neuro-blogo-sphere

First a couple easy review questions:
What are the 3 segments of brainstem?
What are the 12 cranial nerves?
Briefly sketch/describe the paths taken for DSCT, ALT, DC-ML, and CSTs.

Today we look at the sources for these cranial nerves within each segment of brainstem, and how pathways traverse the brainstem between spinal cord, cerebrum, and cerebellum.

First there are a couple basic differences to note as you move up from spinal cord to brainstem: 1. In the spinal cord, sensory was dorsal (alar plate) and motor was ventral (basal plate) with thoracolumbar autonomics in between (sulcus limitans). In the brainstem motor is now medial, sensory is now lateral and visceral is still in between (with visceromotor & viscerosensory either side of the sulcus limitans; 2. In the brainstem, the central gray matter is called the tegmentum; And 3. in addition to corticospinal tract from cortex to spine you also have corticobulbar fibres from cortex to brainstem.
The brainstem is composed in 4 layers, from dorsal to ventral: 1. the "roof"; 2. the ventricular system (ie cerebral aqueduct & 4th ventricle); 3. the tegmentum; and 4. the cortical efferent (where corticospinal & corticobulbar tracts traverse brainstem ventrally).

Landmarks of the Posterior Brainstem.
In order to look at posterior brainstem, you have to remove the cerebellum. Then you get what we've got here...

Moving from rostral to caudal, identify these landmarks:
- superior & inferior colliculi (the "roof" of the midbrain, the inferior has an arm (brachium))
- CN IV trochlear (the only CN that exits posteriorly, & has crossed the midline)
- walls of the 4th ventricle
- cerebellar peduncles: superior, middle, inferior
- facial colliculus (on the floor of the 4th, nuclei of CN VI + axons of VII)
- obex (caudal end of 4th ventricle, where area postrema is located)
- dorsal columns & gracile & cuneate tubercles (overlying their respective nuclei)

Now flipping things over and looking at...

Landmarks of the Anterior Brainstem

Again, moving rostral to caudal identify the following...
- optic chiasm
- cerebral peduncles (the cortical efferent "layer" of midbrain)
- mamillary bodies (part of hypothalamus)
- CN III (emerging from the interpeduncular fossa)
- pons
- CN V (emerging from rostral pons)
- CN's VI, VII, VIII (from medial to lateral at the ponto-medullary junction)
- CN's IX, X, XI (as you go down medulla, with...)
- CN XII (...in between the pyramid & the olive.) or a pyramid of olives?

3 brainstem segments and 12 CN's? Looking at the anterior brainstem, you can remember them as basically 4 CN per segment: CN I - IV are midbrain & above; CN V - VIII are pons; and CN IX - XII are medulla. Though trigeminal is a bit of an exception...

Blood supply to the brainstem

The two vertebral arteries each give off a desending branch that unite to form the anterior spinal artery in the region of the medulla and descends in the anterior median fissure to supply anterior medulla & spinal cord. Posterior spinal arteries also branch from vertebrals to supply the posterior medulla and spinal cord. While branches from each vertebral artery supply the lateral medulla.
The two vertebral arteries unite near the pontomedullary junction to form the midline basilar artery. Prior to forming the basilar the vertebrals give off posterior inferior cerebellar arteries. The basilar itself branches into anterior inferior cerebellar arteries (near CN VII & VIII) and superior cerebellar arteries, all of which supply the cerebellum.
Basilar gives off pontine arteries and anterior inferior cerebellar & superior cerebellar supply caudal & rostral pons respectively.
Between the terminal bifurcation of the basilar into posterior cerebral arteries, and superior cerebellar arteries, you'll find CN III in the interpeduncular fossa. Posterior cerebral and superior cerebellar arteries supply much of the midbrain.
We'll see this again when we go over deficits resulting from stroke, haemorrhage, etc.

next we extend pathways we've already seen into the brainstem, and add an MLF, an olive, a corticopontinecerebellar, and an SCP.

