, the ability to keep a target in the fovea while the head is moving.
 * (4) __Vergence__: moving the fovea to an object closer (convergence) or farther away (divergence).
 * What is the difference between conjugate and vergence eye movements?
 * Conjugate: eyes are moving in the same absolute direction in space (left or right); notice this also means that they're moving in opposite directions relative to midline (one is turning medially and one is turning laterally with respect to the nose).
 * Vergence: eyes are moving in opposite absolute directions in space (one's going left, the other's going right); notice this also means that they're moving in the same direction relative to midline (both turning medially or laterally with respect to the nose).
 * What is a saccade and how is it generated?
 * A saccade is a 'jumpy,' rapid eye movement that brings the foveas to a particular point in space (as coordinated by the superior colliculus).
 * How it works: something determines you want to look at a particular point in space, either auditory (the leaves rustle in the jungle and you want to see if it's a tiger) or visual (something's moving really quickly and you've calculated it's about to be at a particular point in your visual field), or both (your wife and her mother are arguing and you want to look at the wall //right now//). There are two ways to get your ocular muscles to get you to look at that particular point.
 * One is through the superior colliculus, which fires off a signal to the __paramedian pontine reticular formation__; this sends motor signals to the cortex that jump your foveas to exactly that point.
 * Another is an area in front of the pre-motor cortex (the __frontal eye field__) that signals the motor neurons in the motor cortex (through the reticular formation) that do saccadic movements. Note that the frontal eye field also activates the superior colliculus (the two tracts aren't normally independent).
 * Note that saccades can 'track' faster movement than smooth tracking, presumably because saccadic tracking depends on a different, and less precise, set of calculations than smooth tracking (rather that figuring out where an object is going to be in a microsecond, you're figuring out where it's going to be in ten microseconds, or something analogous, and jumping your eyes to where you anticipate it's going to be).
 * [Superior colliculus: Visual map of space superimposed on an auditory map of space superimposed on a somatosensory map; involved in integrating all that junk.]
 * [Note that saccadic movements are lost in Huntington's disease.]
 * What are smooth pursuit eye movements, how fast can they be, and why are they limited to relatively slow speeds?
 * Smooth pursuit: use analysis of position, direction of movement, and speed to figure out where the object's going to be a second later and move the eyes to keep the object on the fovea. Note that this is a continuous centering process (the object never leaves the fovea).
 * As mentioned, can be up to about 50 degrees per second.
 * They can't go faster than this because there's a certain delay built into the information processing; info has to go up to the visual cortex, get processed, get input from the cerebellum, and go back out to the optic nerve again.
 * Describe the control of the VOR for a person sitting on a chair that is rotated to the right (clockwise rotation if you look down on them from above).
 * [He emphasized MLF-lesion clinical pathology a lot: you'll see an inability of an eye to __medially__ rotate to keep track of an object, but the patient can still __converge__ medially (no lesion on the third cranial nerve itself).]
 * Head rotation is detected by semicircular canals on the right; this info is carried by the right vestibular nerve to the right vestibular nucleus. From the **right** vestibular nucleus, the MLF decussates and goes up the brainstem into the **left** abducens nucleus in the pons to stimulate a motor neuron and initiate __lateral eye movement of the left eye__. Interneurons from the left abducens nucleus take over the MLF and immediately re-decussate, going a little higher up to the **right** oculomotor nucleus in the midbrain, from which a motor neuron can extend to initiate __medial eye movement of the right eye__.
 * (note that Dr. Foster described a simpler VOR in her lecture involving only three neurons: to the vestibular nucleus, to the oculomotor nucleus, to the muscle. I would place my bets on Dr. Caldwell here but I could be wrong.)
 * (note also that the MLF doesn't necessarily only involve eye movements originating in signals from the vestibular nucleus- evidently it also involves conjugate gaze when the head is still.)
 * Note that there are also MLF interneurons from the vestibular nucleus that go down to control neck muscles. Note also that the left vestibular system is also activated, but in the inhibitory direction, to inhibit lateral movement of the right eye and medial movement of the left eye. Note further that there are neurons that talk between these systems. Note finally that we don't have to know any of that for the exam but it's good rounding-out knowledge.
 * What is internuclear ophthalmoplegia? Describe what you observe for the patient, how you can decide if the medial rectus motor neurons and/or nerve are intact, and what is the most likely structure that is affected.
 * Internuclear ophthalmoplegia: Interruption of the coordination of lateral/medial movements through the MLF. Note that this seems to be independent of head rotation. This results in that clinical pathology just mentioned where the eye that's supposed to track laterally does fine, but the eye that's supposed to track medially can't do it. Test medial convergence- should be normal in IO, but abnormal if there's a 3rd cranial nerve or medial rectus muscle lesion.
 * Breakdown of likely etiology by age:
 * In a child: brainstem tumor
 * In a younger adult: multiple sclerosis
 * In an older adult: brain infarct.
 * [Nomenclature: the internuclear ophthalmoplegia is named for the eye that can't go medial. That is, if a patient's asked to look to the right and the left eye can't medially rotate, that's called a left internuclear ophthalmoplegia.]
 * [Note that third nerve palsies tend to affect the eyelid and pupil in addition to the muscles.]
 * What is nystagmus? Give examples where nystagmus occurs.
 * As mentioned, nystagmus entails the eyes drifting in the same direction (smooth tracking) and then snapping back in the opposite direction (saccade). Also as mentioned, nystagmus is both a normal process (tracking objects disappearing from field of visual then acquiring a new object to track) and a pathological one (can't stop it from happening all the time).
 * Traumatic head injury, foramen-magnum tumors, Chiari malformations, etc, can all cause downbeat nystagmus (eyes rise slowly, then beat downwards).
 * Note you can artificially induce nystagmus but putting cold water in the ears.

=Cerebellum/Basal Ganglia= [This really seemed to be a rehash of the prior lecture.] [4 general questions to be able to answer for a given structure:] >> cerebellar vermis and hemispheres
 * (1) What is the source of the input?
 * (basal ganglia: input goes into putamen/caudate [striatum] from cortex.)
 * (also basal ganglia: input into globus pallidus internus from striatum and subthalamic nucleus.)
 * (cerebellum: input comes in through the middle [cortical input from the pontine nuclei] and inferior peduncles [largely spinocerebellar and inferior olivary input].)
 * (2) Where is the output going?
 * (basal ganglia: output goes from the globus pallidus internus into the ipsilateral thalamus, which in turn projects to the contralateral cortex.)
 * (cerebellum: output goes into the superior cerebellar peduncle [to thalamus and red nucleus, from lateral zones and paravermis respectively], and also down the lateral descending tract [from vermis] and to the vestibular nucleus [from flocculonodular lobe].)
 * (also cerebellum: notice that most of the output from the cerebellum is going out through [inhibitory] Pukinje fibers onto deep cerebellar nuclei.
 * (3) What information or function is being carried?
 * (basal ganglia: see "Motor Systems IV: Basal Ganglia.")
 * (cerebellum: see "Motor Systems III: Cerebellum.")
 * (4) Where do the input and outputs cross the midline? This last item is especially important for the cerebellum because each cerebellar hemisphere deals with the ipsilateral side of the body but must communicate with the contralateral cortex (what is the pathway from the cortex to the cerebellum and back from the cerebellum to the cortex?).
 * (basal ganglia: from and to ipsilateral cortex. Note that the ipsilateral cortex generally deals with the contralateral lower body.)
 * (cerebellum:)
 * to vermis/paravermis: ipsilateral spinocerebellar (from Clark's column), contralateral inferior olive
 * from vermis/paravermis: evidently ("Cerebellar deficits" in Dr. Ojemann's "Motor System III: Cerebellum notes) mainly ipsilateral descending structures (in the case of paravermal regions, evidently by way of the contralateral red nucleus).
 * to lateral zones: contralateral cortex (via pontine nuclei/middle cerebellar peduncle).
 * from lateral zones: contralateral cortex (see specific pathway several LOs down).
 * to flocculonodular lobe: ipsilateral vestibular nerve/nucleus
 * from flocculonodular lobe: bi?lateral vestibular nuclei (see "Cerebellum" diagram in Caldwell's notes at this point).
 * Be able to locate and identify each of the following structures:
 * vermis, hemispheres, flocculus, nodulus
 * cerebellar peduncles (inferior, middle, and superior)
 * primary fissure, anterior lobe, posterior lobe, flocculonodular lobe
 * inferior, middle, and superior cerebellar peduncles
 * deep cerebellar nuclei (dentate, interposed, and fastigial)
 * inferior olivary nucleus (also called simply, inferior olive)
 * pontine nuclei
 * head, body and tail of the caudate nucleus
 * the putamen
 * globus pallidus
 * substantia nigra
 * subthalamic nucleus
 * (go crazy there.)
 * Trace the circuit interconnecting the cerebral motor cortex and the cerebellar cortex. Identify the thalamic relay nucleus for this system. What is the minimum number of synapses from a cerebellar Purkinje cell (output cell of the cerebellar cortex) to the cerebral cortex?
 * The corticocerebellum projects to the dentate nucleus; from there, more fibers project through the superior cerebellar peduncle, decussating, to the contralateral VA/VL thalamus; it then goes from there to the cortex on the same side. From that side of the cortex, down the internal capsule into the same-sided pontine nuclei; from there, it decussates through the middle cerebellar peduncle back into the original side of the corticocerebellum.)
 * Purkinje cell to dentate nucleus: 1 synapse. Dentate nucleus to contralateral VA/VL thalamus: 1 synapse. VA/VL thalamus to cortex: 1 synapse. Total: 3 synapses.
 * What is the source of climbing fibers reaching the cerebellum?
 * Contralateral inferior olive.
 * Describe the interlocking circuits of the basal ganglia including the caudate, putamen, globus pallidus, subthalamic nucleus and substantia nigra. Which of these contains dopaminergic cell bodies?
 * Circuits: see "Motor Systems IV: Basal Ganglia."
 * Substantia nigra contains dopaminergic cell bodies.

=Ophthalmology I + II= Notes:
 * Locate the structures of the eye, and identify the seven nervous pathways of the visual system.
 * [note that Dr. Sargent mentioned that one of his test questions was going to concern correctly labeling the eye structures.]
 * **Vitreous humor**: gluey, viscous material inside the orb in its main chamber; contains a latticework of collagen and hyalunoric acid holding it firmly in place. With age, this latticework can start to collapse and the vitreous humor liquifies.
 * Note that the vitreous humor has to be avascular (can't have blood or vessels in the way)-- but that means that if you get an infection in the vitreous, the eye usually has to be taken out. Dr. Sargent's expression is that it's an "agar plate" for growing bacteria if given the chance.
 * **Aqueous humor**: watery material inside the eye's anterior chamber, taking oxygen and nutrients to and from the avascular structures therein.
 * **Pupil**: the negative, empty space in the iris that allows light to enter the lens.
 * **Iris**: Colored, donut-shaped portion of outer eye; contains pigments (melanophores). More importantly, relaxes or constricts to change the diameter of the pupil (the hole of the iris donut) and allow more or less light through the pupil.
 * As you know, sympathetic stimulation dilates the pupil by relaxation of the iris. You can also do it with a parasympatholytic (ie. atropine), but this also affects the ability of the eye to focus (see ciliary muscles, last LOs).
 * Color stuff:
 * Blue eyes: not much melanin or connective tissue.
 * Brown eyes: lots of melanin and connective tissue.
 * Green eyes: lots of melanin but not much connective tissue.
 * Gray eyes: lots of connective tissue but not much melanin.
 * Notice that skin pigmentation often corresponds to the degree of pigmentation of the retina on the eye exam.
 * **Cornea**: "Window in the front." Clear; contains lots of parallel layers of keratinocyte stroma but few cell bodies to interfere with light passage. Refracts light into the eye.
 * **Sclera**: tough white part covering the surface of the eye except for the cornea (cornea is continuous with sclera).
 * Note that the sclera is continuous with the **dura** of the brain; the sclera and cornea can be thought of as the dura of the eye.
 * **Lens**: The focusing apparatus. Sits right behind the iris/pupil. Divides the aqueous humor-containing segment of the eye from the vitreous humor-containing segment.
 * **Anterior chamber**: between the lens and the cornea; contains the aqueous humor.
 * **Retina**: photosensitive inner lining of the vitreous chamber. Irreplaceable if damaged.
 * **Uvea**: vessel- and pigment-containing layer between the inner retina and outer sclera. 3 layers:
 * (1) **Choroid**, behind the retina; this nourishes the outer part of the retina (towards the outside world; the inner retina nearer the optic nerve are supplied by the blood vessel accompanying the optic nerve).
 * (2) **Iris** (see above)
 * (3) **Ciliary bodies** (see below)
 * **Conjunctiva**: folded mucosal layer between the sclera and the eyelid. Secretes mucoprotein that adheres to the surface of the cornea. This means that water (tear layer, see below) won't adhere to the cornea.
 * Understand basic optics, including mechanism[s] by which rays from objects focus upon the retina.
 * Light is refracted in through the cornea and hits the (convex) lens, which converges that light onto the retina. Changing the shape of the lens makes it more or less convex to allow perfect convergence onto the fovea: flattening it allows distance vision, bunching it allows near vision.
 * Hyperopia: far-sighted (extra-small eye, rays converge behind the fovea).
 * Myopia: near-sighted (extra-large eye, rays converge before the fovea).
 * Recognize the source of, and function of, the three components of the tear film.
 * Inner layer: Mucoprotein on cornea from conjunctival goblet cells (see above).
 * Middle layer: Water from the lacrimal gland; contains lysozymes and oxygen to deter infection.
 * Outer layer: Lipid layer from oil-secreting glands in the tarsal plate of the eyelids.
 * Explain the two functions of the ciliary body [part of the uvea].
 * (1) It makes aqueous humor in the space behind the iris, but in front of the lens. The humor percolates from there into the rest of the anterior chamber of the eye, and then leaks out from the **trabecular meshwork**.
 * (2) Circumferential muscles attached to ciliary bodies can relax to flatten the lens (make it less convex) or contract to allow it to bulge (make it more convex). The name for this latter phenomenon - the act of visual focusing on a nearby object by increasing the convexity of the lens - is **accommodation**. When you're looking at something up close, you need to increase the convexity of the lens; when you're looking at something far away, you need to decrease its convexity.
 * With age, the ciliary muscles can still contract, but the lens itself can't adjust-- it seems to have lost some of its elasticity.
 * In open angle glaucoma, describe the a] mechanism for increased intraocular pressure; b] the mechanism and nature of visual loss; c] the symptoms; d] three diagnostic signs or exam findings.
 * __Mechanism__: Recall that the ciliary bodies make aqueous humor, which circulates through the anterior chamber and drains out through the trabecular meshwork. If the trabecular meshwork gets clogged up (as can happen with age), the aqueous humor builds up and increases intraocular pressure.
 * Alternatively, the iris can (in some cases) occlude the trabecular meshwork when it's dilated (this is called narrow-angle glaucoma).
 * Also alternatively, there's a genetic condition in which a mesodermal tissue doesn't get resorbed and sticks in the way of the trabecular drainage (congenital glaucoma).
 * In the latter two cases, you can treat it by making a hole in the mechanical obstruction (penetrate the mesoderm or cut the iris).
 * __Visual loss__: The increased intraoptic pressure compresses the capillaries that feed the axons of the optic nerve, causing the nerve fibers to atrophy. **The peripheral axons go first** (axons from the peripheral, non-fovea, retina).
 * __Diagnostic signs__:
 * Asymmetric sizes ("cupping") of the optic discs on each side.
 * Increased intraocular pressure (measured with, no shit, a plunger you stick onto someone's cornea)
 * For ophthalmologists: can measure peripheral visual field with various equipment.
 * Note also that in kids, increased intraocular pressure can cause really big-looking eyes. Cute and glaucomatous.
 * __Symptoms__: Note that, generally, open-angle glaucoma is **insidious**-- it's very hard to detect the gradual loss of vision, especially peripheral vision, in one eye (no pain). So it's kind of up to the docs to find it, since the patient isn't going to usually be complaining about it.
 * __How you treat it__: help the outflow at the trabecular level or stop the production at the ciliary body level.
 * List the etiologic causes of the "red eye."
 * __Conjunctivitis__: foreign body, infection (bacterial, viral, fungal-- often herpes virus)
 * __Irritants__: smoke or fumes, dry eyes, eye strain, etc-- something is causing the blood vessels to dilate.
 * __Toxins__: drugs, alcohol
 * __Iritis__: usually linked to photophobia; look for cloudiness in the aqueous humor.
 * __Glaucoma__ (causing swelling in the vessels)
 * Understand the significance of strabismus and amblyopia.
 * Amblyopia:
 * "The fancy word for not seeing: it means one eye doesn't see very well." More specifically, central acuity of one eye is impaired.
 * Common problem
 * Note that if you patch the eye that has limited vision during development, the other eye can correct itself. Note also that greater neural plasticity when at an early age means that it's easier (and quicker) to do this in infancy/early childhood.
 * Stabismus:
 * Crooked eye, where one eye is looking in an odd direction.
 * Purpose of correcting crooked eyes that can see okay: to develop depth perception and binocular function, as well as cosmetic. Not to improve vision.
 * He seemed to make a big deal out of the fact that these two things are distinct (ie. you can have stabismus but still see okay, or can have straight eyes with amblyopia).
 * List causes or mechanisms of vision loss.
 * Straight from notes:
 * Forced upper eyelid closure
 * Corneal swelling/opacity
 * Aqueous humor murkiness due to inflammation
 * Acute glaucoma
 * Cataracts (lens opacity)
 * Note lack of stimulation of the visual centers of the brain, unilaterally or bilaterally, results in atrophy and degeneration of those areas of the brain.
 * [Note that you can do corneal transplant with relative ease because it's avascular (thus no antibody reaction.]
 * [Cataract: any opacity in the lens. Caused by diabetes, age, inherited, injury, medications, breaking down proteins, causing inflow of fluid into the lens, causing it to swell and become opaque. Note that if it's particularly advanced, the liquid can escape from the lens and cause glaucoma.]
 * [Also retinal detachment: the retina tears; with age, the vitreous humor liquidifies and can flow out; this separates the retina from the back of the eye. Causes flashes of light, lots of floaters. If the macula comes off, complete lack of central acuity in that eye. Note that this separates the retina from its blood supply on the back of the eye (choroid?); equivalent to an infarct in the retina, which will result in permanent loss of vision.
 * (can fix this by laser treatment to seal to back of the hole)
 * [Age-related macular degeneration: macula (area containing fovea/cones) degenerates with age (or lots of exposure to UV light, particularly in early age). Peripheral vision kept; central acuity lost (opposite of glaucoma). Also can be due to neovascularization in the choroid that leaks, pooching up the macula.]
 * [Diabetes: causes microaneurysms in the small eye vessels on angiogram.]
 * [Recall that malignant HTN causes wool-shaped spots, flame-shaped hemorrhage, and papillary edema.]
 * [Blunt trauma: hemorrhage in retina or subconjunctiva, dislocated lens; if the bone around the eye is broken, the muscles running along that break can stop working properly. Note that blood can fill up the trabecular meshwork and cause glaucoma. Often blunt damage and hemorrhage will resolve by itself with rest.]
 * [Lacerating trauma: have to be really careful about the introduction of microorganisms or foreign bodies into the eye.]

=Parkinson's Disease=
 * Know neurochemistry of Parkinson's disease.
 * Damage to the dopaminergic neurons of the substantia nigra; this inhibits the direct pathway (stimulated by dopamine) and promotes the indirect pathway (inhibited by dopamine), resulting in overall suppression of motor stimuli from the thalamus to the cortex. Pathways are listed in "Motor Systems IV: Basal Ganglia."
 * In Parkinson's, the dopamine depletion is particularly profound in the putamen (recall, more responsible for controlling movement) than the caudate.
 * Know rationale for drugs to improve clinical symptoms.
 * Er.. because they work better than a poke in the eye with a stick?
 * Know drugs in drug list:
 * L-DOPA and Carbidopa (Sinemet)
 * 1) L-DOPA: dopamine precursor.
 * 2) Carbidopa: inhibits the metabolism of L-DOPA to prolong its action
 * 3) Dr. Freed: this is still the mainstay, best drug for Parkinson's treatment. When L-DOPA stop working, none of these other drugs are going to work either.
 * 4) However, note L-DOPA promotes dyskinesia at high levels.
 * Bromocriptine (Parlodel)
 * Pergolide (Permax)
 * Pramipexole (Mirapex)
 * Ropinirole (Requip)
 * Cabergoline (Dostinex)
 * 1) These five are __dopamine receptor agonists__; most Parkinson's patients are started with these before L-DOPA is prescribed.
 * 2) Note side effects: nausea, hallucinations, sudden onset of sleep.
 * Amantadine (Symmetryl)
 * 1) (flu med that causes dopamine release; may be a glutamate agonist)
 * Trihexyphenidyl (Artane)
 * Benztropine (Cogentin)
 * Diphenhydramine (Benadryl)
 * 1) (these three are anticholinergic agents, which help balance the ACh/DA imbalance in the striatum)
 * Selegiline (Eldepryl)
 * 1) (MAOI: dopamine is broken down by monoamine oxidases, so inhibiting that breakdown can promote higher levels of dopamine.)
 * Tolcapone (Tasmar)
 * Entacapone
 * Know the pathways of excitation/inhibition in the basal ganglia.
 * See above and "Motor Systems IV: Basal Ganglia."

=Movement Disorders=
 * Be able to name and distinguish between the most common types of involuntary movement disorders.
 * __Hyperkinetic__ movement disorders:
 * **Tremor**: __rhythmic__ oscillatory movement: caused by alternating or synchronous contraction of antagonistic muscles.
 * **Chorea**: irregular, jerky, dance-like movement, that moves from one body part to another.
 * Mostly caused by Huntington's disease; can occur in kids or pregnant women, or in lupus patients.
 * **Tics**:
 * The lots-of-adjectives section:
 * Brief, intermittent movements or sounds.
 * Sudden, abrupt, transient.
 * Repetitive/coordinated.
 * Vary in intensity and frequency
 * Can resemble normal movements or sounds
 * **Dystonia**: sustained muscle contractions in any of a variety of muscle groups. (hands, eyelids, neck, vocal folds); can occur with irregular tremor.
 * **Mycolonus**: sudden, brief, shock-like movements.
 * (dystonia/myoclonus: rarer.)
 * __Hypokinetic__ movement disorders:
 * Mostly, Parkinsonism (Parkinson's and similar disorders like Lewy body disorder):
 * Resting tremor, rigidity, bradykinesia, postural instability.
 * Have a rudimentary understanding of the anatomy and pathophysiology of movement disorders.
 * Generally, problems with the basal ganglia and/or cerebellum. With basal ganglia, note that there's generally scant MRI/imaging evidence of damage.
 * Know the major clinical manifestations and treatment modalities for Parkinson disease, essential tremor, and Tourette syndrome.
 * **Essential tremor**:
 * Usually familial; insidious onset and worsens with age.
 * Exact pathogenesis is unknown, but seems to involve oscillating muscle signals in thalamus or the cerebellum.
 * Clinical features: tremor occurs with posture or action (not, generally, at rest). They usually affect upper extremities more than the lower parts of the body.
 * 75% of essential tremor patients respond well to alcohol (tremor subsides).
 * More conventionally, can also treat with anti-epilepsy drugs or beta-blockers.
 * Surgically, can use thalamic deep brain stimulation or can take part of the thalamus out.
 * **Tourette Syndrome**:
 * Pediatric-onset only (under 16)
 * Motor and vocal tics that are at least partially suppressible
 * Associated with OCD/ADHD.
 * Treatment: if the tic isn't too severe, generally avoid medications, but treat OCD/ADHD if co-present. Use education/support groups as much as possible.
 * If meds are necessary: clonidine (no idea why), SSRIs (also helps OCD); can use neuroleptics, sedatives, or dopamine-depleting drugs.
 * Know how to distinguish between Parkinsonian and essential tremor.
 * Resting tremor, bradykinesia and rigidity are signs of Parkinson's, but not of essential tremor.
 * Understand the difference between idiopathic Parkinson disease and atypical parkinsonian syndromes. What are the implications for treatment and prognosis?
 * Idiopathic: This is Parkinson's disease as we've learned it so far.
 * Atypical: Worse prognosis than Parkinson's (7-10 year survival); only 10-15% respond to dopaminergic therapy. Two:
 * (1) Progressive supranuclear palsy: Parkinson's plus abnormal eye movements (eyes become fixed towards end of disease; lots of falling).
 * (2) Multiple system atrophy: Cerebellar symptoms (ataxia), autonomic symptoms (fluctuating blood pressure).

=Movement Disorders CPC= (no LOs here, just some notes:) Go look at: [] for examples of all gaits and just generally a nice video breakdown of the neuro exams. You'll need QuickTime. Note Romburg test: with a cerebellar lesion, you fall towards the side with the lesion.

=Vision I, II, & III=
 * [5 types of cells in the retina:]
 * (1) Photoreceptor cells (about 100 million rods, about 8 million cones)
 * (2) Bipolar cells (ON-bipolar, OFF-bipolar)
 * (3) Horizontal cells
 * (4) Amacrine cells (function under discussion but not extensively mentioned here)
 * (5) Ganglion cells (bundle up to form the optic disc/nerve).
 * Note that types 1-4 respond to stimuli and release NT in a graded fashion; ganglion cells are the only AP-producing cells in the retina.
 * Note also that all these cells are organized kind of backward: light has to go through the ganglion cells, amacrine cells, horizontal cells, and bipolar cells to actually get to the photoreceptors. Some theories about why this happens (protect the photoreceptors, mirror in and contain light in dim conditions, etc). Note that these structures are more or less clear and don't diffuse light to any appreciable extent.
 * [Distribution of rods and cones:]
 * In fovea: no rods, only cones.
 * Everywhere else (aside from the optic disc): scant cones, lots of rods.
 * Note no cones receptive to blue light are in the fovea (lens preferentially focuses green and red light).
 * Note also that in the periphery, there are lots of rods and cones connected to a single ganglion cell (large receptive fields); in the fovea, there's a smaller number (small receptive field). Note that the photoreceptors in any given ganglion cell's receptive field can have either an excitatory or inhibitory net effect on that ganglion cell. More about this a couple of LOs down.
 * What are the major steps in phototransduction in the outer segments of rods?
 * Light strikes retinal (vitamin A derivative); retinal undergoes a conformational change (to all-//trans//), which in turn changes the conformation of its opsin protein.
 * The changed conformation of the opsin activates a G-protein receptor that activates phosphodiesterase (PDE). PDE lowers the concentration of cGMP in the receptor cell.
 * The lowered cGMP causes cGMP-gated channels that are tonically open to close, thus hyperpolarizing the cell and __decreasing__ the neurotransmitter (glutamate) release from the photoreceptor.
 * That decrease in neurotransmitter release can have a number of effects based on what kind of cells the NT is being released onto.
 * Note something that's really key here: **there's lots of glutamate released from photoreceptor cells in the dark; when light hits any photoreceptor cell, that photoreceptor cell stops releasing glutamate until the light stimulus goes away**. This is the starting point for everything that comes later (and there's a lot that comes later), so make sure you know it.
 * What are the receptive field properties of retinal ganglion cells?
 * Again, in the fovea, they're generally very small (few cones to one ganglion cell). In the periphery they can be quite large (many rods/cones to one ganglion cell).
 * Here's the beginning of the tricky business.
 * Ganglion cells have "donut-shaped" receptive fields. They're set up with a center region (the hole of the donut) and a surround region (the donut of the donut), each of which has rods or cones that make up their input. The amount and color of light coming into either, or both, of these regions influences what input ultimately winds up coming into the ganglion.
 * There are two general kinds of ganglion cells. One gets excited by light coming into its center and inhibited by light coming into its surround (**ON-center**); the other gets inhibited by light coming into its center and excited by light coming into its surround (**OFF-center**).
 * Note a theme: __the reaction to light of the surround region of any receptive field opposes the center region's reaction to light__.
 * Note also a terminology and quick memory point: ON- or OFF-center refers to where light has to hit to stimulate the field, either in the center or off of it.
 * How does this work, and what determines whether a ganglion is ON-center or OFF-center? The answer to both questions lies in the fact that **__bipolar cells__** __are the elements that connect the photoreceptors in the center of the receptive field to the ganglion cells__.
 * [ok, this is going to be a simplification: we're going to assume (a) that we're not talking about color vision at all (just straight-up light vs. dark perception by rods), and (b) that we're talking about a one-receptive-field, one-bipolar cell deal (ie. probably in the fovea). The fact that these two things are sort of mutually exclusive (if you're not seeing color, you're probably in the periphery, but if you've got a small receptive field, you're probably in the fovea) we're also going to ignore with the cavalier attitude of the true academic.]
 * Bipolar cells, as the name implies, can respond to light - that is, the cessation of glutamate from the photoreceptors - in one of two ways. This is another of those fundamental concepts you're just going to have to know for the rest of it to make sense:
 * ON-center bipolar cells are __depolarized (release neurotransmitter) by the **absence** of photoreceptor neurotransmitter__ (ie. when light hits the photoreceptor). ON-center cells are therefore depolarized with a central light stimulus.
 * OFF-center bipolar cells are __depolarized (release neurotransmitter) by the **presence** of photoreceptor neurotransmitter__ (ie. when no light hits the photoreceptor). OFF-center cells are therefore depolarized with a central dark stimulus.
 * So the bipolar cell in the center of the receptive field (the hole in the donut) can either be excited or inhibited by the glutamate released from a photoreceptor.
 * How the surround inhibits the center: **horizontal cells** connect the photoreceptors in the periphery to the central photoreceptor.
 * Photoreceptor glutamate (released more in the __dark__) __depolarizes__ horizontal cells, causing them to release GABA onto that central photoreceptor membrane (hyperpolarizing it, inhibiting the release of glutamate from the photoreceptors onto the bipolar cell).
 * Thus __more__ light causes __less__ GABA release on the central synapse (which in turn will tend to depolarize it and make it easier to release glutamate).
 * Whatever kind of bipolar cell is in the middle there, the __release of neurotransmitter onto it__ from the central photoreceptor will be **promoted by light in the surround** and **inhibited by dark in the surround**.
 * This illustrates another interesting theme: the only thing that changes from an ON-center receptive field to an OFF-center one is the bipolar cell. The actions of everything else - the photoreceptors, the horizontal cells, the ganglion cells - stays constant. In other words, __all the action in determining the response of a receptive field to light is in the response of the bipolar cell to glutamate released by the photoreceptor__.
 * Let's go through this and make sure it makes sense.
 * All photoreceptors react to light in the same way (light = hyperpolarization, resulting in less glutamate release; dark = depolarization, resulting in more glutamate release).
 * All horizontal cells react to photoreceptor glutamate in the same way (release GABA onto the central synapse to inhibit its release of NT).
 * All ganglion cells react to bipolar cell release of neurotransmitter the same way (fire APs to the optic nerve).
 * The only thing that changes is the bipolar cell's response to glutamate secreted by the photoreceptor.
 * I'm trying to abstract this out to where it makes sense intuitively. Bear with me, I'm going to try and explain why each element of this system is here:
 * We want to be able to detect light; thus we have __photoreceptors__.
 * Light in the surround always promotes release of glutamate in the center. The release of glutamate in the center normally happens when there's dark in the center. Thus, light in the surround enhances dark in the middle.
 * Vice versa for dark in the surround (always enhances light in the middle).
 * This is set up this way because __we're not actually interested in sensing light or dark__. We're interested in seeing light __and__ dark; we're interested in sensing the difference between them. The horizontal cell setup enhances ON-center cells' ability to see central light with peripheral dark and OFF-center cells' ability to 'see' central dark with peripheral light.
 * This is why we have the basic setup (inhibitory __horizontal cells__ impacting a central synapse): to sense differences in light intensity.
 * But then why do we have two kinds of bipolar cells? Think about this for a minute. If all you're sensing is difference, that's great, but you need to be able to tell where the difference is. Is the light in the center or in the periphery? This is important-- if you can't localize where it's light and where it's dark, you can't localize nearby predators (or prey), either.
 * So, you want certain fields to fire when it's dark in the center and there's light on the periphery and others to fire when it's light in the center and there's dark on the periphery so that you can localize where the light is relative to the dark.
 * This is why we have __bipolar cells__ (ON-center ones tell light-center, dark-periphery, OFF-center vice versa): to localize the light difference. Rather than setting it up so that you have "reverse photoreceptors" that release NTs when they're exposed to light, you just use the regular ones and switch the wiring around so that the NT stimulates excitation rather than inhibition in the line connecting the photoreceptor to the ganglion cell.
 * Finally, we need a way to get the impulse from the bipolar cell to the brain-- thus the __ganglion cell__.
 * As you might expect from a system set up to preferentially detect light __contrast__, both ON-center and OFF-center fields will respond more (fire more APs through the ganglion cell) if the center stimulus is reinforced (ie. center darkness for OFF-center fields) while the peripheral stimulus is absent (ie. peripheral light for OFF-center fields). So ON-center fields will fire more when there's light in the center and dark in the surround, while OFF-center fields will fire more when there's dark in the center and light in the surround. I refer you to p. 183 in the notes for a good, succinct diagram of this.
 * To sum: if you see a light region next to a dark region, the light region next to the dark looks more bright than a light region of equal intensity that's not next to a dark region. Vice versa with dark regions next to light regions.
 * Note this becomes significant in, say, X-rays.
 * If there is no difference between the light conditions in the center and the surround, the response of the center of the field mildly dominates the response; ie., in total darkness, OFF-center fields will still fire a little faster, despite the inhibition coming from their surround, and ON-center fields will not fire much, despite the excitation coming from their surround.
 * Yet another important concept (which he unsubtly suggested it would be good for our grade to heed): **removing an inhibitory stimulus, whether in the center or the periphery, results in a "rebound" response that prompts a transient, rapid burst of excitation**.
 * So if you shine light directly into the center of an OFF-center field and then shut it off, you'll get a burst of firing when you shut it off.
 * Likewise, if you shine light onto the periphery on an ON-center field and then shut it off, you'll get a burst of firing when you shut it off.
 * Again, refer to p.183's diagram for illustrations.
 * Note receptive fields in __retinal ganglion cells__ are not sensitive to the orientation or shape of light (is the light a circle? a Christmas tree? an upside-down Christmas tree? etc). In the simple cells of the cortex, you begin to develop sensitivity to light shape/orientation (more on this below), but it's not there at the level of the retina.
 * What are color-opponent ganglion cells?
 * The eye contains three photopigments to cover the color spectrum: red, green, and blue. Each given cone responds to one of them. Note that Wiki says it's more like yellow, green, and violet. I propose a third system with fuchsia, phthalo, and cyan.
 * But note that a given cone __can't detect wavelength accurately__. That's because wavelength is encoded in the glutamate response of the cell to the light, which also encodes the stimulus intensity. So what you need is the relative information between two or more cones (with a pure-red stimulus at 559 nm wavelength, you get a much stronger stimulation of red photoreceptors than green receptors, and none at all from blue receptors, regardless of the total intensity) to puzzle out wavelength (color) from intensity (brightness).
 * How we set this up: we use receptive fields again. It's similar to the simple on-off light perception that we modeled earlier with rods.
 * You can have RED-GREEN receptive fields (also called LONG-MIDDLE for the wavelengths of red and green): excited by red in the middle and inhibited by green in the surround, or excited by green in the middle and inhibited by red in the surround, or inhibited by red in the middle and excited by green in the surround, or inhibited by green in the middle and excited by red in the surround.
 * Also have BLUE-YELLOW receptive fields: excited by blue in the middle and inhibited by red and green (red + green = yellow.. you reluctant artists) in the surround, or whatever other combination you care to name, as above.
 * **Color-opponent ganglion cells**, then, are the ganglion cells that are connected to and serve as the output tracts of these multicolor receptive fields.
 * Note that most color-blindness involves an absence, or an abnormal form, of a photoreceptor's photosensitive elements. The most common (red-green color-blindness) involves the green receptor having a peak absorption that lines up with the peak absorption of the red receptor.
 * Where is color processed in the cortex?
 * [General notes on optic processing precede the actual answer here.]
 * Eyes -> lateral geniculate nucleus (LGN) -> primary visual cortex in the occipital lobe via the optic radiations.
 * Recall that each LGN receives __contralateral__ directional input (left visual field goes to right LGN, though from both the left and the right eyes).
 * Note that this is a slightly different concept than we're used to with decussation-- it's not the part of the body that corresponds to the organization of the decussation, it's the region of the sensory field.
 * Note also that the inversion of the image onto the retina means that although the left visual field goes to the right LGN, the right sides of both retina go to the right LGN.
 * In passing, recall also that the visual field on the retina is inverted in both up-down and left-right directions from the actual visual field.
 * I suggest checking out Dr. Tollin's slide "Visual defects" to get a sense of what different lesions in different tracts in the primary visual pathways will do. Note that the lesion in the optic radiations is in a location called "Meyer's loop" that corresponds to the upper visual fields.
 * Note that __there's no mixing of eye-of-origin anywhere in the pathway from the retina to the cortex__-- left eye fibers are always distinct from right eye fibers, even after they decussate and join up.
 * Specifically, in the six layers of the VPL nucleus, contralateral eye fibers are in layers 1, 4, and 6, while ipsilateral eye fibers are in layers 2, 3, and 5.
 * Note that this stops once you get to the higher levels in the cortex. See below under ocular dominance columns and binocular areas.
 * Note, similar if tangential to the LO, that there's another distinction between the layers of the VPL:
 * Layers 1 + 2 receive axons from the **magnocellular ganglion cells**.
 * Layers 3 through 6 receive axons from the **parvocellular ganglion cells**.
 * __Magnocellular__ system: Motion/depth perception:
 * Mostly from the periphery; all rods (can't see color); large receptive fields (low acuity); responsive to __motion__.
 * __Parvocellular__ system: Color/form/detail perception:
 * Mostly from the fovea: lots of cone input (can see __color__); small receptive fields (high acuity, fine detail); not responsive to motion.
 * The magnocellular system is associated with __spatial vision__; the parvocellular system is associated with __object vision__.
 * Color seems to be actually processed for the first time in the primary visual cortex in what are colorfully (no pun intended) known as **blob cells**.
 * From the notes: "These cells do not have center-surround anatomy, but are simpler: their receptive fields comprise a uniform area of retina within which light of one color excites the cell and light of another color inhibits the cell." Essentially they seem to respond, without any spatial coordination or fine color distinction, to different crude colors. Example in the notes is that a red-on, green-on blob cell will be excited by both RED-ON-center, GREEN-OFF-surround and GREEN-OFF-center, RED-ON-surround receptive fields, and be inhibited by the inverse. This cell, then, would say, "Hey, I've got more red than green here." Or, alternatively, "hey, I've got more green than red here."
 * These, as you might expect, get input from the parvocellular system (object/color vision; layers 3-6 of the LGN).
 * What are the receptive field characteristics of cortical simple and complex cells? How are these receptive field properties achieved by synaptic inputs from lower order cells?
 * Simple cells: essentially a number of ganglion cells with contiguous receptive fields set up in a row, converging on one cell (the simple cell) in the cortex. Because they have __spatial orientation__ (the center receptive fields of the ganglion cells form a shape, surrounded by a "shadow" of the inhibitory surrounds from those cells), only a particular __shape__ of light input is going to activate them; effectively there's a rod of ON surrounded by two rods of OFF (or, in principle, vice versa). A rod of light perpendicular to the ON-rod will cross the inhibitory surrounding rods and not set off excitation; only a rod in the correct __orientation__ (parallel) to the ON-rod will avoid the surround inhibition.
 * Note that these simple cells are encoding pretty much every conceivable shape; they're telling us about where the boundaries are between light and dark and helping us to thereby define shape. We use rods because it's easy to visualize.
 * Complex cells: abstract many simple cells into a larger pattern. These seem to have receptive fields in the shape of a simple cell's shape swept through space-- in the case of the rod shape, the complex cell field looks like a rectangle, and is made up of several parallel rod fields from simple cells.
 * Note that, whereas in a simple cell the input has to be exactly on the "on" region (the rod itself) for excitation to occur, in a complex cell the input can be at one of several places (any of the rods inside) for excitation to occur. That is, __the receptive field in a complex cell is no longer position-sensitive__; it no longer has a contiguous "on" region but several scattered throughout, any of which will excite it.
 * Note, however, that __orientation is still important__- the stimulus needs to be in the shape and angle of the original simple cell's receptive field in order to hit the "on" center and avoid the inhibitory surround.
 * Note also that this is the first example of a single cell that can detect motion-- the firing of first one, then another, then another of its "on" regions will set up a particular periodicity of firing that indicates a stimulus moving across its field.
 * Complex cells seem to be used to detect edges.
 * The hierarchical organization continues with hypercomplex cells that, in turn, organize multiple complex cells into an approximation of the simple-cell receptive field (one complex cell in the middle that's excitatory, two flanking it that are inhibitory). This seems to be used to detect corners.
 * Note there's a great summary of the properties of various cells in the visual pathway on p. 189 of the notes, from photoreceptors to hypercomplex cells.
 * Draw the major features of a hypercolumn.
 * **Hypercolumn**: the concept that every little piece of visual cortex represents every possible orientation and shape of light, from both eyes, in that small piece of the visual field.
 * There's a picture on p. 186 of the notes. Helpful for getting the rest of this.
 * Every possible orientation for a shape of light, or combinations of shapes, in that particular chunk of space is represented in that region of cortex.
 * Going deep to the surface through the cortex, the orientation of the receptive fields stay the same; going outward across the surface of the cortex, the orientation of the receptive fields changes.
 * There are also what's called "ocular dominance columns" within that region-- left-eye-input columns and right-eye-input columns
 * At the boundaries of these columns you find __binocular__ columns, sensitive to light from either visual field.
 * Note this is the first exception to the separate-eye-separate-tracts rule.
 * Note also that the cells of the binocular columns have a particular preferred __depth__.
 * There's a "pinwheel" concept I don't understand very well, involving layers of different maps of orientations. Evidently neurons detecting all possible orientations of a given shape in a given chunk of the visual field rotate about the color blobs in the cortex like wavy spokes on a wheel.
 * Note that magnocellular and parvocellular neurons are largely kept distinct in the column.
 * Describe the meaning of a sensitive period in the development of the cortex. Indicate the importance of this concept in diagnosing and treating abnormal development.
 * Sensitive period: period during which, if vision is occluded or damaged and not fixed, the cerebral visual processing system permanently loses its connection to the affected eye.
 * Gone is gone-- if the condition isn't reversed rapidly (usually within about a week in human infants; see below), the connections in the cortex to that eye never come back.
 * For humans, this is about from birth to 2-3 years old.
 * So if you've got an infant with amblyopia or strabismus, you really want to fix that yesterday.
 * Note that in adults, occluded vision doesn't result in the same kind of radical rewiring.
 * Explain the meaning of “ocular dominance” in cells of the visual cortex and indicate its physical basis. Discuss the changes in ocular dominance caused by monocular deprivation, binocular deprivation, and alternating monocular deprivation.
 * As discussed, there are __ocular dominance columns__ in the cortex, indicating from which eye a given input is coming (higher-level neurons in the cortex that respond only to inputs from one eye or the other), and __binocular areas__ between them (higher-level neurons in the cortex that respond to inputs from either eye).
 * __Monocular deprivation__: if you cover one eye of an infant during the sensitive period, the cortical neurons all become responsive __only__ to the other eye.
 * Note no effects on the LGN or optic tract neurons-- this is a cortical thing.
 * __Binocular deprivation__: if you cover both eyes in an infant, then remove them after a bit, there are less overall responsive neurons, but the pattern of neurons responding to one or both eyes is intact.
 * Thus it's not a "use it or lose it" system, since the deprivation of binocular vision results in intact, though muted, vision. Instead, there seems to be a __dynamic competition__ between inputs from each eye; when there's input only from one eye, that eye "wins" and takes over the cortical regions responsible for visual reception of the covered eye, but if both eyes are covered, neither eye "wins," and the cortical wiring remains more or less as it was.
 * To support this, if the non-covered eye is covered at the same time the covered eye is uncovered (__alternating monocular deprivation__), the reopened eye recovers and the previously dominant eye loses its cortical connections.
 * Note also, because it's cool, that if you have strabismus (eyes' visual fields don't match, thus the same stimulus is going to different points on the retina and hence different points in the visual cortex), there are plenty of neurons in the cortex that respond to one eye or the other, but almost no neurons responsive to __binocular__ inputs. This is a good reason to fix strabismus early-- if you let it wait past the sensitive period, the binocular vision can't be recovered.
 * [Note this seems to be due to NMDA receptors sensing co-activation during development.]
 * [Note also that the neurotrophic thing seems to still be in play-- neurons that excite their targets to threshold are 'rewarded' with trophic factors that allow them to grow and thrive, while neurons that fail to do so tend to atrophy (and allow other, more active nearby neurons to take over). Wow, we've got reward pathways on the neuronal level.]
 * Indicate the conditions under which the effects of abnormal developmental experiences can be reversed.
 * Clinical evidence suggests that one week of monocular deprivation in infants can cause permanent amblyopia in adult life.
 * Specifics depend on the age of the infant (there are maximally sensitive and less sensitive parts of the sensitive period) and the type of cells (different types of cells have different lengths of sensitive periods); also, evidently, on the type of input.
 * So: you've got a week.