Longitudinal Pathways of the Brainstem
1. Corticoefferents (including corticospinal & corticobulbar tracts)
These fibres from UMNs in the cortex take on different names as they pass through each brainstem segment: in midbrain they're cerebral peduncles; in pons they're longitudinal fibres of the pons; in medulla they're pyramids. Then 80% cross at the pyramidal decussations to form lateral CST and 20% remain ipsilateral as the anterior CST. Note too that the size of the corticoefferent tract decreases rostral-caudal as fibres jump off at their destinations.
2. ALT (Anterolateral Tract)
This one fortunately stays put in the brainstem, but note it's anterolateral to tegmentum now.
3. DC-ML (Dorsal Column - Medial Lemniscus)
This one we left with DRG axons synapsing in gracile & cuneate nuclei in the medulla. They then cross the midline in the rostral medulla and continue as the medial lemniscus. Unlike ALT however, medial lemniscus gets shoved postero-laterally as it ascends the brainstem. Therefore damage to midline medulla would hit ML but not ALT. Whereas in lateral midbrain ML is next to ALT. No doubt there will be more on this later...
4. Median Longitudinal Fasiculus
This is a new tract and can be divided into a descending component that orients your head to gravity, and an ascending component that coordinates conjugate gaze. Since eye movements require CN III, IV, & VI the ascending MLF runs between these three cranial nerve nuclei. Below the level of CN VI the descending MLF provides input to muscles required for the righting reflex. Since these tracts function in response to changes in gravity & head movement, they receive input from the vestibular ganglion. And because these tracts are both heavily myelinated and located ~ periventricularly they are likely sites for MS lesions - producing blurred vision (loss of conjugate gaze) and loss of balance.
5. Projections from Inferior Olive
Remember that proprioceptive fibres synapsed on Column of Clarke cells, whose axons travelled up posterolateral funiculus as Dorsal Spinal Cerebellar Tract to enter the ipsilateral cerebellum as the ICP? A group of neurons called the inferior olive also projects into cerebellum via the ICP and functions in motor learning.
6. Corticopontocerebellar Pathway
There are no direct connections from cortex to cerebellum. Instead collaterals from CST synapse on ipsilateral pontine nuclei lying in the pons ventral to the tegmentum. From here the axons of the pontine nuclei cross the midline and travel as transverse fibres of the pons to the cerebellum via the MCP.
7. SCP
Cerebellum communicates with cortex by fibres which exit the SCP, cross in the caudal midbrain, and synapse in the contralateral thalamus (& red nucleus if I remember right). From there thalamocortical fibres project to cortex. There is no direct projection from cerebellum to spinal cord.

we've seen external landmarks and added some more paths - because they're weren't enough already - so we'll finish with internal landmarks to locate these new paths & their nuclei. For each brainstem segment the goal is to be able to identify a rostral and a caudal transverse section...

for a closer view you can click the thumbnails...

Midbrain
The key to knowing you're midbrain is that you have: 1. cerebral aqueduct & periaqueductal gray (PAG); and 2. cerebral peduncles are the ventral cortical efferent. Since you're midbrain, here the medial lemniscus will be more posterolateral - closer to the ALT.
Rostral Midbrain

The key to knowing you're Rostral midbrain is Red nucleus . Therefore: 1. the roof is superior colliculus; 2. you have CN III nucleus & its Edinger-Westphall nucleus (preganglionic parasympathetics destined for ciliary ganglion) and a-MLF connecting III with IV & VI below.
Caudal Midbrain

The key to knowing you're Caudal midbrain is X/SCP, the decussation of SCP myelinated axons at the midline. Therefore: 1. the roof is inferior colliculus; 2. you have CN IV nucleus (remember this crosses and exits dorsally); and a-MLF connecting IV with III & VI.

Pons
The keys to knowing you're pons are that 1. you have4th ventricle; 2. the ventral cortical efferent is a midline pontine protruberance (longitudinal & transverse fibres of the pons); and 3 you got big ol' elephant ears of MCP. Here the medial lemniscus is slightly lateral from midline.
Rostral Pons

The key to knowing you're rostral pons is that you have CN V main sensory nucleus (more laterally) and motor nucleus (more medially) with myelinated fibres running anteriorly to project out of rostral pons. Therefore you have 1. locus ceruloeus at the junction of the angle of the 4th ventricle; 2. SCP forming the dorsolateral wall of 4th ventricle; and 3 a MLF running btwn IVabove & VI below.
Caudal Pons

The key to knowing you're caudal pons is that 1. you have facial colliculus formed by the nucleus of CN VI & fibres of VII (CN VII nuclei are more ventrolateral). Therefore: 1. you have spinal nucleus & tract of CN V (P&T for face, the tract is the incoming axons that descend to synapse in the nucleus on the 2nd order cells); and 2. a-MLF connecting VI with IV & III above.