=Cortical Lesions= Neuro-Ophthalmology, 9/23/08:
 * Understand the role of the frontal, temporal, parietal, and occipital lobes in human cognition
 * Frontal lobe:
 * Voluntary movement
 * Language fluency (mainly the left hemisphere)
 * Motor prosody (being able to inflect speech with emotion; mainly the right hemisphere across from Broca's area)
 * Comportment
 * Executive function
 * Motivation
 * Temporal lobe:
 * Language comprehension (mainly the left hemisphere)
 * Sensory prosody (being able to understand the emotional content of someone else's speech; mainly the right hemisphere)
 * Memory
 * Emotion
 * Parietal lobe:
 * Tactile sensation
 * Visuospatial function (mainly the right hemisphere)
 * Attention (right)
 * Reading (left)
 * Writing (left)
 * Calculation (left)
 * (anyone else just think "oh, reading, 'riting, and 'rithmetric on the left"?)
 * Occipital lobe:
 * Vision
 * Visual perception
 * Visual recognition
 * Appreciate the three major frontal lobe syndromes
 * (1) Disinhibition (orbitofrontal lesions): can't integrate emotional/limbic input into appropriate behaviors.
 * Dr. Filley: "the orbitofrontal region rides herd on the limbic system."
 * (2) Executive dysfunction (dorsolateral prefrontal lesions): can't plan, carry out, and correct a goal-oriented action.
 * Specifically, can see //perseveration//: the inability to alter a plan of action - or to see the need for altering it - in response to environmental feedback (ie. it isn't working). Read "The March of Folly," by Barbara Tuchman, for influence of this tendency in governmental history.
 * (3) Apathy (medial frontal lesions or medical school): loss of motivation.
 * (also Broca's aphasia)
 * Recognize the major cognitive disorders related to temporal lobe lesions
 * Wernicke's aphasia
 * Sensory aprosody
 * Amnesia
 * Abnormalities of forming/processing/expressing/repressing emotional reactions
 * Note temporal lobe epilepsy messes with this to produce lasting personality changes between seizures: hyperreligiosity, philosophical interest, hypergraphia (interest in writing a lot). By this standard I am evidently an epileptic, although it depends on a bit of wiggle room conflating the first two attributes.
 * Papez circuit of emotional function: hippocampus, parahippocampal gyrus, cingulate gyrus, anterior nucleus of the thalamus, mamillary bodies, and the fornix.
 * Understand the syndrome of hemineglect as a prototype parietal lobe syndrome
 * Recall that the parietal lobe, and mainly the right side, is responsible for attention. Damage to the parietal lobe can cause __hemineglect__ (failure to respond to one side of sensory stimuli, unexplained by a primary sensory deficit).
 * Patients with this defect tend to create drawings with the left sides not filled in (classically, a clock with all the numbers on the right side). The patient is unaware of the absence.
 * Note that the right parietal lobe can survey both sides of spatial awareness; the left can only survey the right. Right-sided lesions can therefore produce more severe and extensive symptoms than left-sided lesions.
 * Know the difference between visual field deficits and visual agnosia
 * Visual field deficits: can't see a portion of the visual field (lesions in the visual tracts or in the primary visual cortex in the occipital lobe).
 * __Visual agnosia__: damage to regions involved with attaching __meaning__ to things seen. These lesions tend to be localized at the border of the occipital lobe with either the temporal or the parietal lobe-- the projections of the visual cortex to processing centers elsewhere.
 * check out Antonio Damasio, "Descartes' Error: Emotion, Reason, and the Human Brain."**
 * Neuro-Ophthalmology**
 * Tuesday, September 23, 2008**
 * 8:00 AM**

Chemosensation, 9/23/08:
 * **Describe the appropriate clinical examination steps and causes of pupillary disturbances.**
 * **Clinical exam: look at pupils in light and dark; look at response to light.**
 * Anisocoria**: asymmetrical pupil size. Above a normal degree of variation (0-1 mm), this is an indication of a pupillary disturbance and __never a result of vision loss__.**
 * **Normal pupils' anisocoria must be the same in both the light and the dark.**
 * **Pupillary size is driven solely by parasympathetic/sympathetic input into the eye; thus judging the extent of the anisocoria in both the light (parasympathetic-dominated response) and the dark (sympathetic-dominated response) is useful.**
 * **If the anisocoria is greater in the __dark__, probably a problem with sympathetic input.**
 * **__Horner's syndrome__: miosis (constricted pupil), dilation lag (when the light's turned off, the pupil takes a long time to dilate in response), ptosis (drooping eyelid), anhidrosis (decreased sweating). Results from damage to the sympathetic system.**
 * **Medullary stroke, lung disease, carotid disease, etc, can all result in Horner's syndrome. Important to work up patients with Horner's syndrome to discover if there's also damage to the tissue underlying it.**
 * **If the anisocoria is greater in the __light__, probably a problem with parasympathetic input.**
 * **__Tonic pupil__: large pupil with a poor response to light, sometimes with only a segmental constriction (only part of the pupil constricts). Caused by damage to the ciliary parasympathetic fibers.**
 * **Know the key features of visual field loss due to neurologic visual pathway disturbances and key clinical features of optic nerve disturbances.**
 * **__Retinotopy__: concept that a given portion of the retina corresponds to a given portion of the visual field. Recall that the retina inverts (both up/down and left/right) the visual field. A given portion of the retina, in addition, projects to a given portion of the primary visual cortex (central vision is in the most caudal regions, peripheral vision is in the more rostral regions).**
 * **Neurologic visual pathway disturbances:**
 * **(1) Lesions at the optic nerve or beyond: the visual loss is restricted from crossing the horizontal and/or vertical midlines (meridians) of the visual field.**
 * **(2) Lesions at the optic tract or beyond: the visual loss is homonymous (the defect is in the same area of the visual field in each eye).**
 * **Note that you can get both (1) and (2) in lesions beyond the optic tract.**
 * **Clinical features of optic nerve dysfunction:**
 * **Vision loss (nonspecific)**
 * **__Afferent pupillary defect__**
 * **After a normal, bilateral constrictive light response in the contralateral, normal eye, light into the affected eye causes its pupil to dilate from its constriction; it thinks it's receiving less light on that side than the other.**
 * **Color vision loss**
 * **Abnormal optic nerve on ophthalmoscope examination (__nerve loss results in a white/pale nerve after about 6 weeks__).**
 * **Explain steps involved in the clinical approach to complaints of diplopia and describe features of the most common cause for the complaint of oscillopsia.**
 * **Diplopia (double vision): big question: __binocular or not__ (check if it goes away if one eye is closed-- if so, it's binocular). If it's binocular, it's neurological or mechanical.**
 * **Other questions to narrow down the source of the problem:**
 * **Horizontal or vertical?**
 * **Is it worse in any particular position of gaze?**
 * **Is it worse near or at distance?**
 * **To localize the misalignment:**
 * N**erve (III, IV, VI lesion)**
 * E**ye (displaced by mechanical force)**
 * **Neuromuscular** J**unction (myasthenia gravis)**
 * M**uscle (usually thyroid associated, occasionally myopathies)**
 * **Oscillopsia: "everything looks like it's moving even when I'm not."**
 * **Most common cause: nystagmus.**
 * **Recall that nystagmus as we've learned it has a slow (drifting) phase and a fast (beating) phase.**
 * **If it has two slow phases, it's called pendular nystagmus.**
 * **Can also have mixed nystagmus with slow-slow and fast-slow patterns.**
 * **There is no type of nystagmus with two fast phases.**
 * **Also recall that the nystagmus is named for the direction of fast movement.**
 * **Note that precise characterization of nystagmus can lead to specific treatment-- downbeat nystagmus, for example, is never congenital, but is always indicative of a compression at the cervical-medullary junction.**
 * Chemosensation**
 * Tuesday, September 23, 2008**
 * 8:48 AM**

Forebrain and Diencephalon, 9/24/08:
 * **Describe some simple tests you can do in a clinical setting that will enable you to distinguish a deficit of olfaction from a deficit of taste. Know the clinical terms for losses of these senses (ageusia = loss of taste; anosmia = loss of smell).**
 * **Problems with olfaction: can still taste sweet, salt, sour, bitter, glutamate/umami (see below). Clinical test: give one cup with salt or sugar in water, one with plain water, test for ability to detect the difference. If they can, it's probably not ageusia.**
 * **Note that anosmia is much more common than ageusia.**
 * **Most commonly, anosmia is due to a blockage; next most commonly, due to head trauma (axons of CN I sheared off).**
 * **Note that the facial, glossopharyngeal, and vagus nerves all provide taste sensation; a neurological loss of taste resulting from lesions of all 6 (3 bilateral cranial nerves) is quite rare.**
 * **Describe the differences in morphology and functioning of receptor cells for taste, trigeminal and olfactory modalities.**
 * **__Olfactory receptor__: ciliated** neurons **that extend from the epithelium to the olfactory bulb in the brain. Each olfactory receptor only expresses __one kind__ of olfactory binding region ("an olfactory epitope").**
 * **__Taste receptors__ (buds): not neurons but** modified epithelial cells**. Synapse onto nerves going to cranial nerve ganglia. Can be one of five taste types (see below).**
 * **__Trigeminal receptors__:** free nerve endings **in the epithelium on one end of trigeminal neurons (going to trigeminal nuclei). Chemically and thermally sensitive to various stimuli; seem to be polymodal (peppermint/cold temperature, hot pepper/hot temperature). (note that he seems mainly to be discussing the anterolateral system, and specifically C fibers, here; there are, of course, A-deltas and the fine touch-vibration-proprioception fibers to deal with as well.)**
 * **Describe the difference in route of access of odorants to the olfactory epithelium during orthonasal and retronasal stimulation.**
 * **__Orthonasal__: goes "back" across the olfactory chemoreceptors from the nasal cavities towards the nasopharynx. Your buddy offered you a jelly bean and you're smelling it before you try it to make sure that orange color is supposed to be there.**
 * **__Retronasal__: goes "forward" across the olfactory chemoreceptors from the nasopharnyx towards the nasal cavities. You're eating that jelly bean and the volatiles released by your vigorous mastication have wafted up your throat and into your nose to inform you that it is, alas, not tangerine but melon.**
 * **Describe the way odor information is transmitted from the receptor epithelium to the olfactory bulb. Compare how different odors are represented within the receptor sheet and within the bulb.**
 * **[Note that these are the only sensory neurons that go directly from the outside environment to the brain.]**
 * **[Note also that this is the only sensory system that doesn't relay in the thalamus before going into the brain.]**
 * **[Note further that this is the only sensory system in which the primary neurons are constantly being replaced (olfactory neurons have a lifespan of about 30-60 days). Respiratory viruses can sometimes kill off these cells; after a month or so, the sense of smell is usually regenerated.]**
 * **All olfactory neurons have G-protein coupled receptors coupled to their "olfactory epitope." When the epitope target binds, the neuron depolarizes and sends its AP into the olfactory bulb.**
 * **Note that there's a fair amount of amplification of the signal that needs to take place for this to happen (small amount of smell stimulus, large depolarization).**
 * **Note also that there are a limited number of such epitopes expressed, and thus many olfactory neurons will share an epitope.**
 * **Note further that these common-epitope neurons are not grouped together on the receptor epithelium but are scattered hither and yon.**
 * **All the olfactory neurons expressing one "smell epitope," while __not__ grouped on the olfactory epithelium, run __together__ in one bundle ("glomerulus") into the olfactory bulb.**
 * **There's an "ototopic" map on the bulb-- thus all similar smell impulses, though detected at disparate places on the olfactory epithelium, run to the same place on the olfactory bulb.**
 * **That said, having one line light up is not how we identify smells; __patterns__ of glomeruli activation determine the sense of smell. I don't smell coffee due to a specific "coffee epitope," but rather by a combination of many individual epitopes, the varying intensities of which define the odor.**
 * **Note that he put emphasis on the fact that cranial nerve I was the nerve from the olfactory epithelium to the olfactory bulb, __not__ the neurons running in the olfactory tract back from the bulb towards the rest of the brain (those would presumably be the second-order neurons after CN I).**
 * **List the output pathways and targets of the olfactory bulb. What behaviors or cognitive events are associated with each of the telencephalic olfactory target areas?**
 * **Going to the __hypothalamus__ via the olfactory tubercle and amygdala to produce visceral reactions and to alter the set point of homeostasis (get ready to eat, mate, whatever).**
 * **Going to the __orbitofrontal cortex__ via the piriform cortex and the thalamus to prompt conscious perception of flavor.**
 * **Going to the __hippocampus__ via the entorhinal cortex to both access and store memories associated with this smell.**
 * **List the three types of gustatory papillae and indicate which cranial nerve provides their gustatory and general cutaneous innervation to that area of the tongue.**
 * **Types of papillae:**
 * **__Fungiform__: big dots on the front of your tongue.**
 * **__Circumvallate__: bigger dots at the back of your tongue.**
 * **__Foliate__: on the sides of the tongue.**
 * **__Facial__: taste for the anterior two-thirds of the tongue. __Trigeminal__: touch/temperature for the anterior two-thirds of the tongue.**
 * **These nerves generally carry the information from the fungiform papillae.**
 * **__Glossopharyngeal__: both touch, temp, and taste for the posterior third of the tongue.**
 * **This nerve generally carries the information from the circumvallate papillae.**
 * **(Foliate papillae seem to be innervated by both pathways.)**
 * **Note that there is no excusive map of taste on the tongue; all five taste qualities can be detected in all places. There are, however, areas of more or less taste sensation for various taste qualities.**
 * **List the five primary taste qualities and for each indicate whether sensory transduction involves ion channels or G-protein coupled receptors.**
 * **__Salt__: mediated by Na+; opens __ion channels__.**
 * **__Sour__: mediated by intracellular H+; opens intracellular triggers for __ion channels__. Preferentially activated via weak acids (needs to diffuse across the membrane).**
 * **__Sweet and Glutamate__: __G-protein coupled receptors__ (T1R receptor family).**
 * **__Bitter__: __G-protein coupled receptors__ (T2R receptor family).**
 * **Note much more genetic variability in bitter sensation.**
 * **Easy mnemonic: note that the things you thing of as being charged - salt and acid - are the ones that open ion channels.**
 * **Trace the neural pathways and name the central nuclei conveying taste information from taste buds to primary gustatory cortex.**
 * **Taste info: goes to __nucleus of the solitary tract__; from there, goes to both the __VPM thalamus__ (and from there to the __insular cortex__; conscious appreciation of taste) and __hypothalamus/amygdala__ (unconscious effects of taste).**
 * Forebrain/Diencephalon**
 * Wednesday, September 24, 2008**
 * 7:44 AM**

Landmarks for coronal sections: Thalamocortical Physiology, 9/24/08:
 * [All connections to the thalamus are reciprocal- if a region of the thalamus projects to another area in the CNS, that area also projects back to the same region of the thalamus.]
 * [All inputs to the thalamus have already crossed the midline; thus the output of the thalamus to the cortex is always ipsilateral.]
 * [Recall that all sensory information going to the cortex - except smell - goes through the thalamus to get to the cortex. This makes it great for regulation, attention to particular events, and shutting out distractions.]
 * [Nuclei of the thalamus:]
 * __Relay__ nuclei: anterior (limbic system), VA/VL (motor), VPL/VPM (somatosensory), LGN (visual), MGN (auditory).
 * __Association__ nuclei: dorsomedian nucleus and pulvinar. Both of these are quite large and are multimodal-- they respond to visual, somatosensory, auditory, etc. Not much is known about their structure.
 * The dorsomedian nucleus projects to the frontal cortex.
 * The pulvinar projects to the parieto-occiptal cortex. Nearby the medial and lateral geniculate nuclei, useful as a landmark.
 * '__Other__' nuclei:
 * Centromedian nucleus; seems to (Wiki) project to the striatum, but here mainly as a landmark since it's nearby the VPL and VPM.
 * Reticular nucleus: lots of inhibitory output-- seems to be a major source of control over what information doesn't make it to the cortex. See examples in next lecture re epilepsy and delta-wave sleep patterns.
 * Identify the major structures of the telencephalon and diencephalon on coronal and sagittal preparations: thalamus, hypothalamus, components of the basal ganglia, internal capsule, neocortex, hippocampus.
 * I can't help you. Can't nobody help you. You gots to do it for yourself.
 * Prepare a table showing, for each of the following systems, the name of the associated thalamic nucleus and the ultimate cortical target of the system:
 * __Visual__: goes into the lateral geniculate nucleus, projects to the primary visual cortex (area 17) through the optic radiations.
 * __Auditory__: goes into the medial geniculate nucleus, project to the primary auditory cortex (area 41).
 * __Somatosensory__ for the face: goes into the ventral posterior medial nucleus; projects to lateral primary SS cortex (areas 3/1/2).
 * __Somatosensory__ for the body: goes into the ventral posterior lateral nucleus; projects to lateral (hand/body) and mesial (foot and leg) primary SS cortex (areas 3/1/2).
 * __Taste__: per Dr. Finger's lecture, seems to go into the VPM nucleus; projects to the insular cortex (to provide conscious appreciation of taste).
 * __Hippocampal limbic__: goes into the anterior nucleus, projects to the cingulate gyrus.
 * __Amygdalar__: goes into the dorsomedian nucleus, projects to the prefrontal cortex.
 * Identify the following limbs of the internal capsule: anterior, posterior, retrolenticular and sublenticular limbs. List the contents of these four regions.
 * Neuroanatomy: the more anterior nuclei of the thalamus are going to output/input through the anterior limb of the internal capsule; the more posterior nuclei of the thalamus are going to output/input through the posterior 3 parts (see below) of the internal capsule.
 * Note that the anterior limb is mostly flanked by the lenticulate nucleus (ie. the putamen and globus pallidus) and the caudate, while the posterior limb is mostly flanked by the lenticulate nucleus and the thalamus.
 * This means that, in general, if you can see the thalamus, you're past the anterior internal capsule and likely in the posterior.
 * Note that there's another two posterior regions of the internal capsule aside from the posterior and anterior that we'd previously heard about:
 * __Sublenticular__ limb goes underneath the lenticulate nucleus (no kidding). Easy to see on coronal section, hard to see on horizontal.
 * __Retrolenticular__ limb curves back around the posterior tail of the lenticulate nucleus. Easy to see on horizontal section, hard to see on coronal.
 * Contents:
 * __Anterior limb__:
 * Anterior nucleus <-> cingulate gyrus
 * Dorsomedial nucleus <-> prefrontal cortex
 * __Posterior limb__:
 * VPL/VPM <-> primary somatosensory cortex
 * Also carries cortical fibers running to the putamen and fibers from the globus pallidus to the VA/VL.
 * Also, of course, carries descending corticospinal fibers.
 * __Retrolenticular limb__:
 * Pulvinar <-> parietal association cortex
 * LGN <-> primary visual cortex
 * __Sublenticular limb__:
 * LGN <-> primary visual cortex
 * MGN <-> primary auditory cortex
 * List the functional significance of each of the following Brodmann's areas: 1-3, 4, 17, and 41. For each area give the associated thalamic relay nucleus.
 * 1-3: primary somatosensory cortex (VPM/VPL)
 * 4: primary motor cortex (VA/VL)
 * 17: primary visual cortex (LGN)
 * 41: primary auditory cortex (MGN)
 * Identify the following structures in coronal and horizontal sections through the brain:
 * Thalamic nuclei:
 * Anterior nucleus, lateral and medial geniculate nuclei, VA-VL nuclei, pulvinar, VPL/VPM nuclei, centromedial nucleus, dorsomedial nucleus.
 * Parts of the internal capsule:
 * Anterior, posterior, retrolenticular, and sublenticular.
 * At mammillary body level, see the DM nucleus at midline and the VPM/VPL lateral.**
 * At red nucleus level, see the DM and CM inside of it.**
 * At crus cerebri level, see the MGN/LGN and the pulvinar.**
 * By the red nucleus level, you're pretty much behind the lenticulate nucleus; look for the retrolenticular limb of the IC.**
 * Note that anterior, dorsomedian, and pulvinar nuclei are all midline (A to P).**
 * Thalamocortical Physiology**
 * Wednesday, September 24, 2008**
 * 8:45 AM**