Medulla
In the medulla the ventral cortical efferent are the pyramids (now much smaller) and more caudally you'll eventually see the pyramidal decussations.
Rostral Medulla

The key to knowing you're rostral medulla is the inferior olivary nucleus. When you see that you know you have 1. from lateral to medial: nuclei for VIII (vestibular), Nucleus Tractus Solitarius (NTS, a sensory nucleus of Nine Ten Seven for gustatation & cardiopulmonary sensors), dorsal motor nucleus of Vagus (DMV), and CN XII (hypoglossal) All classically arranged with somatomotor medial, somatosensory lateral, visceromotor & viscerosensory either side of the sulcus limitans. 2. lateral to the vestibular nucleus you have ICP; 3. somewhere you have nucleus ambiguus (a motor nucleus of IX, X, XI important in swallowing...); and 4. on the midline you'll have descendling MLF (dorsally) and medial lemniscus (more ventrally)
Mid Medulla

The key to knwoing you're mid medulla is the sensory decussation from dorsal gracile & cuneate nuclei to contralateral medial lemniscus via internal arcuate fibres. Here you'll loook for continuations of NTS, X, XII, spinal tract & nucleus of V and descending MLF that you've seen above.

Sorry about the length! And that's leaving out reticular formation!! Tomorow I have to miss Tony's lecture but will be there for the ongoing saga known as brainstem. Good luck studying tonight!

Today's post is pretty short (unfortunately I had to miss most of Tony's lecture).
For the second lecture today we discussed three cranial nerve related circuits and how they are affected by different lesions...

Horizontal Gaze & Lesions

To consciously direct horizontal eye movements, fibres from the cortex (supplementary/premotor) project to the horizontal gaze center (aka ParaPontine Reticular Formation, PPRF). If these cortical fibres are lesioned, then you cannot initiate that eye movement.
From the PPRF, fibres project to the contralateral nucleus of VI. From nucleus of VI there are two basic outputs:
1. There is a direct output to that CN VI's lateral rectus (contra to cortex). If CN VI is lesioned, you cannot abduct that eye.
2. There is also an interneuron pool within the nucleus of VI, whose axons contribute to MLF that crosses & projects to the nucleus of III (ipsilateral to cortex). If these fibres are lesioned, then you cannot adduct that eye (So an MLF lesion is ipsilateral to the eye that does not follow).
CN III projects from nucleus of III to MR, IR, SR & IO. So if occulomotor is lesioned, you have an LMN syndrome and the eye will be "down & out" due to the remaining SO & LR.
Recall from yesteday that these are the same circuits used to orient you're eye in response to gravity & head movements. If the vestibular system or nuclei are lesioned then you get nystagmus; where the eye(s) slowly drift toward the side of the lesion, then rapidly jerk back in the opposite direction.

Facial Nerve & Lesions
If you damage nucleus of VII or if you damage the whole nerve you get an ipsilateral face LMN syndrome including: wider palpebral fissure (due to loss of tone to orbicularis occuli), flattened nasolabial fold, no blink reflex, and no tearing.
If you disrupt the cortical drive to the nuclei of VII, you only affect the contralateral lower quadrant (quadratic facial paralysis) because there is bilateral cortical input to the upper face but only contralateral input to the lower face.
So Jean was saying you may see Bell's Palsy maybe fairly often, but if a patient looks like they have Bell's Palsy but can wrinkle their forehead and close their eye then that could be a stroke!

Blood Pressure Reflex & Autonomic Dysreflexia
At rest, blood vessels are tonically constricted by sympathetic (& myogenic) tone producing a resting blood pressure. If BP goes up, it is sensed by baroreceptors in the aortic arch & carotid sinus and signals are sent via IX and X to the NTS within rostral medulla. The NTS activates inhibitory neurons to slow down the pacemeaker for this system in the RostroVentral Lateral Medulla (RVLM). This leads to reduced firing in preganglionic sympathetics, reduced firing in postganglionic sympathetics, and reduced vascular tone to allow vasodilation.
In the case of autonomic dysreflexia, when a noxious stimulus triggers sympathetic output that constricts splanchnic vasculature, blood pressure becomes elevated. But if the spinal cord injury is above the level of the splanchic nerves (above T5-6), then these splanchnics can no longer receive the descending signals to reduce their firing to allow vasodilation. So below the lesion everything is clamped down and above the lesion everything is vasodilated (flushed, sweating, headache). Additionally heart rate drops in an attempt to compensate for the increased blood pressure (reflexive bradycardia).

more along these lines tomorrow!

Trigeminal

Tri not, do or do not!

Trigeminal does nociception...
At the level of the trigeminal nerve in rostral pons you have the motor & main sensory nucleus of V. Extending caudally down the brainstem from this level is the spinal nucleus and tract of V. Where this nucleus ends, substantia gelatinosa begins (with similar form & function in the SC). Pain & temperature fibres (c-fibres & Aδ's - interestingly myelinated in the CNS) enter with the trigeminal nerve (rostral pons) then descend spinal tract of V to synapse at on spinal nucleus V. 2nd order axons cross midline at that level & jump on ALT (occasionally called trigeminothalamic tract). So damage to caudal brainstem can take out P&T but not sensory face until you reach at least the level of main sensory nucleus of V.
Trigeminal does jaw stretch reflex...
Above the motor & main sensory nucleus of V, CN V nuclei are stretched out into the midbrain (mesencephalon) as the mesencephalic nucleus of V. This is like other neural-crest derived sensory ganglia (eg pseudounipolar neurons) except it has been incorporated into the brainstem. The mesencephalic nucleus functions in the stretch reflex for the jaw, so the peripheral processes are !a (& Ib) afferents from muscles of mastication and the central processes descend to synapse on α-MNs in the motor nucleus of V that innervate the same (homonymous) muscle.
Trigeminal does stereoognosis...
The main sensory nucleus is just like a dorsal column nuclei - afferent fibres (pseudounipolar cells with cell bodies in trigeminal ganglion) synapse here on 2nd order cells. Axons from the 2nd order cells cross midline & add on to the medial lemniscus to add "head" information. From there it's similar - on to thalamus, and from there to somatosensory cortex (now lateral for face).
Blink 182? No, it's Blink 527!
If you touch a person's cornea and only the other eye blinks, you probably just have a problem with VII (orbicularis occuli). However, if you touch one side and neither eye blinks but touching the other side causes both to blink, you likely have a problem with sensation on that side. The pain fibres that extend from free nerve endings in the cornea have their cell bodies in trigeminal ganglion, enter rostral pons with trigeminal nerve, and descend spinal tract of V to synapse in spinal nucleus of V. One pathway leads to consious perception of pain as we've seen above, the other pathway inputs to an interneuron that branches bilaterally to motor nuclei of VII ("5 to 7"). If no signal comes in, there's no reflex on either side. (If VII were damaged, information still gets in, so other eye blinks but ipsilateral does not).

Also someone had asked recently about GSA, GSE, etc. If this helps...

GSA more than just a Graduate Student Assistant
When classifying neurons this way maybe it helps to start with what it is, where it goes, & what it does: 1. a neuron is either sensory (Afferent) or motor (Efferent); 2. to either Somatic or Visceral targets; 3. to perform either General or Special (sight, taste, hearing, smell, etc.) function.
If you made all possible combinations of these three 3-2-1 you’d have: GSA, GSE, SSA, SSE, GVA, GVE, SVA, SVE. However there are no SSE so there’s really only 7 possibilities:
GSA: you’re basic sensory afferent to skin, joints, etc.
GSE: motor to skeletal muscle derived from somites
SSA: the special senses (sight, hearing, etc. so cranial nerves)
GVA: visceral pain, distension, etc.
GVE: your autonomics to cardiac muscle, smooth muscle & glands
SVA: I think of these as being like GVA except related to smell & taste (I think technically the distinction must be whether the target organ was derived from somites (somatic) or splanchnic mesoderm/brachial arches (visceral) see SVE ↓
SVE: these innervate skeletal muscle derived from brachial arches (muscles of soft palate, larynx etc. so X with a couple exceptions; also muscles of mastication (1st brachial arch) so CN V; I think muscles of facial expression too, so that’s VII; and IX would be stylopharyngeus).
Hope that helps, I’m not so good on brachial arch derivatives but that’s what wikipedia is for I suppose!

Speaking of trigeminal (V3), see you IN LAB tomorrow!