Physiological of Sleep, 9/25/08:
 * **Understand why the thalamus, which is a deep structure and therefore cannot contribute //directly// to the EEG, does contribute to the signals recorded in an EGG. Understand that the contribution of thalamus to EEG recording is due to thalamocortical connections.**
 * **You're measuring cortical activity directly mediated by changes in thalamic firing. Like you can't see motor neurons fire but you can watch the muscles move.**
 * **[Note the nature of the relay between the thalamus and the cortex:]**
 * **The thalamic relay neurons project excitatory fibers onto the cortex.**
 * **The cortex, in turn, projects excitatory fibers onto the thalamic relay neurons.**
 * **Obviously, you need some kind of inhibitory input in there somewhere to avoid seizures.**
 * **The inhibitory input comes from a cell in the reticular nucleus (recall that the reticular nucleus is the main source of inhibitory fibers in the thalamus, see last lecture).**
 * **So both the corticothalamic fibers and the thalamocortical fibers also project excitatory fibers onto the inhibitory neuron, which in turn projects inhibitory fibers onto the thalamic relay neurons.**
 * **[Now let's discuss patterns of inhibitory firing:]**
 * **When you're awake, the reticular fibers are much less active than when you're asleep, and the resting potential of the thalamic relay cell is about -55 mV. When you're asleep, the reticular fibers hyperpolarize the freak out of the thalamic relay neurons by releasing a bunch of GABA all over them, driving the resting potential down to -85 mV.**
 * **Thing is, the thalamic relay neurons can't sit still (restless axon syndrome?). Every 300 msec or so (3x/second, or** 3 Hz**), they build a slow, rising spike that's capped with an AP.**
 * **The slow rising spike is driven by an influx of calcium through T-type calcium channels.**
 * **Let's talk about these calcium channels. Like the Na+ channels we're used to, they have a voltage-gated activation gate (opens above a certain voltage) and a voltage-gated inactivation gate (closes above a certain voltage).**
 * **Their activation gates open at quite negative potentials (below -85 mV).**
 * **However, their inactivation gates close at quite negative potentials as well (about -65 mV).**
 * **This means there's a 'sweet spot' between the two, during which the activation gates are open and so are the inactivation gates. At these voltages, calcium will enter the neurons, causing a slow depolarization.**
 * **At a certain point during this Ca++-induced depolarization, the threshold is reached for voltage-gated Na+ channels to open. These generate your usual AP spikes.**
 * **At the normal resting potential (-55 mV), the inactivation gates of T-type calcium channels in thalamic neurons are perpetually closed (which is why there's no slow drift towards depolarization when you're awake, even though the activation gates are open).**
 * **So, when you go into deep sleep, the GABA released by the reticular neurons polarizes the thalamic relay neuron to a point (around -85 mV) where the activation gates remain open and the inactivation gates open as well, allowing a slow, calcium-induced depolarization to the point where the voltage-gated sodium channels open and a burst of high-frequency APs are fired. After this point, the inactivation gates for the calcium channels close and the membrane potential fades back down to around -85, at which point the process begins again. As mentioned, the frequency of the depolarization waves is about 3 Hz.**
 * **(note that the threshold for AP generation here is lower than we're used to, somewhere between -65 and -75 mV-- which is why the inactivation gates on the calcium channels don't close before the APs get generated.)**
 * **Thus if the T-type calcium channels have a mutation that causes the inactivation gate voltage threshold to raise to where the calcium is allowed to enter when the subject's awake, they can go into __'absence' epilepsy__ in which the EEG shows marked similarity to delta-phase sleep (3 Hz thalamic firing).**
 * **Duplicated in mice; mice that have no T-type calcium channels are refractory to the seizures.**
 * Valproic acid **and** ethasuxamide **are T-type calcium channel antagonists that are used to halt absence seizures through knocking out this pathway.**
 * **Note that the same absence-epilepsy manifestations can occur if the reticular thalamic neuron is firing inappropriately (releasing GABA while you're awake).**
 * **Understand that thalamic relay neurons have conductances that endow them with the ability to respond to a hyperpolarization with slow Ca2+ spikes that fire at a frequency of ~3 Hz (the delta frequency). Riding on top of the Ca2+ spike are several action potentials. Understand the role of the T-type Ca2+ channel in the generation of the slow Ca2+ spike.**
 * **Mentioned above.**
 * **Understand that unless thalamic relay neurons are hyperpolarized by inhibitory interneurons in the thalamic reticular nuclei, the thalamic relay neurons cannot fire the slow Ca2+ spikes that give rise to the slow delta wave recorded in the EEG during slow wave sleep and 'absence' epileptic attacks.**
 * **Mentioned above.**
 * **Understand how thalamocortical connections - between the thalamic relay neurons and the pyramidal cortical neurons - are such that the Ca2+ spikes occurring in thalamic relay neurons at the delta frequency give rise to a slow wave in the delta frequency in the EEG.**
 * **(delta frequency = 3-Hz thalamic slow-wave EEG patterns recorded in stage IV [deep] sleep.)**
 * **Mentioned above.**
 * **Know that the slow EEG waves recorded in absence epilepsy (at the δ frequency ~3Hz) are thought to stem from thalamocortical oscillatory activity. Understand why a mutation in the T type Ca2+ channel could give rise to this type of epilepsy. Know that the drugs valproic acid and ethoxosuximide, that are used to control epilepsy, both inhibit T type Ca2+ channels.**
 * **Mentioned above.**
 * **Understand that ascending brainstem circuits sending axons to the thalamus regulate the thalamocortical circuit. Know that when the cholinergic cells of the reticular activating system are stimulated the animal awakes from sleep and the corticothalamic slow waves stop.**
 * **Lots of things send projections to the thalamus, releasing a variety of neurotransmitters onto it: neurons from the locus coeruleus release norepinephrine (fight or flight, sympathetic activity), neurons from the raphe nucleus release serotonin.**
 * **The reticular activating system (in the brainstem) sends cholinergic stimuli to the thalamus to interrupt the slow EEG waves.**
 * **More on this in lectures to come.**
 * Physiology of Sleep**
 * Thursday, September 25, 2008**
 * 7:59 AM**

Treatment of Sleep Disorders Treatment of Sleep Disorders, 9/25/08:
 * Be able to describe the characteristics of REM and N-Rem sleep.
 * Dr. Weissberg: "Does this lion have an erection?"
 * (REM sleep: genital engorgement. Non-REM sleep: none of that.)
 * Brain/body regeneration occurs during NREM sleep; brain development and memory processing seems to occur during REM sleep.
 * REM sleep is essential for the developing mammalian brain.
 * Slow-wave (NREM) sleep: high amplitude, slow brain waves (like the delta waves we talked about yesterday); decreased muscle movements; depressed respirations/heart rate/metabolism. Occasional dreams. Recall that there's four stages of NREM sleep, getting progressively deeper with shorter EEG wave patterns (deepest is delta sleep at the 3-Hz frequency mentioned in the last lecture).
 * REM sleep: "You essentially have an awake brain in a paralyzed body." The EEG is similar to wakeful patterns. Lots of dreams.
 * Mostly you get NREM sleep early in sleep and REM sleep late in sleep.
 * Normal time to REM sleep: 90 minutes. Alcoholism and depression and especially narcolepsy decrease this.
 * Note that the percent of sleep time in REM sleep decreases from 50% in infancy to about 25% as adults.
 * Note also that early in sleep you spend more time in NREM sleep, while later on you spend more time in REM sleep. So if you only get 4 hours of sleep, the odds are you haven't gotten much of a chance to hit your REM stride.
 * [Note that the suprachiasmatic nucleus is thought to contain the master circadian clock that synchronizes the sleep cycle.]
 * Be able to describe the major neurotransmitters involved in wake, NREM and REM sleep.
 * ACh: seems to be involved in both wakefulness and REM sleep, released by the laterodorsal and pedunculopontine tegmental nuclei (LDT and PPT) in the pons.
 * GABA: seems to be involved primarily in non-REM sleep (from hypothalamus and reticular neurons in thalamus); inhibits thalamic relay neurons, as we discussed yesterday.
 * Serotonin, histamine, and norepinephrine seem to be most important for wakefulness but not so much for the other two.
 * Note there's a summary slide in his lecture if you want more details. It's also recapitulated in the French notes that follow ("Treatment of Sleep Disorders").
 * [Note that __REM-sleep disorders can be an early sign of Parkinson's__.]
 * Be able to describe the interaction of the circadian (process C) and homeostatic system (process S) and their effect on wake and on sleep.
 * Homeostatic drive (process S, under control of adenosine): more you're awake, the more you need to sleep. __Promotes sleep, inhibits wakefulness__. This is why if you don't get enough sleep one night you need more the next. This system monitors whatever it is that sleep does for us and forces us to get more sleep if we're running low.
 * Circadian alerting system (process C): originates in alerting signal in suprachiasmatic nucleus. __Promotes wakefulness, inhibits sleep__. Note that there is a inbuilt circadian clock in the suprachiasmatic nucleus that cycles about every 24.5 hours-- it's corrected/entrained by light stimuli.
 * Note that the circadian system controls not only alertness but also core body temperature (lowest in the night, highest in the day) and cortisol/melatonin secretion.
 * Although the homeostatic drive is increasing through the day (more sleepy), the circadian system is increasing along with it (more alert). At some point the circadian system stops increasing, but the homeostatic system is still increasing-- thus sleep signals dominate. Note that this means you tend to be most alert (most circadian input, countering increased homeostatic input) an hour or two before you crash.
 * There's a good picture of this in his slides (p. 11 in notes).
 * [Note distinction between primary insomnia, caused by hyper-arousal or learned behavior, and secondary insomnia, secondary to medical/psychiatric conditions, pain, etc.]
 * Thursday, September 25, 2008**
 * 9:04 AM**

Hypothalamus + Temperature Regulation, 8/25/08:
 * **[Note graded scale of sedative effects on CNS:]**
 * **[less drug] Sedation**
 * **Hypnosis/induced sleep**
 * **Anesthesia**
 * **Medullary depression**
 * **[most drug] Coma/death**
 * **[CNS depressants:]**
 * **General anesthesia**
 * **Barbiturates**
 * **Ethanol**
 * **Benzodiazepines**
 * **Non-benzodiazepine receptor agonists**
 * **Relate the pharmacokinetic profile of benzodiazepines (BDZs) and nonbenzodiazepine receptor agonists (NBRAs) to their clinical utility in the treatment of insomnia.**
 * **Why you use benzodiazepines for insomnia: their dose-response curve (see p.5 in the notes) flattens out before it begins to have effects on the medullary CNS. Thus it's hard to accidentally overdose a patient and get respiratory depression/coma/death.**
 * **Note that general anesthetics, barbiturates, and ethanol have much more straight-line dose-response curves; it's fairly easy to get life-threatening side effects.**
 * **This is why you __don't combine ethanol or other CNS sedatives and benzodiazepines__: the EtOH exacerbates the normally safe CNS effects of the BDZs to a potentially fatal extent.**
 * **NBRAs aren't benzodiazepines but have agonist action at the same sites at the benzodiazepines.**
 * **Note that both benzodiazepines and NBRAs are controlled, Class IV substances.**
 * **[How BDZs/NBRAs/barbiturates work:]**
 * **BDZ/NBRAs target BZ "receptors" (actually just subunits of the GABA receptors); agonists at these sites __potentiate__ the GABA receptors they're found on.**
 * BZ1 **receptors are mostly in the cortex and relate to hypnosis/__sleep-promoting__ activity.**
 * BZ2 **receptors are mostly in the brainstem and limbic system, and relate to __anxiolytic__ activity.**
 * **Note that __NBRAs can be targeted to one or the other of these__ (mainly the BZ1 sleep receptors, to reduce abuse potential).**
 * **Note barbiturates have a different mechanism of action (they __prolong__ GABA effect at low doses, and __directly__ exert agonistic action on the GABA receptors at high doses).**
 * **Note that barbiturates lower glutamate levels as well.**
 * **Relate the effects of benzodiazepines and nonbenzodiazepine receptor agonists on sleep stages to their clinical utility in the treatment of insomnia.**
 * **Decrease latency of sleep onset (help sleep come faster)**
 * **Increase duration of stage 2 sleep (help stay asleep)**
 * **Decrease duration of stage 3-4 sleep (but the sleep doesn't get as deep)**
 * **Decrease duration of REM sleep (and your brain doesn't get as much memory processing and development time)**
 * **Note that use for longer than a week generally leads to tolerance.**
 * **However, this varies widely between drugs.**
 * **Compare the side effect profiles of the three broad categories of drugs for insomnia (BDZs, NBRAs, and non-GABA drugs) as they relate to limitations on the clinical utility of each.**
 * **Benzodiazepines:**
 * **Daytime (morning-after) sedation can pose a problem (worse with BDZs with longer half-lives). Note this side effect gets more common with age (impaired metabolism/drug excretion).**
 * **Anterograde amnesia effects, related to the increased effect of GABA (interferes with glutamate-related memory formation), particularly with triazolam.**
 * **Rebound insomnia after abrupt withdrawal.**
 * **Occasionally hypersensitivity or dry mouth with chronic use.**
 * **Note potential for abuse and dependency due to anxiolytic effects on limbic system.**
 * **NBRAs:**
 * **Minor side effect profiles. Zolpidem: drowsiness, amnesia, dizziness, headache, GI complaint. Zaleplon: dizziness, headache, somnolence (isn't that the point?). Neither has any significant effect on next-day psychomotor performance, nor do they have abrupt withdrawal insomnia or tolerance symptoms. Due to selectivity to non-limbic BZ receptors, they also have less potential for abuse and dependency.**
 * **Non-GABA:**
 * **Trazodone (serotonin modulation): oversedation, orthostasis, priapism.**
 * **Tricyclic antidepressants: anticholinergic and antiadrenergic effects; cardiac disturbances.**
 * **Ramelteon (melatonin agonist) or melatonin itself: dizziness, somnolence, fatigue, nausea. All are relatively rare.**
 * **Antihistamines (decreased muscarinic ACh/histamine H1 stimulation): minimal; some anticholinergic effects.**
 * **Essentially: NBRAs are coming into vogue, especially zolpidem, as zaleplon doesn't reliably increase total sleep time. But note BDZs are generally cheaper (generic).**
 * **[Note there's a BZ-receptor __ant__agonist, Flumazenil, for BDZ overdose situations.]**
 * Hypothalamus + Temperature Regulation**
 * Thursday, September 25, 2008**
 * 9:59 AM**

Limbic System/Hippocampus and Memory/Amygdala, 8/26-29/08:
 * **[Repeated point: the hypothalamus's main function is to integrate and organize responses from 3 systems: the autonomic nervous system, the somatic motor system, and the endocrine system.]**
 * **Describe the location of the major nuclei of the hypothalamus.**
 * **[Neat little table in the notes describing the boundaries of the hypothalamus:]**
 * **Anteriorly: optic chiasm**
 * **Posteriorly: midbrain**
 * **Dorsally: thalamus**
 * **Ventrally: pituitary gland**
 * **Medially: walls of the third ventricle**
 * **Regions of hypothalamus: anterior, tuberal (above pituitary stalk), and posterior.**
 * **Anterior region: lateral and medial** preoptic **nuclei,** anterior **nucleus,** suprachiasmatic **nucleus.**
 * **Tuberal region:**
 * Paraventricular **nucleus and** supraoptic **nucleus (these two make hormones and regulate their release from the posterior pituitary)**
 * Dorsomedial **nucleus,** lateral **nucleus,** ventromedial **nucleus.**
 * **Posterior region:** posterior **nucleus,** mammillary bodies**.**
 * **[Note there are regions in the hypothalamus without a blood-brain barrier! This means both that the hypothalamus can be affected by substances in the bloodstream and also that substances made by the hypothalamus can get into the blood and circulate to other organs.]**
 * **Describe the pathways connecting the hypothalamus with the autonomic and somatic motor systems, the endocrine system, and the limbic system.**
 * **From hypothalamus to the autonomic nervous system:**
 * **__Dorsal longitudinal fasciculus__ (to autonomic nuclei in the reticular system and spinal cord)**
 * **__Medial forebrain bundle__ (to reticular formation)**
 * **__Mammillotegmental tract__ (to tegmentum/reticular formation of midbrain)**
 * **From hypothalamus to the somatic motor system:**
 * **Same tracts as above (going to reticular formation); coordinates activities with both somatic and autonomic components like laughing, crying, vomiting, etc. Note also influence on activities required for homeostasis (chewing, swallowing).**
 * **From hypothalamus to the endocrine system:**
 * **As mentioned, two nuclei in the paratuberal region synthesize hormonal compounds and package them to send to the posterior pituitary, where they're stored until their release into the circulation.**
 * **We're talking here specifically about __vasopressin__ and __oxytocin__ (the only two hormones released from the posterior pituitary).**
 * **The hypothalamus also synthesizes hormones that are released directly into the hypothalamo-pituitary portal system, allowing them to act on the __anterior pituitary__. This hormonal signal regulates the release of other hormones from the anterior pituitary.**
 * **Hormones released from the hypothalamus and the resultant hormone that's released from the anterior pituitary:**
 * **Corticotrophin releasing hormone -> adrenocorticotrophic hormone (acts on the adrenal cortex to stimulate release of cortisol).**
 * **Gonadotrophin releasing hormone -> luteinizing hormone and follicle stimulating hormone (regulates testosterone, estradiol, progesterone release).**
 * **Prolactin releasing factor (opposed by dopamine, prolactin inhibiting factor) -> prolactin (acts on the mammary glands to stimulate milk production)**
 * **Thyrotrophin releasing factor -> thyroid stimulating hormone (acts on the thyroid to stimulate release of thyroxin).**
 * **Growth Hormone Releasing Hormone (opposed by somatostatin) -> growth hormone (stimulates growth of bone, muscle, and skin).**
 * **From hypothalamus to the limbic system:**
 * **Pathways mainly seem to go to the amygdala.**
 * **Note that, like the thalamus, most pathways from the hypothalamus include efferent as well as afferent pathways (good to maintain homeostasis).**
 * **Describe the role of the autonomic nervous system in homeostasis and emotional responses.**
 * **The ANS is the thug of the hypothalamus; the way the hypothalamus regulates homeostasis is largely through the autonomic system.**
 * **Eg.: ANS causes blushing (vasodilation), blanching (vasoconstriction), 'butterflies' (vagal stimulation of GI motility), sweating (sympathetic activation).**
 * **Note the general rule that stimulation of the anterior hypothalamus increases __parasympathetic__ activity and stimulation of the posterior hypothalamus increases __sympathetic__ activity.**
 * **(This is in contrast to the role of the somatic nervous system and limbic systems, which might better be described as the femme fatale of the hypothalamus-- they get you to go do something and then convince you it was your idea.)**
 * **Describe the neuroendocrine function of the hypothalamus: How does it control the anterior pituitary? What is its role in posterior pituitary hormone secretion?**
 * **As described above.**
 * **List the endocrine, autonomic, and somatic motor responses initiated by the hypothalamus for maintenance of water balance, body temperature, and body weight.**
 * **Hypothalamus monitors osmolality through osmoreceptors. Water-balance effects:**
 * **Endocrine: vasopressin regulation through the posterior pituitary gland.**
 * **Somatic: go-find-water behavior pattern stimulation, drinking, swallowing.**
 * **Hypothalamus monitors satiety, glucose, hunger, etc. Body-weight effects:**
 * **Endocrine: promote insulin, glucagon, and/or growth hormone release.**
 * **Somatic: go-find-food behavior, chewing, swallowing.**
 * **Autonomic: regulate digestive processes and epinephrine.**
 * **Note that a lesion in the ventromedial nucleus leads to voracious appetite; lesions in the lateral hypothalamus lead to aphagia and starvation.**
 * **Lots more details than that in the notes (page 13).**
 * **Body temperature effects: see next LO.**
 * **Define __fever and pyrogens__. Describe the changes in the hypothalamic mechanisms regulating body temperature that result in fever and its associated symptoms.**
 * **Stuff that makes you hot:**
 * **The basal metabolic rate: heat production through incompletely efficient cellular metabolic processes and automatic muscle activity. Note thyroxin kicks up the BMR.**
 * **Exercise.**
 * **Shivering (involuntary skeletal muscle contractions)-- sort of low-impact exercise that gets your temperature up.**
 * **Also (this one is interesting) non-shivering thermogenesis, mainly important in infants. Involves sympathetic activity in brown adipose tissue (adults don't have much of it, infants have more).**
 * **How this works: brown fat cells' mitochondria's proton channels can become uncoupled (via a protein called __thermogenin__) and allow H+ to leak across the membrane. This is absolutely inefficient at making ATP, but very good at producing heat.**
 * **Stuff that makes you cold:**
 * **Conduction/convection to the surrounding air.**
 * **Sweating - essentially just helps convection.**
 * **How body temperature is normally regulated: 2 main areas:**
 * **Thermoreceptors in the __preoptic anterior__ hypothalamus (POAH): directly promotes heat dissipation through heat loss mechanisms. These mainly receive input from the local brain temperature, and only minimally from the skin.**
 * **Effects: panting and shade-seeking (somatic), sweating and vasodilation (autonomic).**
 * **Thermoreceptors in the __posterior__ hypothalamus: directly promotes heat conservation. These receive input only from the skin.**
 * **Effects: warmth-seeking and shivering (somatic), vasoconstriction (autonomic).**
 * **The defense of a constant body temperature (thermal homeostasis) is brought about by a combination of these two factors (how hot is the brain? how hot is the skin?). To get a coordinated and effective heat conservation response, you need overly-hot input from both systems (brain/skin).**
 * **Note that this means that although each system has a different direct action, they each influence the other's effects.**
 * **Note also that there's got to be a particular temperature point you're defending. That point is called the __set point__ and seems to be largely determined by the POAH.**
 * **__Fever__: a regulated increase in body temperature, brought about by altering the body's hypothalamic thermoregulatory set point by agents called __pyrogens__.**
 * **Note emphasized point: the fever is not stochastic or uncontrolled; it's directed by the abovementioned mechanisms.**
 * **The fever "breaking" is the activation of heat loss mechanisms (sweating, flushing) to bring the temperature back to the newly re-lowered set point.**
 * **Pyrogens (cytokines) act by affecting a portion of the hypothalamus without a BBB (the OVLT); they increase PGE2 production to increase the set point in the POAH.**
 * **Note that pyrogens can be both endogenous (normal response to many infections) and exogenous (toxins).**
 * **Describe the role of the hypothalamus in generation of circadian rhythms.**
 * **The suprachiasmatic nucleus, on its own without any light information, will set an endogenous 'clock' that coordinates activity patterns. However, it normally gets light/dark information from the retina in order to coordinate its own clock with the environmental light/dark status.**
 * **This affects lots of stuff: temperature, excretion of potassium, computational speed, etc. The SCN sends projections all over the cortex and thalamus, not to mention back to the hypothalamus to control homeostasis regulation.**
 * **Describe the role of the hypothalamus in emotional and motivated responses. What is ‘sham rage’?**
 * **Emotions are connected, through the hypothalamus, to release of various ANS effects (blushing, dry mouth, sweating, GI effects, fainting), hormones (cortisol, epinephrine), and somatic responses (facial expression, violent behavior).**
 * **Sham rage: animal responds with short-lived but coordinated, aggressive responses (biting, etc) to inoffensive stimuli (soft sounds, movement, gentle touch). Note it's often inappropriately directed (at self, objects, etc).**
 * **Seen when the hypothalamus is disconnected from the limbic system but left connected to the brainstem.**
 * **Note that if you separate the hypothalamus from the autonomic and somatic motor systems but leave it connected to the limbic system, you stop the sham rage behavior.**
 * **If you lesion the ventromedial nucleus on both sides, you get sham rage. If you __stimulate__ the dorsomedian nucleus on one side, you also get sham rage.**
 * Limbic System/Hippocampus and Memory/Amygdala**
 * Friday, September 26, 2008**
 * 7:46 AM**