Day 15 was a pure lab day... hopefully the post for brainstem covers a good bit of it. I might add something I understand better now thanks to Jean! - the principal sensory nucleus of V is analagous to a dorsal column nuclei - it's where the central processes of pseudounipolar neurons with cell bodies in the trigeminal ganglion synapse to carry fine touch, etc. However pain fibres with cell bodies in TG synapse in brainstem caudal to the rostral pons in the spinal nucleus of V, and proprioceptive fibres of V involved in the jaw-stretch reflex have their cell bodies rostral to rostral pons within the mesencephalic nucleus of V, rather than in TG.

Today is an overview of diencephalon & forebrain...

Diencephalon
Diencephalon is part of the forebrain (prosencephalon) that includes thalamus, hypothalamus, subthalamus, epithalamus, and part of the pituitary (neurohypophysis):
Thalamus is bounded by the hypothalamic suclus (between foramen of Monro & the mamillary body)... There are many nuclei within the thalamus which we will soon see...and three of which we have already seen: medial geniculate, lateral geniculate, and pulvinar.
Hypothalamus is bounded by the anterior commissure, lamina terminalis, mamillary body, and hypothalamic sulcus.
Subthalamus (diencephalon) lies close to substantia nigra (mesencephalon) and is part of the basal ganglia which also include caudate, putamen, & globus pallidus (see telencephalon below). To find subthalamus in coronal section look for a cap over the substantia nigra. Damage to the subthalamus can cause hemiballism.
Epithalamus sits "above" thalamus (but is really more posterior in the adult). It consists of 4 parts: 1. pineal gland produces melatonin and functions in circadian rhythm; 2. On each side of pineal sits habenula, with many connections to basal forebrain and thought to function in pain tolerance; 3. Stria medullaris thalamicus is the fibre tract from habenula to the basal forebrain; 4. Posterior commissure connects left & right colliculi (the two halves of the brainstem) and possibly other structures.

Telencephalon
Telencephalon includes: basal forebrain nuclei, basal ganglia, and cerebral cortices (frontal, parietal, occipital, temporal, limbic &/ insuluar).

Basal Forebrain nuclei are located anterior to anterior commissure & lamina terminalis and include septal nuclei (reward), nucleus accumbens (addiction) and nucleus basalis of Meynert (cholinergic neurons that die in Alzheimer's). Nucleus accumbens can be found at the point where the internal capsule does not comppleteley separate the caudate from putamen.

Basal Ganglia
The basal ganglia consist of: caudate, putamen, globus pallidus, substantia nigra, & subthalamic nuclei. Caudate & putamen together are referred to as striatum. Putamen & globus pallidus together are referred to as the lentiform nucleus. Some also include nucleus accumbens as a component both of basal ganglia and basal forebrain. Caudate consists of a head, body, & tail that wrap around the lateral surface of lateral ventricle starting in anterior horn.

(from medial to lateral) lateral ventricle-caudate-internal capsule-lentiform{globus pallidus(internus/externus)-putamen}-external capsule-claustrum (thin strip of gray)-external capsule (whilte) - insular cortex. (In horizontal section lentiform (putamen laterally, globus pallidus medially) sits between anterior & posterior limbs of internal capsule).

Frontal Lobe
Frontal lobe can be divided into motor & prefrontal cortex.
Motor areas include Primary motor (BA 4), Premotor (BA 6), Frontal Eye Fields (BA 8, drives PPRF), and Broca's area (BA 44/45, located in inferior frontal gyrus). Damage to Broca's causes nonfluent/motor aphasia. Like Wernicke's, Broca's is often associated with hemiparesis & apraxia, but less frequently associated with visual deficits than Wernicke's aphasia. A student had asked about stuttering & Broca's and a quick look has at least one PET study that shows a functional deficit in Broca's & Wernicke's associated with stuttering - but it looks like a complex topic, though an interesting field!
Prefrontal Association Cortex can be divided into 1. dorsolateral prefrontal cortex (PFC) involved in working memory; 2. orbitofrontal cortex involved in social & emotional decision making; and 3. anterior cingulate & medial PFC involved in motivation & executive attention. "Executive attention refers to our ability to regulate our responses, particularly in conflict situations."

Parietal Lobe
Parietal lobe contains primary somatosensory Cortex (BA 3, 1, 2) and sensory association cortical areas (5 & 7). Stroke of the parietal cortex can cause a syndrome of hemineglect, or more broadly perhaps hemispatial neglect.