Anxiety Disorders, 9/30/08:
 * **[Limbic system control:]**
 * H**omeostasis**
 * O**lfaction**
 * M**emory**
 * E**motion**
 * **Understand the difference between declarative and procedural memory. What kind of memory is impaired in lesions of the hippocampus vs the cerebellum/basal ganglia?**
 * **__Declarative__ memory: the ability to recollect events or facts that have a specific temporal and spatial context ("Yesterday I sat on the couch and watched the Saints get their asses kicked by the Broncos, damn it. Who can't make a 3rd and 1 conversion, for God's sake?") or general knowledge about a subject ("every time the Saints start out 1-2 they never manage to make anything of the season").**
 * **__Procedural__ memory: the ability to learn, and recall, new motor skills ("I decided to become a fullback to make sure that they can make the 3rd and 1 next time").**
 * **Hippocampal lesions tend to result in declarative memory loss.**
 * **Cerebellar/basal ganglia lesions tend to result in procedural memory loss.**
 * **Understand the concepts of short-term, working and long-term memory. What kind of memory is affected by lesions of the frontal cortex?**
 * **Short-term memory: memory that lasts up to a few seconds. Employed by sensory systems, and stored in the sensory cortex, to provide sensory continuity (which is why, to borrow an Eastern concept, you only step into the stream once- after that, you're already standing there).**
 * **Working memory: memory of slightly longer but still relatively immediate length (few minutes). Stored in the frontal cortex where executive function control centers are located.**
 * **When you're hunting for your keys, remembering where you've already looked is working memory. Remembering that there's somewhere you always put your keys and that you should probably look there is long-term memory (see next).**
 * **Other examples of working memory from the notes: remembering if you've just added salt to what you're cooking, being able to recite a sequence of numbers forward and backwards.**
 * **Germane to the LO, working memory is particularly affected by frontal-cortex lesions.**
 * **Long-term memory: memory that lasts for days and years (eg. memory of faces). It's stored in the cortex (but not, mainly, in the hippocampus; see below).**
 * **Understand the reason for the memory deficits displayed by patient HM.**
 * **Bilateral medial temporal lobectomy (including hippocampus and amygdala; to treat temporal lobe epilepsy) resulted in a severe deficit in being able to __form new declarative memories__ (anterograde amnesia).**
 * **Working memory is intact; short-term memory is intact; procedural memory is intact.**
 * **Long-term memory of events before the surgery is absent up to a certain point (partial retrograde amnesia) but relatively complete before that point (can recall the house he grew up in).**
 * **What is the experimental evidence showing that the neocortex is the site for long term memory storage?**
 * **HM can't make new long-term memories, but can still access most of the ones he had before the surgery (thus hippocampus can't be the site of long-term memory storage, though it's involved in the act of storing them).**
 * **Also lesion/fMRI studies indicate that the neocortex (6-layered, vs. the 3-layered archicortex hippocampus) is active in storing long-term declarative memory.**
 * **[Input to the hippocampus: the __perforant path__ (axons from the** entorhinal cortex**) synapses onto the dentate gyrus and also the CA3 neurons in Ammon's horn.]**
 * **[Interconnections in the hippocampus:]**
 * **Mossy fibers from dentate gyrus to CA3 neurons.**
 * **Schaeffer collateral fibers from CA3 neurons to CA1 neurons.**
 * **[Output from the hippocampus: from CA3/CA1 neurons through the fornix to the mammillary bodies and septal nuclei.]**
 * **Understand how Long Term Potentiation (LTP) can account for associative memory.**
 * **__Associative memory__: use a subset of cues to recall other things you've learned to associate with those cues (ringing bells and food, or scents and exits to a maze, etc).**
 * **Essentially this gets back to "neurons that fire together, wire together."**
 * **Cues that co-occur with sufficient strength of stimulation become stronger, eventually such that you need to stimulate a smaller subset of those cues, and you don't need to stimulate them as strongly, to fire the hippocampal 'memory' neuron associated with all of them.**
 * **Say you have 12 cues from the 2006 NFC championship game (Bears, Saints, NFC, championship game, 2006, snow, loss, final score, missed field goals, etc), all of which synapse weakly onto a hippocampal neuron that is involved with the memory of that game. By themselves, no one or two of these stimuli are enough to fire that hippocampal neuron's AP. But with enough repetition and co-exposure to those cues, the hippocampal neuron that corresponds to that NFC championship game will fire whenever you get "Bears vs. Saints," or "Saints in the snow," etc.**
 * **Under what circumstances do hippocampal synapses undergo LTP?**
 * **Essentially, whenever they're firing at the same time that the postsynaptic membrane is depolarizing (whenever they're contributing to the depolarization, whether or not they're strong enough to cause the depolarization on their own). See next LO.**
 * **Describe the molecular basis for LTP.**
 * **You have a bunch of neurons connected with various cues that all weakly synapse on a hippocampal neuron's dendrites.**
 * **Recall that co-activation of presynaptic terminals onto a depolarizing postsynaptic membrane increases the strength of those terminals (more NT released, more receptors inserted in the postsynaptic membrane) and only those terminals.**
 * **Plasticity of dendritic spines (a given 'spine' off a dendrite presumably being where a given axon synapses) seems to be involved in memory-- the cytoskeletal arrangement of the dendrite alters, possibly in response to the insertion of additional AMPA receptors into its membrane.**
 * **Refer to the "Molecules to Memory" discussion on LTP for specifics on AMPA/NMDA receptor roles in all this.**
 * **Note that this mechanism seems mainly to apply to perforant path axons synapsing onto CA3 neurons (input, not to the dentate gyrus) and Schaeffer axons from those CA3 neurons synapsing onto CA1 neurons (interconnection, not from the dentate gyrus).**
 * **How could synapse formation and adult neurogenesis be involved in learning and memory?**
 * **Yeah. How can adding new associations and having neurons fire with new trained stimuli be involved in learning and memory, anyway?**
 * **Understand the amyloid hypothesis of Alzheimer’s. What are the implications of this hypothesis for development of new treatments for this disease?**
 * **Amyloid precursor protein (APP): a membrane protein of unknown function in CNS neurons.**
 * **There are three proteins that cut APP: alpha-, beta- and gamma-secretases.**
 * **Alpha secretase cuts APP in the middle of the lipophilic portein; this doesn't seem to cause Alzheimer's.**
 * **If the APP is cut by both beta- and gamma-secretases, they clip off the hydrophilic regions on each side of the lipophilic portion. This leaves a big lipophilic APP region floating around, which is ideal conditions for forming aggregations (or plaques) of such proteins-- they'll clump together to reduce lipophilic exposure to the aqueous extracellular environment. That's the amyloid plaques that you see on histology, and they seem to contribute to Alzheimer's (along with fibrillary tangles made of tau protein).**
 * **Understand the role of the limbic system and the amygdala in emotion.**
 * **Kluver and Bucy lesioned the entire anterior temporal lobe (hippocampus intact) in monkeys. Effects:**
 * **(1) Oral fixation**
 * **(2) Hypersexuality**
 * **(3) Total absence of fear and visual agnosia**
 * **This constellation is called __Kluver-Bucy syndrome__.**
 * **The amygdala is involved in the associative learning that connects stimuli with other, unpleasant stimuli (drink too much = coyote morning).**
 * **Rats with excised amygdalas can't learn to associate stimuli with negative consequences. See next LO.**
 * **Understand the mechanism of conditioned flavor aversion.**
 * **Essentially if you couple a normally pleasant flavor with a very unpleasant effect - even once - you can create a visceral aversion to the flavor.**
 * **Note that there's a fair amount of wiggle room in that coupling (there's an awkward sentence)-- stimuli that are separated by half an hour can still produce the association.**
 * **So how does this work? Clearly it's not a simple fire-together-wire-together deal-- the neurons aren't firing together, one follows the other by 30 minutes.**
 * **So say you eat something, wait about 30 minutes, and then puke it up again. This means the taste signal (to insular cortex) has to stick around for half an hour before the gut signals (from vagus nerve) get around to doing their thing.**
 * **Taste neuron from the basal forebrain releases ACh on a muscarinic receptor in the insular cortex. This activates __kinases__, which potentiate NMDA receptors to be more easily activated by glutamate.**
 * **Note this has to be a __novel__ taste signal.**
 * **Upset insides send a signal through the amygdala, which in turn sends out a fiber to release glutamate in the insular cortex. This activates only the NMDA receptors that were 'primed' by the kinase potentiation, resulting in traditional co-activation synapse strengthening. Obviously, since only one instance can result in conditioned aversion, this synapse strengthens quite significantly.**
 * **Essentially it's kinase-mediated, delayed-action associative learning. The kinase's phosphorylation can stick around for quite a while, leaving the NMDA receptors primed to pair with an unpleasant stimuli.**
 * **This is the basis for flavor aversion in chemotherapy: anything you eat, you learn to associate with all the unpleasant effects of chemotherapy. So those flavors are stuck being associated with the vomiting, etc. This is why you make sure your patients on chemo eat bland food after their treatments (to avoid associating specific tastes with the side effects).**
 * **Note this same general mechanism works in the amygdala for lots of types of stimuli, not just taste.**
 * Anxiety Disorders**
 * Tuesday, September 30, 2008**
 * 7:58 AM**

Anxiolytics, 9/30/08:
 * **Summarize the available knowledge concerning the etiology and pathophysiology of panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder.**
 * **OCD: essentially an imbalance of the direct-indirect dopamine-driven pathways in the basal ganglia. The indirect pathway (inhibitory) is repressed relative to the direct pathway (excitatory); this results in thalamic disinhibition for specific pathways of behavior.**
 * **The others: less is known, but they seem to result from a deficit in the relay between the cortex (prefrontal/SS/hippocampus)/thalamus and the amygdala (decreased BDZ receptor activity/decreased GABA efficacy? increased NE release?). This results in increased amygdalar activity:**
 * **Increased __norepinephrine release__ from the locus coeruleus**
 * **Increased __respiratory rate__ (through lateral nucleus of the hypothalamus)**
 * **Increased stimulation of the paratuberal hypothalamus to prompt __release of cortisol__**
 * **PAG effects (not the ones we're used to, but other effects that stimulate __defensive behavior__)**
 * **Discuss the diagnosis and management of panic disorder, agoraphobia, social phobia, generalized anxiety disorder, and obsessive compulsive disorder.**
 * Panic disorder**: sudden, overwhelming anxiety, without a specific trigger; also anticipatory anxiety about the next panic episode. Note this has both a somatic component (mainly sympathetic over-activation symptoms) and a psychological component (dread, feeling of dying, etc). Usually starts in early adulthood. Note that there's always a '__herald symptom__' that precedes the panic attack.**
 * Generalized anxiety**: anxious not in "discrete episodes," but all the time. Frequently their worries don't allow for rational resolution; they also catastrophize. Sound like anyone you know? __Extremely high comorbidity rate__ with other psychiatric disorders.**
 * Social phobia**: anxious about relating to others, particularly when the patient is the center of attention. Most common anxiety disorder.**
 * Agoraphobia**: anxiety about being in certain places or situations (outside alone, in a crowd, in a vehicle, etc) where escape is difficult or help is unavailable.**
 * OCD**: either obsessions (persistent thoughts, usually about violence or sex) or compulsions (repetitive behaviors), or both (typically __obsessions cause anxiety and the compulsive behavior relieves it__).**
 * **Management: see below under "treatments."**
 * **List the common general medical and substance-induced causes of anxiety, and assess for these causes in evaluating a person with an anxiety disorder.**
 * **Thyroid/parathyroid disorders, CV abnormalities, pheochromocytoma, hypoglycemia, smoking pot (wow. really?), and withdrawing from EtOH and other drugs.**
 * **[Note that the physiologic response to anxiety frequently causes cognitive distortions that feed the anxiety, causing more symptoms, etc.]**
 * **Outline psychotherapeutic and pharmacologic treatments (as appropriate) for each of the anxiety disorders.**
 * **Panic disorder: SSRIs, BDZs, MAOIs, tricyclics. Also cognitive-behavioral therapy (CBT) for relaxation techniques, graded exposure, and to fix cognitive distortions about the meaning of the attacks.**
 * **Generalized anxiety: SSRIs, BDZs, buspirone (partial agonist of seratonin receptors), venlafaxine; CBT to stop catastrophizing.**
 * **Social phobias: MAOIs, SSRIs, BDZs, beta-blockers. CBT in groups works well.**
 * **OCD: high-dose SSRIs, serotonin-specific tricyclics, atypical antipsychotics. Also exposure therapy/response prevention.**
 * **Discuss the role of anxiety and anxiety disorders in the presentation of general medical symptoms, the decision to visit a physician, and health care expenditures.**
 * **Note these are quite common (social phobia affects 1 in 8 people).**
 * **Note that most patients won't come in specifically complaining of anxiety (and about a quarter of patients with anxiety disorder will specifically deny it). Need to keep in mind that the more symptoms that a patient comes in complaining of, the more likely an underlying diagnosis is depression and/or anxiety.**
 * **Note that patients with panic disorders tend to come in to the doctor a lot for reassurance about their symptoms. Note also that patients with social phobias usually don't come in for treatment of it.**
 * Anxiolytics**
 * Tuesday, September 30, 2008**
 * 9:06 AM**

Mood Disorders, 9/30/08:
 * **Know that sedatives and hypnotics can act to produce anything from mild sedation to anesthesia, depending on the class of drug being used and the dose being administered.**
 * **Yeah. See "Treatment of Sleep Disorders."**
 * **[Helpful little scale of effects moving down GABA vs. glutamate tone:]**
 * **Convulsions (most Glu-tonic)**
 * **Insomnia**
 * **Anxiety**
 * **Enhanced learning and memory**
 * **Normal (midpoint)**
 * **Anxiolytic/hypnotic**
 * **Medullary effects (depressed respiration, etc)**
 * **Coma (most GABA-tonic)**
 * **Understand that anxiolytic drugs reduce anxiety, but most anxiolytics (notable exception being buspirone) also produce some sedation and interact with other sedative hypnotics, particularly alcohol.**
 * **Ok. Note, though, that buspirone takes a week or so to start working.**
 * **Have a clear understanding that GABA is the major inhibitory neurotransmitter in the central nervous system and both benzodiazepines and barbiturates potentiate GABA's actions in the CNS.**
 * **You betcha.**
 * **Understand that benzodiazepines do not have action on their own at the GABA receptor, but only act to potentiate GABA's actions. In other words, they need GABA to have an effect.**
 * **Sure thing.**
 * **But note that the BDZs __do__ bind to the GABA receptors (specifically to the alpha subunit; also need gamma subunit); they have no direct agonist action there, but they increase the opening frequency of the receptor's Cl- channel.**
 * **Understand that barbiturates can activate the GABA receptor chloride channel complex without GABA present.**
 * **Oh, ya.**
 * **But note that barbiturates at low doses just bind to keep the Cl- channel open for longer when it's been bound with GABA. Only get direct agonist activity at GABA receptors with higher doses.**
 * **Barbiturates bind the alpha and beta subunits; don't need gamma subunits.**
 * **Note also that barbiturates have effects on non-GABA receptors as well.**
 * **Know that benzodiazepines have a high therapeutic index, while barbiturates have a low therapeutic index.**
 * **No kidding?**
 * **Understand that barbiturates are currently used primarily as anticonvulsants and not often used as sedatives or anxiolytics.**
 * **How about that! Bet it has to do with safety and efficacy profiles!**
 * **Understand that both barbiturates and benzodiazepines can produce physical dependence.**
 * **Verily, sirrah. Anxiolytic, what? Perhaps they associate with ye olde ventral tegmental dopaminergic pathways mentioned in "Pharmacology of Reward."**
 * **Understand the toxicities associated with barbiturates and benzodiazepines.**
 * **BDZs: amnesia, additive interaction with other sedatives and EtOH, dizziness, nausea, psychological effects, dependence, tolerance (not to anxiolytic effects), dry mouth with chronic use.**
 * **Barbiturates: hypotension, depression of myocardium, respiratory depression, low pain threshold, porphyria (inhibition of heme synthesis, buildup of porphyrins [heme precursors]: cause abdominal pain, psychological and sympathetic effects, nausea, vomiting, neuropathy, seizures).**
 * **Understand the major limitations in the use of benzodiazepines for treatment of insomnia and know a suitable alternative drug.**
 * **BDZs: daytime somnolence, reduction of stage 3/4 NREM sleep and REM sleep. Since they act as anxiolytics, they also have abuse potential.**
 * **Alternative drug of choice these days is zolpidem (Ambien). Less daytime somnolence, less reduction of stage 3/4 NREM and REM sleep. Only acts on BZ1 (alpha-1 subunit-containing) receptors and not BZ2 receptors, so no anxiolytic activity and less potential for abuse. This is now the drug of choice for insomnia.**
 * **Have a clear understanding that differences in the duration of action and potency of benzodiazepines many times determines whether these agents are used primarily as sedatives to treat insomnia, anxiety or panic attacks. Also understand how the structure relates to the duration of action and potency of BDZs.**
 * **__Insomnia__: generally want drugs with short half-lives (avoid daytime sedation):** triazolam **(Halcion) and (for nighttime awakening)** alprazolam **(Xanax).**
 * **__Antianxiety__: generally want drugs with longer half-lives-- __anything except triazolam__. In the elderly, preferably use drugs that don't need intact Phase I metabolism (see below): specifically** oxazepam**/Serax and** lorazepam**/Ativan.**
 * **__Panic attacks__: generally want high-potency, medium- to long-acting drugs; drug of choice is** alprazolam **(Xanax).**
 * **Here follows a long discussion on chemical structure and metabolism.**
 * **Structure that determines __activity__ (as distinct from binding): R7 group and C ring. Note that this is the basis for the action of __flumazenil__ (competitive antagonist of BDZs): has no C ring, thus no action, but still binds to the same BZ receptor sites.**
 * **Structure that determines __potency__: R'2 group. Note also that whether or not the drug binds to plasma proteins affects potency (less binding = more potency).**
 * **Metabolism (ie. duration of action):**
 * **Phase I metabolism:**
 * **Stage 1: any substituents at R1 or R2 are rapidly removed. This generally __activates__ the compound. Note this doesn't apply to __triazolam__ and __alprazolam__, which are rapidly inactivated (2-4 and 10-15 hours' half-lives, respectively) due to hydroxylation of their triazolo rings and subsequent conjugation.**
 * **Stage 2: R3 is very slowly (half-life of 80 hours) hydroxylated. This doesn't inactivate the compound.**
 * **Note that __oxazepam__ and __lorazepam__ are already hydroxylated there and thus have an intermediate half-life (10-20 hours).**
 * **Note that this means that the metabolism of those two BDZs isn't dependent on CYP function, which is why you use them preferentially in the elderly.**
 * **Note that this leaves __diazepam__, __flurazepam__, and __chlordiazepoxide__ as having half-lives of 80 hours.**
 * **Phase II metabolism:**
 * **Conjugation of R3-hydroxylated drugs finally inactivates the suckers.**
 * **[Note that enough decrease in REM sleep produces psychosis.]**
 * **[Note that BZ1 receptors (sedation and amnesia effects) contain alpha-1 subunits; BZ2 receptors (anxiolytic and muscle relaxant effects) contain alpha-2 and alpha-5 subunits. This is the basis for the NBRAs' specificity for the BZ1 receptor.]**
 * **[Note alternative anxiolytic drug: __buspirone__: binds to serotonin and dopamine receptors, doesn't cause sedation, no interaction with EtOH, some antidepressant activity, no effect on GABA system. Note that it takes about a week to start working, so not good acutely.]**
 * Mood Disorders**
 * Tuesday, September 30, 2008**
 * 9:53 AM**
 * [Lecture, notes, and LOs intersect at crazy skewed angles (where they intersect at all). Best guess follows.]**