Occipital Lobe
Occipital lobe contains primary visual cortex around the calcarine fissure (BA 17) with surrounding visual association cortex (BA 18 & 19 - thanks Megan!).

Temporal Lobe
Temporal lobe contains primary auditory cortex (BA 41) and two visual association areas: 1. a "what" for object recognition; and 2. a "where" for motion detection. Perhaps falling under the what category, an area in the inferior temporal gyrus specializes in recognizing faces, and when damaged causes prosopagnosia. In terms of auditory function, damage to Wernicke's area (BA 22) in superior temporal gyrus produces a "fluent" aphasia and is more often associated with visual field deficits than Broca's(upper quadrantanopia). Wernicke's aphasia may involve use of neologisms and/or paraphasias (word substitutions).

Limbic System structures include the hippocampal formation (important for learning & memory) and the amygdala (emotion). Amygdala can be found anterior to the inferior horn in the temporal lobe. The hippocampal formation rests along the medial surface of inferior horn of the lateral ventricle. Fibres connecting hippocampus (fornix) and amygdala (stria terminalis) to hypothalamic huclei and other targets also course along the lateral ventricle.

Insular Cortex
Insular cortex derives from telencephalon and is sometimes considered a separate lobe, sometimes part of limbic. It functions in visceral sensation & autonomic components of pain. Damage to insular cortex can cause deficit in speech articulation by muscles of the tongue (conduction aphasia).

Connecting the dots...
Association fibres connect ipsilateral cortex. Commissural fibre bundles connect left & right hemispheres (eg corpus callosum). Corpus callosum has 3 parts: genu, body & splenium. Other connections include the: Anterior commissure which connects temporal lobes & olfactory bulbs; Hippocampal commissure near the splenium of corpus callosum; Optic radiations; and the Internal capsule

Finally a few more members of the A-team: & a musical a-ccompaniment

acalculia
agnosia
anomia
agraphia
alexia
apraxia

That's all for today, lot's more tomorrow!!

First a review from yesterday...
Where would you look to find subthalamic nucleus?
Subthalamic nucleus is part of the basal ganglia, what are the other 4 parts?
What are 4 parts of epithalamus & where would you find them?
Name 3 divisions of prefrontal cortex & their associated functions.
What are Brodmann's areas for Broca's & Wernicke's? Damage to which of these two produces a fluent-aphasia?

Now on to Cortex & Thalamus ...

Cortical Organization functional - horizontal - vertical
As we've seen, cortex is organized into functional areas (visual, hearing, motor...) and these functional areas are further divided topographically into maps representing a given physical sense on the cortical surface (eg motor/sensory humnuculus, acoustic frequency, retinotopic maps...). In addition to primary cortices, the human brain has large association areas. As an example, in the case of motor areas, 1° motor cortex controls movement of individual muscle, premotor cortex controls movement around a joint, and supplementary motor cortex controls whole limb movements.
Structurally cortex is organized into 6 horizontal layers (specifically neocortex is 6 layers, evolutionarily older archaecortex is 3 (eg hippocampus) and paleocortex 5 (eg subiculum)).

Layers II & III communicate to and from other regions of cortex; if contralateral they are commissural fibres, if ipsilateral they are association fibres. Contrast these with projection fibres that travel to subcortical areas.
Layer IV receives input from specific thalamic nuclei, so this layer is comparatively large in somatosensory cortex.
Layer V pyramidal cells project to subcortical targets (eg in the brainstem, basal ganglia, and spinal cord), so this layer is comparatively large in motor cortex.
Layer VI fibres project out to thalamus.
Note that noradrenergic fibres (from locus coeruleus) and serotonergic fibres (from the raphe) input to every layer, as do association nuclei of the thalamus. see below...
Cortex is also organized vertically into columns of cells perpendicular to the pial surface that form functional units. Often these columns are defined by the width of their associated pyramidal neuron in somatosensory cortex:

Another example of verticle organization in the visual system are are occular dominance columns which we will "see" later...

Travelling from layer VI of neocortex to...
Thalamus

What does thalamus do?
The thalamus is primarily a relay center for sensory (and motor) circuits. (Note that ascending inputs have already crossed before reaching thalamus). Thalamocortical radiations then go on to connect thalamus to cortex, and cortex to thalamus. Those to the occipital cortex are specifically called optic radiations.