Anti-Psychotic Agents Anti-Psychotic Agents, 10/1/08:
 * Understand the differences between depressive symptoms and major depression, why the distinction is important, and consistently attempt to differentiate between the two in general medical patients.
 * Major depression is a diagnosis; depressive symptoms are just that: symptoms. As detailed below, major depression has specific requirements for diagnosis. I imagine it's important because treatment of major depression is tailored to patients with those specific symptoms (and also because psychiatry is over-eager to maintain itself as an exact science with exact, neat diagnostic borders).
 * Discuss whether or not treatment of the syndrome of major depression should depend on whether sadness seems "understandable" in a given patient.
 * Foundations moment: here's your mandatory personal growth experience.
 * Discuss the common signs and symptoms, differential diagnosis, course of illness, comorbidity, prognosis, and complications of mood disorders.
 * Look for SIGECAPS (sleep, interest, guilt, energy, concentration, appetite, psychomotor disruption (observable), suicidal ideation). Must be a change from normal function.
 * __Five__ of those in addition to either anhedonia or subjective depression are required for the diagnosis of.
 * Differential:
 * Medical disorders
 * Medication effects
 * Substance abuse
 * Personality ("sorry, son, you're just plain nuts.")
 * Mood disorder
 * Natural history: Age of onset: ~40 yrs (50% between 20-50). Often preceded by stressful events. Untreated can last 6-13+ months. Treated can last 3+ months. Tends to happen with greater frequency as disorder goes on.
 * Comorbidities: common.
 * Prognosis: risk of recurrence goes up with the number of episodes the patient's had.
 * Complications: Altered stress response (hyperactive cortisol axis), hippocampal atrophy.
 * Compare and contrast the epidemiologic and clinical features of unipolar depression and bipolar (I) disorder.
 * Unipolar depression: no manic episodes (elevated mood/sustained irritability). Tends to run in families (risk of __both__ unipolar and bipolar depression increases; unipolar depression risk goes up more).
 * Bipolar disorder I: manic episodes. __Technically does not include depression__ but the vast, vast majority have depression too. Also tends to run in families (and again, risk of both unipolar and bipolar depression increases; bipolar depression risk goes up more).
 * Note that bipolar disorder tends to occur earlier in life than unipolar depression.
 * Manic episodes:
 * Most commonly euphoria and irritability; also risk taking, agitation, appetitive behaviors increase, talking fast, inflated self-esteem, diminished need for sleep, easily distracted, etc.
 * [Note that bipolar II disorder is depression and hypomania with or without manic episodes. Just to confuse the issue.]
 * Summarize the available knowledge concerning the etiology and pathophysiology of major depression and bipolar disorder.
 * The idea that depression is purely a monoamine deficiency has been shown to be incomplete. However, monoamine supplementation obviously has an effect.
 * Psychosocial theory of depression: Loss, particularly at an early age, high-conflict relationships, depression feeds on itself, learned helplessness.
 * Bipolar disorder: inferred from effective treatment (lithium, anticonvulsant meds), but very limited understanding. There are a list of potential molecular culprits on page 11 in her notes. Note that the depression in bipolar disorder is very refractory to treatment.
 * Know the most common general medical causes of the depressive syndrome.
 * __Endocrine__ disease: thyroid disorders, diabetes mellitus.
 * __Malignancy__: pancreas, breast, brain, lung, lymphoma; resultant nemias.
 * __Infections__: HIV, hepatitis, mononucelosis.
 * __Autoimmune__: SLE, rheumatoid arthritis, fibromyalgia.
 * __Neurological__: traumatic brain injury, Parkinson's, Huntington's, brain tumors, dementia.
 * [Hokey mnemonic: New Autos Incite Malign Emotion.]
 * Consistently include general medical causes of depression in the differential diagnosis of major depression.
 * Yeah.
 * Discuss the impact of major depression on morbidity and mortality in patients with general medical/surgical illness.
 * It makes it worse.
 * Discuss the identification and management of suicide risk in general medical setting, including discussion of the physician's responsibility.
 * Not much in notes on this. I imagine it's fairly self-explanatory, at least in this setting.
 * Screen for depression in general medical patients, and evaluate more fully when indicated.
 * Yeah.
 * State the characteristics and techniques of psychological treatments for depression, including cognitive therapy and interpersonal therapy.
 * Not much in notes on this.
 * Pharmacology + psychotherapy: one by themselves for less severe depression, both for more severe depression.
 * Electroconvulsive therapy: very effective, very safe. Has side effects, particularly on memory function. Good for actively suicidal patients or if the depression's refractory to all other treatment.
 * Wednesday, October 01, 2008**
 * 8:00 AM**

Antidepressants and Mood Stabilizers, 10/1/08:
 * **Know the diagnostic criteria for schizophrenia, its prevalence, and usual age of onset.**
 * **Criteria: generally, 2 required for at least a month:**
 * **Delusions**
 * **Hallucinations**
 * **Disorganized speech**
 * **Grossly disorganized or catatonic behavior**
 * **Flattened emotional affect (note that typical antipsychotics can cause this as well; see below)**
 * **Also look for social withdrawal and symptoms lasting for more than 6 months.**
 * **Ensure that symptoms are not due to mood disorders, other medical conditions, or substance abuse.**
 * **Prevalence: about 1% of population.**
 * **Usual age of onset: late adolescence/early adulthood.**
 * **Note suicide has a 10% lifetime prevalence in schizophrenics.**
 * **Know the role of dopaminergic neurons in psychosis and movement disorder.**
 * **[Effectively, in schizophrenia you have a __lack of appropriate inhibition of input__: you get sensory overload, not being able to distinguish relevant from irrelevant (free information flow to the cortex). This seems to be caused by an underlying loss of GABA-ergic tone and dominance of glutamatergic tone in pyramidal neurons, possibly due to lack of inhibitory interneurons. Note this is also likely to cause seizures.]**
 * **Agonism of dopaminergic neurons with cocaine and amphetamines can cause schizophrenic symptoms (psychosis, hallucination, delirium): it increases the pyramidal neuron response to glutamate excitation.**
 * **Note that norepinephrine releasing agents and serotonin agonists can cause these symptoms as well; they all seem to involve increasing the stimulatory tone, or decreasing the inhibitory tone, of pyramidal neurons.**
 * **Note also that cholinergic antagonists at high doses (become anti-nicotinic) can have similar effects.**
 * **Dopaminergic neurons makes the cortical pyramidal neurons more responsive to input: they create hypervigilance. Dr. Freedman: "every time you go into a new place your dopamine levels go sky-high."**
 * **The dopamine levels generally __don't go any higher than normal people__ in schizophrenics, but without inhibitory interneurons, they can't choose what to pay attention to-- so they have to pay hypervigilant attention to everything at once without being able to effectively discriminate.**
 * **Again, note that the problem generally isn't in the dopaminergic neurons per se but in the lack of interneurons causing an increased stimulatory tone or decreased inhibitory tone in the pyramidal neurons. Normal, fluctuating levels of dopamine just expose and exacerbate the problem.**
 * **Note that smoking seems to help the inhibitory (discriminatory) interneurons work (helps focus attention), at least for a short time; thus nearly all schizophrenics are heavy smokers.**
 * **Know the two major classes of neuroleptic drugs, their side effects, and proposed mechanism of action.**
 * **Note that neuroleptics are also called antipsychotics.**
 * **Typical (or first-generation) antipsychotics, aka major tranquilizers (**chlorpromazine **and related drugs):**
 * **Mechanism of action: block dopaminergic neurotransmission by competing for post-synaptic D2 receptors in the caudate nucleus (recall that a blockade of D2 receptors will prevent dopamine from inhibiting the indirect, inhibitory pathway; an inhibition of the inhibition of thalamic inhibition results in more thalamic inhibition). Reduces catatonia, reduce acute psychotic episodes in about 75% of schizophrenia patients.**
 * **Note that this mechanism does nothing to address the underlying pathophysiology; it affects the __normal__ functional of dopaminergic neurons to avoid exacerbating the underlying disorder.**
 * **Side effects: mostly due to effects on dopaminergic neurons and interference with other catecholamine receptors.**
 * **__Parkinsonian syndromes__ (decreased dopaminergic transmission); they also produce a flat, fixed, indifferent affect.**
 * **Prolactinemia: dopamine normally inhibits the release of prolactin from the anterior pituitary.**
 * **Hypothalamic dysregulation: increased appetite, poikilothermia (loss of ability to regulate body temperature). Watch out for malignant hyperthermia.**
 * **Depression (CNS neurotransmission blockade)**
 * **Hypotension (sympathetic blockade effect)**
 * **Sunburn (interference with melanocyte function)**
 * **Agranulocytosis**
 * **Atypical (or second-generation) antipsychotics (**clozapine **and related drugs):**
 * **Mechanism of action: weaker dopaminergic blockade; blocks several types of receptors for serotonin, norepinephrine, and acetylcholine as well.**
 * **Side effects:**
 * **No Parkinsonian syndromes, but high incidence of __agranulocytosis__.**
 * **Also drooling, increased weight gain, obsessions, hypercholesterolemia, diabetes mellitus.**
 * **[Note also "aripiprazole" ("Abilify"): mixed dopamine agonist (at low levels of dopamine) and antagonist (at high levels of dopamine). The problem is that it's not a strong antagonist, which can allow acute schizophrenic effects. Some patients see a benefit from combining it with a lower dose of a typical antipsychotic.]**
 * Antidepressants and Mood Stabilizers**
 * Wednesday, October 01, 2008**
 * 9:03 AM**

Pharmacology of Reward Pharmacology of Reward, 10/2/08:
 * Know the major classes of mood altering drugs, their mechanism of action, and major side effects.
 * Antidepressants:
 * Common mechanism of action: all stimulate serotonergic neurotransmission, noradrenergic neurotransmission, or both. Note that all of them only have mood effects __several weeks after__ beginning treatment.
 * Common side effect: induction of mania.
 * Watch for agitation about a week or a week and a half after beginning treatment; these patients more commonly attempt suicide.
 * Selective serotonin reuptake inhibitors:
 * Work by blocking serotonin reuptake transporters.
 * Low toxicity; thus safer vis-a-vis intentional overdose by patients than tricyclics or MAOIs.
 * Side effects: anxiety, motor restlessness. Nausea, weight loss. Cause delayed orgasms. Don't combine with MAOIs or you get __serotonin syndrome__ (fever, hyperreflexia, sweating, tremor, diarrhea). Can be CYP inhibitors (thus decrease metabolism of barbiturates and BDZs).
 * Norepinephrine and dopamine reuptake inhibitors:
 * Work by inhibiting some of DA, NE, and 5-HT reuptake transporters.
 * Side effects: anxiety, restlessness, and headache.
 * "Other" serotonin reuptake inhibitors:
 * Work by antagonizing serotonin reuptake transporters as well as postsynaptic receptor antagonists.
 * Side effects: somnolence; occasionally priapism.
 * Tricyclics and tetracyclics:
 * Work by blocking norepinephrine and serotonin reuptake transporters.
 * Note that these prevent relapse of depression for many years, as opposed to the others, which often lose effectiveness in 6-12 months.
 * Note also are the only drugs with proven efficacy in treating __melancholia__ (severe depression).
 * Side effects: __highly anticholinergic__; cause dry mouth, constipation, blurred vision. Overdose causes anticholinergic coma. Also act like quinidine (class Ia, Na+ channel-blocking antiarrhythmic) and can thus cause arrhythmias and orthostatic hypotension. Blocks guanethidine (antihypertensive medication). Certain tetracyclics can cause seizures as well.
 * Monoamine oxidase inhibitors:
 * Work by inhibiting the presynaptic terminal's mitochondrial oxidation of monoamines.
 * Side effects: can cause chronic __hypo__tension (packaging of false neurotransmitters into vesicles) or acute, sometimes fatal __hyper__tension if a stimulant is taken or high-tyramine foods are ingested.
 * Antimanics:
 * No known mechanism of action.
 * Side effects:
 * Lithium carbonate: narrow therapeutic window, nausea/vomiting, tremor, __nephrogenic diabetes insipidus__ (no ADH effect), nontoxic goiter, CNS and cardiac depression, endocardial cushion defect in fetuses. Note that it's absorbed in competition with sodium in the proximal tubule and the stomach.
 * Antiseizure drugs (carbamazepine and valproic acid): increase hepatic metabolism of other compounds. Carbamazapine can cause bone marrow suppression.
 * Stimulants (amphetamines):
 * Mechanism of action: catecholamine-like compounds (bind to reuptake and vesicle transporters, not to receptors); bind to, but are resistant to the effects of, monoamine oxidase. Have no direct agonist action, but displace catecholamines from vesicles, whence they are released into the synapse. Highly lipophilic (orally absorbed, cross BBB).
 * Used for narcolepsy and ADHD. Watch out for people using it for weight loss.
 * Get rapid development of tolerance.
 * Side effects: with long-term use, reduce stores of NTs (releasing it faster than you can make it) and create depression and postural hypotension. With long-term or high-dose use can also see psychosis. Also can see choreoathetosis (movement disorder with a combination of chorea and slow writhing movements). Generally get dysphoria.
 * Note that the dysphoria can be avoided with concurrent use of an opioid. A popular way to combine the effects is meperidine or cocaine + heroin.
 * Anti-migraine agents:
 * Mechanism of action: decreases or increases release of serotonin.
 * Side effects: migraine-like aura, sterile inflammation, vasoconstriction and/or dilation.
 * Know the role of serotonin and norepinephrine in mood disturbance.
 * It's not clear whether monoamine levels are the primary culprit or a secondary effect in depression. The fact that the antidepressant effects are only seen several weeks after initiating therapy also muddies the waters. That said, there is clearly an effect there.
 * [Note that none of the drugs are as effective as electroconvulsive therapy-induced seizures.]
 * Thursday, October 02, 2008**
 * 9:03 AM**

Drugs of Abuse Drugs of Abuse, 10/2/08:
 * Identify the brain systems important for reinforcing (rewarding) properties of abused substances.
 * Ah. Gotta love the "summarize my notes and lecture for me" LOs. Here goes.
 * __Ventral tegmental__ dopaminergic systems (dopaminergic neurons in the midbrain) are activated by various abused substances.
 * These release dopamine onto the prefrontal cortex (PFC), amygdala, striatum, and nucleus accumbens.
 * This provides a "salience signal" to those systems-- "this is a stimulus worth paying attention to."
 * [The PFC and amygdala decide if the stimulus is worth paying attention to because it's good or because it's bad. In the case of addictive drugs, it's usually good.]
 * The main thing we're paying attention to here: there's one line from the PFC to the nucleus accumbens, and another from the nucleus accumbens on to the amygdala.
 * The first line (PFC to NAc) is significant because the PFC contains the executive centers, which normally decide (based on memory input from the hippocampus) whether or not to perform a given action given context, self-concept, etc. This means they can inhibit the second line (see next point).
 * The second line (NAc to amygdala) is significant because the amygdala, through striatum, affects the pallidum, which in turn affects (through modification of the thalamus) movement; specifically, drug-seeking movement.
 * In the early or light stages of drug usage, excitation (or, more precisely, the cessation of inhibition caused by dopaminergic stimuli; see below) of the amygdala by the NAc can be inhibited by the PFC via the first line.
 * But under certain conditions, the first line's input can be dulled or stopped entirely. The conditions in question involve __potentiation of dopaminergic midbrain neurons__ caused by chronic/heavy use of drugs, and is the neuro-adaptive basis for drug dependence. Dependence is caused by the loss of the PFC's ability to send inhibitory signals to the amygdala through the nucleus accumbens (specifics follow), meaning that the individual has a diminished degree of control over whether or not to engage in drug-seeking behavior. This is also called "hypofrontality."
 * Here's the skinny.
 * The nucleus accumbens is GABA-ergic to the amygdala (sends inhibitory signals to it).
 * Dopamine input to the nucleus accumbens (as from the midbrain tegmental neurons during drug stimulation), without a concomitant signal from the PFC, inhibits (via D2 receptors) the inhibition on the amygdala, producing drug-seeking behavior.
 * Normally, the PFC sends discretionary __glutamatergic__ input to the nucleus accumbens, thus stimulating its inhibition of the amygdala through the following mechanism: if the nucleus accumbens gets inhibitory DA input from the tegmentum and excitatory Glu input from the PFC at the same time, the dopamine from the tegmentum stimulates (rather than inhibits) the nucleus accumbens' amygdalar inhibition.
 * But with enough dopaminergic input (as with potentiation of dopaminergic neurons with chronic drug use), certain gene expression patterns get altered such that the PFC is incapable of sending this stimulatory Glu output any more.
 * [Not to confuse this issue further, but I can't see how the article he gave us to read (see below) doesn't say exactly the opposite (increased glutamatergic stimulus from the PFC to the nucleus accumbens is seen in addicted drug-seeking behavior, p. 166). I've emailed him on this; haven't heard back yet.]
 * Recall also that the hypothalamic system controls release of hormones from the pituitary; dopamine secreted from tegmental stimulation will also, through the hypothalamus, inhibit secretion of growth hormone and prolactin from the pituitary.
 * [Note negative reinforcement defined as something that __produces relief from a negative stimulus__ (not something that discourages behavior with negative stimuli: that's aversive conditioning). As it's defined here, reinforcement is always __towards__ a behavior and not __away__ from one.]
 * [Article we're supposed to read on this: Kalivas, P, and O'Brien, C. Drug Addiction as a Pathology of Staged Neuroplasticity. Neuropsychopharmacology Reviews, 2008 vol. 33, p. 166-180. You may be able to access it directly from on campus through [].]
 * Thursday, October 02, 2008**
 * 10:06 AM**

Alcohol, 10/2/08:
 * **Know the criteria which make up the definition of substance abuse and dependence (DSM IV criteria).**
 * **Substance abuse: one or more of the following:**
 * **Recurrent substance use resulting in a failure to fulfill obligations at work, home, or school.**
 * **Recurrent substance use in physically hazardous situations (while driving, operating heavy machinery, or doing brain surgery).**
 * **Recurrent substance-related legal problems.**
 * **Continuation of drug use despite persistent social problems arising from it.**
 * **Substance dependence: three of more of the following:**
 * **Tolerance: either a need for markedly increasing amounts of the drug to achieve the same effects or a markedly decreased effect of the same amount of the drug.**
 * **Withdrawal: either the characteristic withdrawal syndrome for that drug or taking the drug or a related drug to avoid the withdrawal syndrome.**
 * **The substance is taken in larger amounts or for a longer period than was intended.**
 * **Persistent desire or attempts to cut down or control substance use.**
 * **Obtaining the substance, using the substance, or recovering from the substance takes a lot of time and/or energy.**
 * **Various social/recreational/occupational activities are given up due to substance use.**
 * **Substance use continued despite knowledge of negative physical and psychological effects of substance.**
 * **Be able to identify the brain systems important for reinforcing (rewarding) properties of abused substances.**
 * **I think we talked about this in the last lecture.**
 * **Identify six major classes of abused drugs. Be able to provide an example from each class. What properties do the drugs of these classes have in common? In what respects are they different? What are their mechanisms of action?**
 * **[Five of the major classes can be recalled as: coke, smack, bourbon, pot, acid.]**
 * **Stimulants: cocaine, amphetamines, nicotine, caffeine**
 * **Mechanism: inhibition of catecholamine reuptake transporters (coke), release of catecholamines/MAOIs/inhibition of reuptake transporters (amphetamines-- see below), direct action on nicotinic cholinergic receptors (nicotine), 2nd-messenger systems (caffeine). Note that they all increase dopaminergic signaling or storage of dopamine (which, of course, is a catecholamine) in the ventral tegmental pathway.**
 * **Talked with Dr. French about the amphetamine thing. Turns out amphetamines look enough like catecholamines that they bind to reuptake receptors, vesicular transporters, and MAOs, but not alpha-1 and beta-1 adrenergic receptors. So although their main action is through prompting catecholamine release by binding to VMAT, they can also act as competitive antagonists for MAOIs and reuptake transporters.**
 * **Withdrawal: depression/dysphoria (decreased dopamine/5-HT)**
 * **Opiates: heroin, morphine, meperidine**
 * **Mechanism: act on mu opiate receptors. Recall that this has a number of inhibitory (hyperpolarizing through K+ channels) effects, including analgesia on C fibers; of addictive note here, you get promotion of the dopaminergic neurons in the ventral tegmental dopaminergic system (by inhibition of the inhibitory input to those neurons).**
 * **Withdrawal: mydriasis, diarrhea, muscle cramps, tremors, dysphoria.**
 * **Depressants: EtOH, barbiturates, benzodiazepines**
 * **Mechanism: __anxiolytic__, __anticonvulsant__, and __sedative__ activity through __potentiating GABA transmission__. Also inhibit NMDA receptor activity. See next lecture's LOs for more on EtOH.**
 * **Withdrawal: seizures, anxiety, insomnia.**
 * **Cannabinoid: cannabis, tetrahydrocannibinol (THC)**
 * **Mechanism: agonist at cannabinoid receptors (Gi receptors).**
 * **Withdrawal: anxiety**
 * **Note that cannabinoids produce only a low level of dependence relative to cocaine, opioids, etc.**
 * **Hallucinogens: lysergic acid diethylamide (LSD), mescaline**
 * **Mechanism: LSD = serotonin receptor agonist.**
 * **Withdrawal: flashbacks**
 * **Note that hallucinogens do NOT seem to produce much significant physiological or psychological dependence.**
 * **Dissociative anesthetics: not mentioned in lecture (and since he mentioned that his exam questions would come from his lecture content, I'm not that worried about it). Ketamine, however, is an example, and works by blocking NMDA receptors.**
 * **Know the major therapeutic strategies used for detoxification and/or relapse prevention in treatment of drug dependence.**
 * **Cocaine and amphetamines: psychotherapy, antidepressants, naltrexone, and buprenorphine (substitution drugs).**
 * **Nicotine: slower administration/elimination of nicotine (transdermal patch, gum, etc), buproprion (antidepressant).**
 * **Opioids: block opioid receptors with nalaxone; also can substitute a different opioid like methadone or buprenorphine.**
 * **Depressants: BDZs (more acutely), or homotaurine/acamprosate (more chronically-- they potentiate GABA-ergic and/or inhibit NMDA Glu-ergic neurons, see next point).**
 * **Note that alcohol, although it depresses NMDA receptor activity in the short term, promotes NMDA receptor Glu-ergic activity in the long term by increasing the number of NMDA receptors. If you do a sudden withdrawal from alcohol, you can cause seizures due to the increased glutamatergic tone in the CNS. BDZs can be useful in avoiding this reaction. The increased Glu-ergic tone fades fairly rapidly (in several days) in the absence of additional alcohol.**
 * **Acamprosate and homotaurine can be used to inhibit NMDA receptors and potentiate GABA receptors to treat alcohol dependence. See next lecture for more on alcohol withdrawal syndrome.**
 * **Know the major toxic effects of commonly abused/addictive compounds.**
 * **Cocaine and amphetamines:**
 * **Acute: cardiovascular toxicity (HTN, arrhythmias, stroke).**
 * **Chronic: paranoid psychosis.**
 * **Nicotine:**
 * **Acute: nausea/vomiting.**
 * **Chronic: stroke (note** no **increased risk for cancer with nicotine alone-- that's mainly the tar).**
 * **Caffeine:**
 * **Acute: anxiety/insomnia/GI symptoms/heart palpitations.**
 * **Chronic: similar to acute.**
 * **Opioids:**
 * **Acute: confusion, respiratory depression, death.**
 * **Chronic: no major chronic toxicities.**
 * **Alcohol:**
 * **Acute: ataxia, nystagmus, coma, respiratory depression, death .**
 * **Chronic: vitamin B deficiency-induced neurodegenerative disease (dementia, ataxia, depression) (note this includes pernicious anemia from cobalamin and Wernicke's/Korsakoff's from thiamine).**
 * **Benzodiazepines:**
 * **Acute: amnesia, confusion.**
 * **Chronic: no major chronic toxicities.**
 * **Barbiturates:**
 * **Acute: confusion, sedation, coma, respiratory depression, death.**
 * **Chronic: no major chronic toxicities.**
 * **Cannabis:**
 * **Acute: confusion, hallucination.**
 * **Chronic: possibly flashbacks, psychosis, and memory loss.**
 * **Hallucinogens:**
 * **Acute: confusion and terror.**
 * **Chronic: possibly flashbacks and psychosis.**
 * Alcohol**
 * Thursday, October 02, 2008**
 * 10:54 AM**

Addiction I + II Addiction I + II, 10/3/08:
 * Know that ethanol is a CNS active drug that is similar to other sedative hypnotics. Ethanol produces sedation, is anxiolytic, and has anticonvulsant properties. Be clear that ethanol interacts and potentiates the acute toxic effects of a number of other drugs, particularly, other sedative hypnotics. These interactions many times are more than additive and can result in respiratory depression and death.
 * Worth repeating that __EtOH is anxiolytic, sedative, and anticonvulsant__ due to potentiation of GABA pathways.
 * The drug interaction specifically mentioned here was that EtOH is an inducer of the CYP450 pathway; drugs with toxic metabolites (like acetaminophen) will be broken down to that metabolite much more quickly.
 * Know that ethanol acutely potentiates the inhibitory actions of GABA and inhibits the excitatory actions of glutamate in the brain.
 * (but note that, as per last lecture, long-term it potentiates them, which is why you have to be careful for seizures with sudden EtOH withdrawal.)
 * Know that ethanol is metabolized primarily in the liver and that metabolism of ethanol slows down the metabolism of other energy producing compounds, such as fats and carbohydrates. This is why fats accumulate in the liver of individuals who consume high quantities of alcohol.
 * __Metabolism of alcohol__: Alcohol into acetylaldehyde by ADH, acetylaldehyde into acetic acid by aldehyde dehydrogenase. Acetic acid can be coupled to CoA and enter the Krebs cycle.
 * Note that ethanol preferentially competes for ADH with methanol and ethylene glycol; if your patient's going to die from toxic breakdown products of drinking printer toner, this is why you can get them drunk and save their life (yes, you too can save lives just by watching House). I saw a guy who'd chugged an entire half gallon of antifreeze (ethylene glycol) and lived to get into the hospital because he was also drunk as a skunk at the time.
 * Note that all of these steps __reduce NAD+ to NADH__ (one from ADH reaction, one from ALDH reaction, more from Krebs cycle metabolism).
 * All this NADH has some other effects:
 * Inhibit Krebs cycle activity by using pyruvate to convert all that NADH back to NAD+; __this produces lactate from pyruvate__, which deprives the Krebs cycle of its primary substrate. Also, increased NADH levels directly inhibits various Krebs cycle enzymes.
 * Increased amounts of circulating lactate can produce increased anion-gap __metabolic acidosis__.
 * Also, lactate competes for secretion in the kidneys with endogenous uric acid; this __decreases excretion of uric acid__, which increases its accumulation, which can cause (da) gout.
 * Shuts down metabolism of fats and stores triglycerides in liver
 * Decreases gluconeogenesis (blood glucose rises if liver glycogen level is high)
 * Cirrhosis: death of hepatocytes and their replacement by fibrotic scar tissue. Seems to be a source of controversy about why exactly this happens; the theory advanced by Dr. Tabakoff is that the alcohol causes local hepatic ischemia, possibly by inhibiting Na/K ATPase pumps.
 * Cardiac effects: with low doses of alcohol, elevation of HDL cholesterol exerts a protective effect; with higher doses, can damage cardiac muscle tissue.
 * Know that the major enzyme for the initial metabolism of ethanol is alcohol dehydrogenase and that enzyme uses NAD as a co-factor. The reason that NAD metabolism is important for consideration, is that alcohol changes the redox state of the liver and, in this way, generates lactic acidosis.
 * As mentioned.
 * Understand why alcohol levels in blood follow pseudo zero-order elimination kinetics.
 * Essentially you're saturating your alcohol dehydrogenase stash (recall, converts alcohol to acetylaldehyde with the help of NAD -> NADH).
 * At very low levels, the alcohol begins to be eliminated at first-order rates as you have more ADH than alcohol.
 * Understand the mechanism by which Antabuse® acts to reduce alcohol intake by an individual.
 * It blocks the conversion of acetaldehyde to acetate. Acetaldehyde evidently has a variety of hangover-like side effects, and its rapid accumulation leads to what seems to be a hangover-in-half-an-hour.
 * You try keeping up at the pub when one pint makes you puke.
 * Know the criteria for DSM-IV diagnosis of alcohol dependence.
 * Three or more of the following:
 * Drinking in larger amounts or over a longer period of time than intended.
 * Persistent desire/unsuccessful attempts to cut down.
 * A lot of time spent obtaining, drinking, or recovering from alcohol.
 * Important social/occupational/recreational activities given up in favor of alcohol.
 * Continued drinking despite knowledge of physical or psychological damage drinking causes.
 * (ok, I feel stupid for having typed this out, it's the same as the list in the preceding lecture for substance dependence.)
 * Know that alcoholics and chronic drinkers are __cross tolerant__ to general anesthetics and other CNS sedative drugs.
 * Right. Maybe effect on similar receptors?
 * Know the common clinical presentations associated with the Alcohol Withdrawal Syndrome.
 * Early phase (generally to about 6 hours): hyperexcitability due to residually increased glutamatergic tone in CNS. Increased level of anxiety, tremors, and possible convulsions. The convulsions are the most dangerous; if a patient's in danger of seizing, can use a benzodiazepine, but if given too early, it can interact with the residual alcohol in the system and cause respiratory depression.
 * For the same reason, you want to be careful about administering acamprosate or homotaurine too soon after alcohol cessation-- if given too early, can further depress the still-depressed Glu system.
 * Later phase: //delirium tremens//; only seen when first stage is allowed to develop and BDZs aren't used to relieve seizure risk. Delirium tremens entails hallucinations and autonomic dysregulation, resulting from continued hyperexcitability in the CNS. Note __visual and tactile__ hallucinations are normal; __auditory__ hallucinations are not and are usually a sign of schizophrenia.
 * Know which classes of drugs are commonly used to treat the Alcohol Withdrawal Syndrome and the rationale for such use.
 * As mentioned, the drugs of choice for this are benzodiazepines-- they stimulate some of the same receptors as alcohol (inhibiting the hyperexcited Glu neurons), and it's tough to cause respiratory depression with them (unless, as also mentioned, there's still significant alcohol levels in the blood). Note also that, as mentioned, they seem to reduce the incidence of delirium tremens.
 * Know the main characteristics of the Fetal Alcohol Syndrome. (note he didn't lecture on this.)
 * Growth retardation, both in utero and postnatally
 * Facial characteristics:
 * Short palpebral fissure
 * Indistinct philtrum
 * Epicanthic folds
 * Ptosis
 * Upturned nose
 * Thin upper lip
 * Underdeveloped jaw
 * High arched palate or cleft palate/lip
 * Microencephaly
 * Limb/joint characteristics (lots of specifics-- in notes)
 * Friday, October 03, 2008**
 * 7:53 AM**

General Anesthetics I + II General Anesthetics I + II, 10/3/08:
 * Define behavioral reinforcement, describe brain processes mediating reinforcement, and describe animal and human studies demonstrating reinforcement from drugs of abuse.
 * Behavioral reinforcement: behavior that leads to reward makes that behavior more likely. This is the circuit that was, albeit haltingly, described in "Pharmacology of Reward:" dopaminergic neurons to the nucleus accumbens prompt amygdalar signaling to the striatum and pallidum to drive motion in drug-seeking behaviors.
 * If an electrode is placed into the brain of a rat on the dopaminergic fibers from the ventral tegmental area to the nucleus accumbens, and that electrode is hooked up to a lever, the rat will continue pressing the lever pretty much constantly. If memory serves, they will self-administer drugs until they starve or OD (monkeys do this too).
 * There are a variety of human studies that show the same general thing-- humans will keep self-administering drugs and upping the dosage.
 * Drugs that produce substance abuse can have an initial rise in dopaminergic neurotransmission up to 5 times better than sex.. although no data are available on how good the sex is.
 * [speculation alert] I think the important point here is that two effects are going on. One is pleasure (hedonic effects). The other is adaptation of the drug-seeking pathway.
 * The pleasure effect declines with chronic use (tolerance develops).
 * The drug-seeking pathway __does not decline__ with chronic use but stays strong and becomes stronger.
 * What this means: pleasure fades; the biochemical stimulus to acquire and take the drug does not. The idea that addicts go acquire drugs because they need to feel good is not wholly accurate-- I would guess that you could cauterize the pleasure centers and the drug would still need to be sought, because the specific pathways involved in the two are distinct.
 * That said, the development of hedonic tolerance does certainly drive the __increase__ in the dose taken (which in turn strengthens the dopaminergic seeking pathway).
 * The dopaminergic pathways in the brain are involved with both of them as a common base.
 * Describe in broad terms the conditions of Conduct Disorder and Antisocial Personality Disorder, the relationship of these disorders to Substance Use Disorders, and describe how a risk-taking temperament may contribute to all of these disorders.
 * Antisocial Personality Disorder and Conduct Disorder: the latter is an adolescent disorder, the former is an adult disorder (and requires a previous diagnosis of conduct disorder). Effectively they're about what you would expect: violence, stealing, etc, largely undeterred by negative consequences. They have a high coincidence rate with substance use disorders. A risk-taking temperament may - wait for it - contribute to all of these disorders.
 * Summarize recently-observed differences in brain function between normal youths and those with Conduct Disorder and Substance Use Disorders during risk-taking decision-making, and describe what those findings may suggest recurrent substance-taking and antisocial behavior in such youths.
 * Forebrain structures, as mentioned previously, are important in inhibiting behaviors.
 * There are abnormalities in these structures in individuals with APD and CD. Rather than activating the dorsolateral prefrontal cortex and insular cortex to compute risk (and hence inhibition), this activation is blunted.
 * Specifically, there are a wide number of areas in the brain in controls that light up when analyzing risk and choosing a less risky behavior option; all of those areas are less active in people with CD/APD. Note that there are no brain areas (as analyzed by fMRI) that are __more__ active in CD/APD-- no magical "risk-taking cortex."
 * Describe the sub-categories of Substance-Related Disorders, and describe in broad terms the diagnoses of Substance Abuse and Substance Dependence.
 * Note distinction in substance-related disorder:
 * Substance Use Disorders: maladaptive pattern of use of drug. Note that this can be either "abuse" (less severe) or "dependence" (more severe).
 * Substance-Induced Disorders: adverse effects developing after use of the drug.
 * The distinction between "abuse" and "tolerance" can be found under "Drugs of Abuse," first LO.
 * Discuss the prevalence of Substance Use Disorders and their impact in general medicine.
 * Prevalence: about 20+% addicted to nicotine; about 30+% addicted to alcohol. This rate is comparable to anxiety disorders-- very common. Unlike anxiety disorders, this is frequently fatal. Alcohol-related deaths are about 3 times more common than firearms; tobacco-related deaths are about 4 times more common than alcohol deaths. Note the specifics of causality aren't explained here so take it with a grain or two of salt.
 * Discuss the role of social acceptance of substance use in the prevalence of Substance Use Disorders.
 * Social acceptance: tends to increase alcohol usage.
 * Discuss the role of social punishment of substance use in the prevalence of Substance Use Disorders.
 * Social punishment: tends to decrease alcohol usage.
 * [For a less mommy-state approach, go read "Nudge" by Thaler and Sunstein.]
 * Describe the chaotic life-circumstances that confront many youths with these conditions, and how those circumstances may contribute to the antisocial and substance problems.
 * Use your imagination. Doesn't take much.
 * Discuss the role of “free will” and “personal responsibility” for behavioral transgressions if the patient’s brain functions aberrantly while deciding whether to do high-risk behaviors.
 * Again, use your keenly developed "what does this person want to hear?" sensors.
 * Discuss how these matters influence substance-taking and what treatment interventions may address which items:
 * Substance availability, acceptability
 * Pharmacological reinforcement
 * History of prior substance use
 * Genes
 * Gender
 * Age
 * A risk-taking disposition
 * Stress
 * Pharmacological punishment of substance use
 * Social punishment of substance use
 * Social reinforcement of non-use of substances
 * The first 8 points are pro-abuse. The last 3 aren't. You can do something about pretty much the ones you think you can.
 * Friday, October 03, 2008**
 * 10:01 AM**

Cortex and Lateralization, 10/6/08:
 * **Describe the physicochemical properties of inhaled general anesthetics that determine anesthetic potency.**
 * **Note that inhaled GAs tend to only be effective at much higher concentrations than those used for drugs that act on specific receptors. More on why this is in the next LO.**
 * **Potency is determined by how __lipid-soluble__ the drug is (also known as how low the minimal alveolar concentration, or** MAC**, is). Technically, since these are volatiles, it's not called "lipid solubility" but "__oil:water partition coefficient__." Whatever. If it likes to get into lipids, it'll be more potent.**
 * **Note: 1 MAC makes 50% of patients anesthetized. 1.3 MACs makes 99% of patients anesthetized. Very steep response curve.**
 * **Describe the current thinking regarding the mechanism of action of inhaled anesthetics in producing anesthesia.**
 * **Unlike local anesthetics, the mechanism of action of inhaled general anesthetics is not well-understood.**
 * **In general, they seem to act by potentiating the activity of GABA-A and glycine receptors (chlorine channels)-- increase by increasing the likelihood that these channels will open.**
 * **They seem to work by partitioning into the lipid-soluble portions of the GABA-A and glycine receptors.**
 * **Dr. Sather: "they're little mechanical marbles that fit into pockets in proteins." By filling up those pockets, they seem to have a particular effect. Again, they don't seem to bind to receptors-- they seem to either inhibit or facilitate ligand-stimulated protein folding by simply filling up the empty spaces in it. This seems to be why GAs need to be relatively small.**
 * **Describe the ideal characteristics of a general anesthetic.**
 * **Rapid/smooth onset of action**
 * **Rapid recovery upon cessation of administration**
 * **Wide therapeutic window**
 * **Note that most GAs are fatal at 2-4 times their MAC dose. Dr. Sather: "The therapeutic window for most general anesthetics is pathetic."**
 * **Describe the rationale for use of a combination of pharmacological agents to achieve effective surgical anesthesia.**
 * **If no one drug produces all three of the above effects (and none does), need a combination instead.**
 * **Also an important concept: __anesthetic effects of GAs are additive; overdose effects are generally not__. So it's better to use a fraction of the MAC of one drug and a fraction of the MAC of another drug to avoid getting close to a dangerous dose of one or the other.**
 * **Recall that at 1.3 MACs, you're getting 99% of the population down. So instead of using a 1.3-MAC dose of a drug and getting closer to the danger zone, you can use 0.7 MACs of one drug and 0.6 of another and get the same effect without the threat of medullary depression.**
 * **Describe the signs and stages in the development of general anesthesia.**
 * **Signs (in order of increasing dose of GA):**
 * **Loss of fine motor control/coordination**
 * **Alteration of consciousness, analgesia**
 * **Loss of temperature regulation**
 * **Unconsciousness**
 * **Impairment of eye motion, pupil size, light reflex**
 * **Loss of muscle tone**
 * **Respiratory failure**
 * **Cardiovascular failure**
 * **Coma**
 * **Death**
 * **Stages:**
 * **I: analgesia**
 * **II: excitement and delirium (we don't really know why this happens)**
 * **III: surgical anesthesia (not reached by N2O by itself)**
 * **III.1: regular, metronomic respirations**
 * **III.2: onset of muscular relaxation, fixed pupils**
 * **III.3: muscular relaxation, less action of intercostals during breathing**
 * **III.4: diaphragm-only breathing, dilated pupils**
 * **IV: medullary paralysis: respiratory failure, CV collapse, death.**
 * **Describe the fundamental physical principles that determine uptake and elimination of inhaled anesthetics.**
 * **__Blood:gas partition coefficient__ (distinct from the oil:water partition coefficient) __determines uptake/elimination__. The more soluble it is, the more volume it has to go into and the slower its uptake and elimination is.**
 * **Note he made a point in lecture of distinguishing between the oil:water/oil:gas coefficient (same thing), which determines potency, and the blood:gas coefficient, which determines onset and elimination.**
 * **From notes: "The upshot is that induction of anesthesia is slower with a more [blood-]soluble anesthetic gas because the concentration of anesthetic in the brain can rise no faster than does the concentration of anesthetic in blood."**
 * **Ie.: more blood solubility, more volume, less concentration in blood, less concentration in brain, slower action.**
 * **Note, however, that Dr. Sather made the point that you don't really care as much about how fast the __onset__ of inhaled anesthetic is as much as how fast its __elimination__ is. With a high solubility in blood (slow onset), it will take longer for the anesthetic to pass out of all that blood (and other tissues) through the lungs.**
 * **Note that there usually isn't significant metabolism of inhaled GAs-- they're eliminated solely by respiration. A significant exception to this is halothane (see below).**
 * **Describe the differences between tissue groups that are important in determining uptake of general anesthetics.**
 * **In well-vascularized tissue (ie. lung and brain), the level of anesthetic in that tissue rises quickly with anesthetic administration and fades quickly with cessation of administration.**
 * **In less-vascularized tissue (passive muscle and above all __fat__), the level of anesthetic rises slowly and takes a long, long time to leach out again. Fat in particular, because the anesthetic can be dissolved very readily in it, makes a really annoying reservoir.**
 * **Thus increased % body fat = longer recovery time from anesthetic.**
 * **So really there are two things that determine uptake: (1) extent of vascularization and (2) solubility in the tissue of the anesthetic. Muscles, for example, have the same low anesthetic solubility as lungs, but are less well vascularized at rest. Fat has an extremely high anesthetic solubility and is also poorly vascularized, and hence has the slowest uptake and longest elimination.**
 * **Describe the advantages, disadvantages and problems associated with specific anesthetics on the drug list.**
 * **[Note * denotes that he discussed it in class. The others are from the drug list.]**
 * ***Nitrous oxide:**
 * **[The only true gaseous GA that's used (ie., it's not a volatized liquid).]**
 * **Low potency: the MAC is over 1 atm, so not used by itself (can't reach MAC with N2O alone).**
 * **Very rapid onset (not very soluble in blood).**
 * **Very effective analgesic and anxiolytic (I recall I was singing "Do You Know What It Means To Miss New Orleans" while they took my wisdom teeth out).**
 * **Used with barbiturates, opioids, neuromuscular blockers.**
 * ***Halothane:**
 * **Moderate to high potency.**
 * **Rapid onset (not very soluble in blood).**
 * **Not an effective analgesic.**
 * **Problems with it:**
 * **It can be metabolized in the liver-- but the metabolites are toxic, particularly to the kidney. This is one main reason we don't use it much any more.**
 * **Easy to fatally depress cardiac or respiratory function.**
 * **Associated with elevated incidence of __malignant hyperthermia__. Remember this one? Activates mutant-variant ryanodine 1 receptors in the SR in muscle tissues, leading to Ca++ release, muscle rigidity, and a steady rise in body temperature due to burning ATP from attempts to pack the Ca++ back in (pouring water out of a leaky boat).**
 * Dantrolene**: drug that prevents progression of malignant hyperthemia by blocking the ryanodine 1 receptors.**
 * **If a patient's at risk for MH, use IV anesthetics instead.**
 * ***Isoflurane:**
 * **High potency.**
 * **Rapid onset (not very soluble in blood)**
 * **Also no analgesic effect.**
 * **No seizure risk, no significant toxic metabolites, no direct cardiac depression.**
 * **Most popular inhaled GA.**
 * **Can cause cough due to pungent odor (not good in inhaled-gas situation). IV agents are used to overcome this drawback.**
 * **Enflurane:**
 * **Similar to isoflurane but can cause seizures during induction or recovery.**
 * **Desflurane:**
 * **Recently developed inhaled GA with moderate to high potency.**
 * **Rapid onset but a particularly rapid recovery time.**
 * **Similar pharmacokinetics to N2O, but stronger (enough to induce surgical anesthesia)**
 * **Can also cause coughing due to pungent odor and airway irritation-- so it can't be used for induction.**
 * **Sevoflurane:**
 * **Most recently developed inhaled GA.**
 * **Very high potency and very low blood solubility (low onset/recovery).**
 * **Pleasant odor, doesn't cause coughing/airway irritation.**
 * **However, it does release fluoride ions (may be toxic to kidneys).**
 * ***Thiopental (IV barbiturate):**
 * **Extremely rapid onset (15-20 seconds). Patient also wakes up in 3-5 minutes, so want to use concomitantly with slower-acting inhaled anesthetic.**
 * **Note patients tend to get nausea/vomiting when coming out.**
 * **Etomidate (non-barbiturate, IV hypnotic):**
 * **Similar to thiopental, but with a wider safety margin (minimal cardiac and respiratory depression).**
 * **Note a high incidence of nausea, vomiting, and pain on induction.**
 * ***Propofol:**
 * **Similar to thiopental but an even faster recovery with less nausea.**
 * ***Diazepam (benzodiazepine):**
 * **Used to relax patient before surgery.**
 * ***Ondansetron:**
 * **5-HT3 receptor antagonist used as an antiemetic.**
 * ***Fentanyl:**
 * **Opioid often used to supplement analgesia effect of anesthetic.**
 * **Morphine:**
 * **Can also be used, but has a longer duration of action than fentanyl.**
 * ***Glycopyrrolate:**
 * **Anticholinergic to counteract hypotensive and bradycardic effects of GAs.**
 * **Ketamine (dissociative anesthetic):**
 * **NMDA receptor blocker; no effect on GABA receptors.**
 * **Administered IV; relatively slow onset (2-5 minutes).**
 * **Bronchodilator (asthmatic patients).**
 * **Can get hallucination and disorientation on induction; avoid this by pre-administering BDZ.**
 * **Can cause involuntary movements during induction.**
 * ***NMJ blocking agents:**
 * **Often used to relax muscles before surgery.**
 * **[You can give an anxiolytic to relax the patient, then use IV drugs to knock the patient down, and use inhaled anesthetics to keep them under til you're done. Note that anti-emetics can be useful to make sure they don't have an emetic reaction to the IV anesthetic. Note also that if you're not using an inhaled anesthetic with analgesic properties, you can also throw an opioid into the mix.]**
 * **Describe the basic mechanisms of action of distinct classes of intravenous general anesthetics and adjunctive agents.**
 * **Thiopental, propofol, and etomidate also potentiate GABA A receptor activity.**
 * **Note that they're all metabolized to inactive compounds.**
 * **Ketamine is an antagonist of the NMDA receptor (produces dissociative anesthesia).**
 * **NMJ blockers agents work like curare.**
 * **Opioids work like opioids.**
 * **Etc.**
 * **Describe the methods of application of inhaled anesthetics.**
 * **I'm not sure what he's getting at with this. You use a machine to add volatile anesthetic to gas and administer that. CO2 can be blown off and the level of residual anesthetic in the gas allows a more thorough interpretation of the depth of the anesthesia.**
 * Cortex and Lateralization**
 * Monday, October 06, 2008**
 * 7:42 AM**