How do you find the thalamus?
If you can see 3rd ventricle you can see thalamus. (though in this particular cut we're riding in the "way back" with cerebral aqueduct) In coronal section, thalamus always sits on top of internal capsule (and putamen & globus pallidus are below)

To find thalmus in horizontal plane...
...look medial to posterior limb of internal capsule, either side of 3rd ventricle:

Thalamic nuclei
There are 3 basic types of thalamic nuclei: specific, association, & non-specific.

Specific Thalamic Nuclei
Specific thalamic nuclei, like primary cortices, are associated with specific functions. There are 7 specific nuclei to know (roughly from anterior to posterior):
1. anterior nucleus receives input from limbic structures (eg cingulate & mammillary bodies) and projects out to cingulate gyrus
2. ventral anterior VA receives input from globus pallidus & premotor cortex, and projects out to premotor cortex (BA 6)
3. ventral lateral VL receives input from globus pallidus, 1° motor cortex & cerebellum, and projects out to 1° motor cortex (BA 4)
4. ventral posterior lateral VPL receives input from DC-ML (body), ALT, & somatosensory cortex, and projects out to 1° somatosensory cortex (BA 3,1,2)
5. ventral posterior medial VPM receives input from trigeminal lemniscus (face) & somatosensory cortex, and projects out to 1° somatosensory cortex (BA 3,1,2)
6. medial geniculate receives input from inferior colliculus & 1° auditory cortex, and projects out to 1° auditory cortex (BA 41).
7. lateral geniculate recives input from retina (via optic tracts) &1° visual cortex, and projects out to 1° visual cortex (BA 17)
In all cases you will note a pattern where the cortex to which a thalamic nuclei projects also provides input back to that nuclei. Additionally, inputs from specific thalamic nuclei synapse in layer IV of the cortex, and layer VI fibres project to thalamus.

Association Nuclei
Association nuclei do not project to 1° cortices, but rather to association areas. There are 4 to know:
1. medial dorsal MD nucleus receives input from limbic structures (amygdala, olfactory system & hypothalamus), and projects out to prefrontal cortex.
2. lateral dorsal nucleus functions in emotional control of muscle, and receives input from cingulate gyrus, and projects out to posterior cingulate gyrus & medial parietal lobe
3. lateral posterior nucleus functions in sensory integration, receives input from parietal & neospinothalamic tract, then projects out to parietal lobe & superior colliculus.
4. pulvinar functions in integration of visual, auditory & somatosensory inputs from superior colliculus and temporal, paritetal, occipital lobes & 1° visual cortex, and projects out to temporal, parietal, & occipital cortices & visual association areas (BA 18 & 19)
In contrast to the specific thalamic nuclei, fibres from association nuclei can synapse in all layers of cortex, however outputs from cortex to thalamus still originate in layer VI.

Non-Specific Thalamic Nuclei
There are 3 to know:
1. Intralaminar nuclei are associated with motor & limbic function and found embedded within the internal medullary lamina (the "Y" on the dorsal surface of thalamus)
2. Midline nuclei (eg masa intermedia) are limbic and project to basal forebrain.
3. Reticular nucleus of thalamus is a meshwork of neurons important for negative feedback loops in thalamus. The idea is that every time you turn a cell on, you want to turn it off (like Renshaw cells for α-MNs, except these thalamic neurons use GABA).

Sensory Systems
Now that we have covered the basic structures from peripheral nerve to spinal cord to brainstem to thalamus & cortex the next series of lectures looks at whole systems. We start with a few basic concepts of sensory systems: receptive fields, adaptation, and surround inhibtion...
Receptive Fields
In a basic sensory system, you start with a receptor that takes a physical stimulus and "transduces" it into an electrical signal the nervous system can use. The type of sensory information is the modality (vision, taste...) and may include submodalitites (sweet, sour, 旨み...) The area covered by a given receptor is termed it's receptive field. These can be small & discrete (as in finger tips) or large & overlapping (as on the arm). In the later case, lower resolution reflects a lower density of receptors. A collection of receptive fields for all sensory DRG neurons at one SC level would be a dermatome. However convergence & divergence can alter properties of receptive fields (eg convergence can broaden a field)
Adaptation
Continued stimulation of a receptor produces two types of response: a slowly adapting response in which the receptor responds continuously (sensing sustained input); and a rapidly adapting response in which the receptor fires then quickly stops (sensing change). For example a Pacinian corpuscle sensing vibration is rapidly adapting; as the sinusoidal wave alternately excites the receptor it is able to fire with a frequency equal to that of the vibration.
Surround Inhibition (lateral inhibition)
An important background piece for this concept is that most neurons always exhibit some level of basal activity. In surround inhibtion, a fibre from one receptive field branches to synapse on inhibitory interneurons which synapse in turn on fibres from neighboring receptive fields. If a stimulus specifically increases firing in that first fibre, it also causes inhibition of it's neighbours (decreased firing from basal levels) and thus sharpens the boundaries of the stimulus.