Epilepsy I + II Epilepsy I + II, 10/6/08:
 * Know and understand the basic anatomy of the cerebral cortex.
 * Yeah. No sweat.
 * Note the layers of the cortex are numbered from the outside (I) to the inside (VI).
 * Know and understand the basic concepts of cortical localization and lateralized neurobehavioral function and how they apply to language, praxis and attention.
 * __Primary__ cortices: areas of the cortex that serve a single, unimodal function (primary motor or somatosensory cortex). (basic nugget of sensory information)
 * __Secondary__ cortices: still serve a unimodal function but integrates association from that sensory modality into it. (integration of sensory information in time and space)
 * __Tertiary__ cortices: multimodal function; integrate information from multiple secondary cortices of different modalities. (integration of sensory modalities)
 * __Quaternary__ cortices: also multimodal function; integrate information from multiple tertiary cortices for higher processing. (integration of meaning)
 * Lobe functions, once again:
 * Occipital: visual processing
 * Parietal: sensory processing and visuospatial processing
 * Temporal: auditory processing
 * Frontal: motor programming, voluntary movement, complex cognition
 * Microscopic cortical anatomy:
 * Layer I: plexiform layer
 * Dendrites from pyramidal cells in lower cells. These run horizontally (allowing information flow to spread across the cortex).
 * Layer II: external granular layer
 * Stellate and pyramidal cells; dendrites from layer V pyramidal cells have synapses here.
 * Layer III: external pyramidal layer
 * Stellate and pyramidal cells.
 * Layer IV: internal granular layer
 * Mainly stellate cells; this layer is particularly thick in the primary auditory and visual cortices. Those areas are therefore called the __granular cortex__. Others with less stellate cells are called the __agranular cortex__.
 * Layer V: internal pyramidal layer
 * Pyramidal cells; these are particularly large in the primary motor cortex (where they're called Betz cells), whose axons will become the corticobulbar and corticospinal tracts.
 * Layer VI: fusiform layer
 * multiple cell types; projects axons that cross the midline in the corpus callosum and anterior/posterior commissures.
 * __Lateralization__:
 * Motor handedness, language, prosody, praxis (ability to perform a complex motor movement), visuospatial function, and spatial attention are all lateralized to one hemisphere or the other.
 * Note about 70% of the population is right-hand dominant (left hemisphere), 10% is left-hand dominant (right hemisphere), and 20% is, to some extent, ambidextrous.
 * Note also that Broca's area (speech production) is proximal to the primary and secondary motor cortices for the face and tongue. So if you've got something that looks like Broca's aphasia, you might also be looking for lesions in motor cortices (contralateral weaknesses in face, tongue, possibly arms).
 * Similarly, Wernicke's area (speech comprehension) is more proximal to the primary and secondary somatosensory cortices. So if you've got something that looks like Wernicke's aphasia, you might also be looking for lesions in sensory cortices (contralateral sensory deficits in face, tongue, possible arms).
 * Recall that nearly all right-handed people and the majority of left-handed people are language-lateralized to the left hemisphere. People who are left-handed or ambidextrous are more likely to have mixed-hemisphere language dominance (thus retain more function post-stroke).
 * Prosody tends to lateralize on the __opposite__ side of language.
 * Praxis (which is, like language production, a coordination of intention and motor signals) tends to lateralize on the __same__ side as language.
 * Visuospatial attention: recall that the right hemisphere is dominant since it receives input from both sides, while the left hemisphere receives only contralateral input. This is why a left parietal lesion doesn't generally impair attention (right side is still covering both sides), but a right parietal lesion causes left-sided hemineglect (left side doesn't cover the left).
 * Monday, October 06, 2008**
 * 9:02 AM**


 * The first part of these lectures was another shining example of a decent enough presentation that was only distantly connected with its LOs. Best guess follows.**

Anticonvulsants Anticonvulsants, 10/6/08:
 * Notes:]
 * Medical history is extremely important; observations of the seizures from witnesses are valuable. Information about the __behavior that immediately precedes the seizure__ may indicate which area of the brain is affected (eg. one arm jerks, indicating a problem with the contralateral motor area).
 * Get information about:
 * Length
 * Aura (immediately prior to seizure)
 * Experience during seizure (the ictal period)
 * Postictal state
 * Note that chemical changes in the brain can last for days after the seizure.
 * Frontal and temporal lobes are the most susceptible to seizures in the presence of injury.
 * Absence seizures (a type of primary generalized seizure): motor layers are relatively uninvolved, but the afferent layers are affected (no awareness).
 * Classically these begin in childhood and 2 out of 3 outgrow them by high school. Note often provoked by hyperventilation.
 * Myoclonic seizures (another type of primary generalized seizure): sensory layers are relatively uninvolved (awareness), but the motor layers are affected.
 * Other types of primary generalized seizures: tonic-clonic, tonic, atonic.
 * In tonic-clonic seizure:
 * Tonic phase: limb stiffness
 * Clonic phase: jerking of muscles
 * Note about 10% of US population experiences a seizure; about 10% of those have epilepsy diagnosis.
 * Know the signs of epileptic seizures (paroxysmal change in behavior or movement, or an alteration of consciousness).
 * Positive symptoms during the seizures, depending on which area of the brain is affected (visual hallucinations from seizure in the visual cortex, etc).
 * Negative symptoms after the seizures (in the __postictal period__): loss of function in affected area due to neuronal exhaustion and inhibition from other neurons.
 * Know the various etiologies of an epileptic seizure.
 * (notice there's not actually much on etiology here. See lower LOs for more on this.)
 * Classification of epilepsies:
 * Know the two major types of epilepsy: partial onset and primary generalized.
 * (as delineated in next LO)
 * Know the difference between a primary generalized tonic-clonic seizure and a secondarily generalized tonic-clonic seizure.
 * (as delineated in next LO)
 * Be able to differentiate between a complex partial seizure and a primary generalized absence seizure.
 * Complex partial: begins localized in one place, can spread from there. The most common type of seizures are complex partial seizures that begin in the temporal lobe and limbic system (often with auras of intense fear that precede the seizure).
 * __Simple__ partial seizures: awareness is maintained during seizure (involves a smaller part of the brain).
 * __Complex__ partial seizures: awareness is impaired during seizure (involves a larger, bilateral part of the brain).
 * __Primary__ generalized: entire cortex is diffusely hyperirritable; seizures begin more or less everywhere as normal signals are overreacted to.
 * (Note that __secondary__ generalized seizures refer to seizure spread from a localized origin; primary generalized seizures occur more or less everywhere at once and do not begin localized.)
 * Understand that epilepsy is a heterogeneous condition, characterized by spontaneous seizures and that epilepsies are classified into “generalized” and “partial” syndromes.
 * See above.
 * Understand that temporal lobe epilepsy is the most common epilepsy syndrome in adults. Describe some of the etiologies for temporal lobe epilepsy. Recognize the brain structures and neural circuits involved in temporal lobe epilepsy. Describe the process of diagnosing epilepsy.
 * TLE can be caused by some manner of injury; note that the TLE itself also causes damage to the lobe, which predisposes to more seizures. Alcohol, trauma, etc, but it's largely idiopathic.
 * TLE involves the hippocampus, amygdala, and adjacent parahippocampal cortex.
 * __Mesial temporal sclerosis__: common pathological finding in TLE. Caused by loss of neurons in dentate gyrus, CA3, and CA1, followed by gliosis (scarring) and hardening of those areas.
 * Synaptic reorganization in mesial temporal sclerosis: in the presence of damage, the axons of the dentate gyrus cells (mossy fibers) send out lots of excitatory fibers to neighboring regions and the cells of origin. This can in turn cause seizures (positive feedback loops).
 * Diagnosis: clinical.
 * Get a history and physical exam (esp. cardiac, neuro).
 * EEGs can be useful. Note you can provoke (lights, other stimuli, sleep deprivation) and watch EEGs for changes.
 * MRI can often pick up hippocampal sclerosis.
 * CT is useful emergently to rule out stroke and hemorrhage.
 * Recognize animal models of epilepsy and how they have helped in discerning etiologies for epilepsy. Recognize that the paroxysmal depolarization shift is an in-vitro correlate of the interictal spike on EEG.
 * Animal models:
 * "Kindling": repeated stimulation at the same intensity will produce seizures.
 * Chemoconvulsants: excitotoxin application will produce seizures.
 * Acute brain slices: study electrical activity and effects of GABA inhibition.
 * PTZ and MES (see next lecture).
 * Paroxysmal depolarization shift: the interictal spiking pattern in vitro (see next point).
 * Interictal spikes: relatively regular EEG spikes between seizures. Seem to be indicative of a __wind-up process__ potentiating more seizures.
 * Recognize that status epilepticus is a medical emergency and the clinical definition of status epilepticus. Recognize potential causes for status epilepticus in adults.
 * Status epilepticus: a seizure lasting over five minutes or multiple sequential seizures lasting more than five minutes together. Note that this can be convulsive or non-convulsive.
 * Causes (in order of decreasing frequency):
 * Chronic epilepsy
 * "Remote symptomatic causes"
 * Stroke
 * Metabolic causes
 * Alcohol withdrawal
 * Treatments:
 * Stop seizure activity (with BDZs or anticonvulsants), maintain brain oxygenation and CV function.
 * Understand the definition of febrile seizures, that febrile seizures are not considered “epilepsy” and risk for developing epilepsy following febrile seizures.
 * Febrile seizures: occur mainly in the 6 month to 2-5 year age range, accompanied by > 38 degree Celsius fever but without an underlying CNS infection or electrolyte imbalance.
 * Simple febrile seizure: generalized tonic-clonic seizure, no focal symptoms, brief (< 1 minute), not recurring, resolves spontaneously.
 * Complex febrile seizure: focal onset, prolonged duration, recurs in a 24-hour period.
 * About 1/3 of febrile seizure patients have recurrent seizures in the same year.
 * Tends to occur in children with a low fever at the time of the seizures.
 * Can be genetic, involving a mutation in a neuronal sodium channel gene or a mutation in a potassium channel gene.
 * Risk factors for developing epilepsy afterwards: family history of epilepsy, complex febrile seizures, individuals with neurological abnormalities.
 * [Note that seizure surgeries can be extremely effective, but frequently long wait times.]
 * [A "ketogenic diet" (high fat, low carbohydrate) can also be used for treatment; not sure exactly why it works.]
 * [Also vagus nerve stimulation or deep brain stimulation.]
 * Monday, October 06, 2008**
 * 11:02 AM**

Gender and the Nervous System, 10/7/08:
 * **Know the seizure classifications important for selecting a particular drug therapy. The choice of drug usually depends on the type of seizures being treated.**
 * Generalized**: classified into grand mal (spread by increased __sodium__ channel excitability through cortex) and petit mal (spread by repetitive cycles of __calcium__ channel excitation back and forth from the cortex to the thalamus and back again).**
 * **Note that __massive electrical stimulation__ (MES) in animal brains tends to produce grand mal seizures. Therefore drugs that inhibit the effects of massive electrical stimulation also are good for stopping grand mal seizure (eg. phenytoin and carbamazepine).**
 * **Note that __pentylenetrazol__ (PTZ) administration in animals tends to produce petit mal seizures. Therefore drugs that inhibit the effects of PTZ are also good for stopping petit mal seizure (eg. ethosuximide).**
 * **There's a good, concise, surprisingly clinical summary of grand mal vs petit mal seizures on page 4 of the notes.**
 * Partial**: classified into simple, complex, and secondarily-generalized, as discussed in the last 2 lectures.**
 * **Very difficult to treat the seizure just in its primary location in partial seizures; it's much easier to treat it when it's already spreading.**
 * **Theme here: the spread of seizure seems to be much easier to treat than an initial event (possibly because the inciting events seem to be a much subtler alteration of normal status than massive propagation waves). Our current meds seem to target spreading mechanisms (like sodium and calcium channels) for that reason.**
 * **Know the mechanisms of action, drug interactions, and primary signs of toxicity for phenytoins, barbiturates, valproate, carbamazepine, and succinamide drugs used in treatment of epilepsy.**
 * **Phenytoin and carbamazepine:**
 * **MoA: block sodium channels that are involved in the spread of sodium channel excitability; used in grand mal seizures. Note that they do this in a __use-dependent fashion__, which means they can be given interictally as effective prophylaxis without generating a great deal of sedation.**
 * **Phenytoin side effects: at or around the therapeutic level, is eliminated by __zero-order kinetics__; also has side effects of megaloblastic anemia, hirsutism, CV arrhythmias and hypotension, blurry vision, dizziness, ataxia, etc.**
 * **Carbamazepine side effects: It's an inducer of the CYP system (as well as being metabolized by it). Actually, phenytoin induces CYP enzymes as well.**
 * **Valproate (valproic acid):**
 * **MoA: blocks sodium channels and inhibits breakdown of GABA; can be used in both grand mal and petit mal seizures.**
 * **Note that this contradicts what Dr. Restrepo told us about valproic acid mainly being used to block t-type calcium channels. Having asked further, it seems unlikely that that has a significant effect (VP acid's efficacy on absence seizures seems due to its GABA effects, not its calcium channel effects). I'd go with the pharmacologist on this one.**
 * **Side effects: increase in GABA levels can cause sedation. Also look for hepatic failure and GI upset.**
 * **Barbiturates:**
 * **MoA: potentiate/activate GABA receptors; inhibit calcium channels and sodium channels. Due to these widespread targets, can be used in both grand mal and petit mal seizures.**
 * **Side effects are legion, as they target so many channels (respiratory and CV depression are problems at doses high enough to treat seizures); also CYP inducers, like carbamazepine.**
 * **Note they are only actually used to treat refractory seizures (due to medullary depression), but can treat either the grand mal or the petit mal variety.**
 * **Ethosuximide:**
 * **MoA: blocks t-type calcium channels; used in petit mal seizures. Note that this effect, like phenytoin and carbamazepine, is __use-dependent__.**
 * **Side effects: (none listed for ethosuximide; some of the non-ethosuximide succinamides are teratogenic and have a variety of serious side effects in major organs).**
 * **[Note can use BDZs as anticonvulsants as well, primarily against absence/petit mal seizures; they're first line to treat status epilepticus.]**
 * **Know the mechanism of action of the newer drugs used in treatment of epilepsy such as gabapentin and vigabatrin.**
 * **(note most of these are used as co-therapy along with the abovementioned drugs, particularly to control partial seizures.)**
 * **Gabapentin: GABA structural analogue; may block GABA breakdown (no direct agonist action, though). Some efficacy in refractory seizures. Some effectiveness in treating partial seizures at their origination sites before they spread. Side effects are fatigue and sedation.**
 * **Vigabatrin: "suicide inactivation" of GABA breakdown enzyme (GABA transaminase)-- inhibits breakdown of GABA. Can __aggravate__ petit mal seizures; works ok in grand mal and complex partial seizures.**
 * **Felbamate: inhibits NMDA receptors. Generally not used except in refractory seizures due to aplastic anemia side effects.**
 * **Tiagabine: inhibits GABA reuptake.**
 * **Understand how animal seizure models help to predict the type of seizures a particular drug may affect.**
 * **Massive electrical stimulation and PTZ administration, as mentioned above-- MES corresponds to grand mal seizures, PTZ corresponds to petit mal seizures.**
 * **Know the drug of choice for treatment of grand-mal, petit-mal, and status epilepticus.**
 * **Grand mal: Phenytoin and carbamazepine plus adjunctive second-generation drugs; can also use selected second-generations as monotherapy, maybe with valproic acid.**
 * **Petit mal: drugs of choice are succinimides (esp. ethosuximide), plus valproic acid.**
 * **Status epilepticus: benzodiazepines**
 * **[Partial: carbamazepine, with or without second-generation adjunctives.]**
 * Gender and the Nervous System**
 * Tuesday, October 07, 2008**
 * 7:51 AM**
 * (not, as per Dr. French, on the test; a few off-the-cuff notes during Dr. Finger's breakneck run-through on Friday, is all.)**

Coma Coma, 10/7/08:
 * Explain why women have a lower incidence of aphasia and relate this to gender-based differences in functional representation in the cerebral cortex.
 * Women's language centers tend to be more delocalized (which is presumably why my wife can talk with her mother, our cats, and the neighbors simultaneously while I can barely focus on breakfast). This means that the destruction of any given area of the brain (as by stroke) is less likely to wipe out the entirety of language representation; thus a lower incidence of aphasia.
 * Describe how prenatal and perinatal exposure to sex steroids can irreversibly influence brain structure.
 * Circulating testosterone will pattern the brain in a characteristic 'male' way.
 * List 3 ways that sex steroids can influence brain activity and structure in adults.
 * High levels of testosterone: prevent gap junctions from forming between neurons in the preoptic hypothalamus. These gap junctions (in women) synchronize the discharge of LH and FSH (via LHRH), leading to larger cyclic releases.
 * As mentioned, language areas are more widely distributed in women.
 * Low levels of estrogen/progesterone in adults (menopause, menses) leads to low GABA-A inhibition, leading to an increased susceptibility to seizures
 * Explain how the cerebral cortex and hippocampus can be major targets for the effects of androgens.
 * Relatively slowly: free diffusion of steroids through lipid membranes to bind to steroid receptors in the cytoplasm; the receptor-steroid complex further needs to migrate into the nucleus to affect gene transcription.
 * More quickly:
 * 2nd-messenger systems (as opposed to direct DNA binding), both on the cell surface and in the cytoplasm.
 * Direct interaction between steroids and GABA-A receptors (tend to increase open time of GABA-A Cl- channels
 * Tuesday, October 07, 2008**
 * 9:06 AM**


 * **Define the following terms: delirium, stupor, coma, decerebrate posturing, decorticate posturing.**
 * **Delirium: fluctuating course of mental status, inattention, misconceptions.**
 * **Stupor: sleep-like state, but patient can still be aroused with vigorous effort.**
 * **Coma: sleep-like state but patient cannot be aroused and only exhibits certain stereotyped reflexes.**
 * **Recall that the Glasgow coma scale (3-15) is used to grade this.**
 * **Glasgow coma definition: can't follow commands, speak any recognizable words, or open either eye.**
 * Decerebrate**: both upper and lower extremity extension.**
 * Decorticate**: upper extremity flexion with lower extremity extension.
 * Note that the decerebrate prognosis is worse (lesion in brainstem).
 * Understand the criteria for establishing brain death.
 * (1) Totally unresponsive (__Glasgow score = 3__)
 * (2) __Cerebral motor responses are absent__ during application of painful stimulus (no seizures or flexion/extension allowed, though spinal reflexes may still be present)
 * (3) __Absent brainstem reflexes__ (pupil, corneal, oculocephalic, oculovestibular, cough, gag, apneic respirations)
 * Also need a core body temperature of at least 32.2 C (90 F), no toxicological reason for coma, a systemic BP > 90, and a pulse > 50.
 * [Note that comas can follow damage to the reticular activating system in the brainstem (Duret hemorrhages following uncal herniation).]
 * [Not brain death:]
 * Vegetative state: eyes open spontaneously and sleep-wake cycles are re-established, but no sign of cognitive function is intact.
 * Considered permanent (less than 1% chance of recovering function) __12 months after injury when due to trauma__.
 * Considered permanent __3 months after onset when not due to trauma__.
 * Frequent non-traumatic cause: hypoxia-ischemia; worse prognosis than trauma-induced.
 * Minimally conscious state: eyes open spontaneously; sleep-wake cycles are re-established; arousal levels can occasionally be normal or near-normal; there are reproducible displays of perception, communication, or purposeful motor activity.
 * Discuss ethical, legal, and cultural issues related to brain death and organ transplantation.
 * Note the law sez the cessation of function of the entire brain and brainstem is, legally, death, just like complete cessation of circulatory and respiratory functions.
 * Note also that the time of death is declared to be whenever the patient's examined.
 * Note that no one in the surgical team harvesting the organs can be the one to pronounce the patient brain dead. Also, patients sometimes refuse to die when you take them off life support, which can evidently prove distressing.
 * Life support can be withdrawn from permanently vegetative patients (12 months after trauma, 3 months after non-trauma onset). Minimally conscious patients is more of a legal gray area.
 * Note you can see fMRI brain patterns in coma after stimulation that are completely unlike conscious patient's fMRIs (occipital lobes activated on pain stimulus). fMRI patterns are odd with vegetative and minimally conscious states as well, but they're not quite as off.
 * Describe the anatomical pathways tested with: the corneal blink reflex, cold water calorics, the cough and gag reflexes.
 * Corneal: V-I afferent (sense touch), VII efferent (blink)
 * Oculovestibular (cold water caloric): VIII afferent (vestibular), III, IV, and VI efferent (eye movement)
 * Cough: X afferent (sense suction on carina), X efferent (cough)
 * Gag: IX afferent (sense touch on oropharynx), X efferent (gag)