More on this tomorrow, and as a note for the pain case Megan had presented a journal club paper recently on a study in Nature that neatly ties a voltage dependent sodium channel channelopathy to pain pathways and the potential for a new type of analgesic without the side-effects of opiods. There was also I hear a Grey's Anatomy episode about this one!

Instead of review questions, I thought I might start this post with how I generally approach studying for this course, so for what it's worth here it is:

In a nutshell, the idea is to create a study guide for yourself for each exam.
1. List out the lecture/lab/imaging topics for that block: make that your table of contents.
2. Each chapter is going to be one topic (lab, imaging module, etc.) and your goal is to take notes from the handouts (written), and/or from the figures (visual), and/or from the lectures (auditory) and group them in a way that makes sense to you. Ideally you want no more than 7 blocks per chapter. You may also want to include like 2 or 3 really, really important figures that say what words can't.
Do this for each topic listed in the ToC and check them off as you go - that way you know you've covered everything. In the end you should aim for no more than 50 - 60 pages of notes & figures for each exam block. The rationale for this approach being if you have a 100 question test and 30 or so lectures/modules then you'll likely get 2 -3 questions from each lecture, and so if you look for the 5 - 7 main ideas from each lecture you're likely to cover the test question without getting bogged down in details for which there's just no time (at least until class is over).
The blog is just an example of how I put mine together. Let me know if it helps!

Now for today I had to miss an hour of this morning's lecture, but from notes it looks like review of DC-ML and ALT pathways so I'll just note receptors for these (many of which are also review) then go on to analgesics...

Receptors for the DC-ML
Cutaneous mechanoreceptors are generally associated with Aβ or Aδ fibres and include 2 rapidly adapting receptors sensitive to vibration (Pacinian and Meissner corpuscles) and 2 slowly adapting receptors sensitive to sutained pressure (Merkel cells and Ruffini endings).
Muscle and skeletal mechanoreceptors include muscle spindles (Ia afferents), Golgi tendon organs (Ib afferents), and joint mechanoreceptors (Aβ )

Receptors for the ALT
Nociceptors respond to tissue damage by sensing mechanical, thermal, or chemical stimuli (often via TRP channels) and transducing these stimuli into a pain signal. These receptors are generally free nerve endings, though certain mechanoreceptors (eg Pacinian) will signal pain if the stimulus exceeds normal limits. As we've seen these signals are carried by Aδ (for sharp localized "epicritic" pain) and c-fibres (for slow burning "protopathic" pain). Prostaglandins increase the sensitivity of these receptors to pain (hyperalgesia).

which leads us to...

Prostaglandins & Cyclooxygenase (COX)
Cyclooxygenase converts a starting substrate arachidonic acid to PGG2/PGH2, then depending on what enzymes are present witin the cell intermediates are converted to various prostanoids (including prostaglandins, prostacyclins, and thromboxanes. Thromboxane facilitates platelet aggregation (thrombosis) whereas prostacyclin functions in preventing platelet aggregation, so these two may function in an homeostatic loop. Prostaglandins have various functions, mostly involving inflammation but also in maintaining GI mucosa & renal function. So if COX is inhibited, you can block inflammation but you may also cause vascular effects and GI, hepatic & renal toxicities. There are two major forms of cyclooxygenase COX 1 (which is basically constitutive) and COX2 (which is basically inducible, by inflammation).

NSAIDs
All NSAIDS, including aspirin, are non-selective cyclooxygenase inhibitors, blocking both COX1 & COX 2.
Aspirin acetylates the COX active site causing irreversible loss of the enzyme, and so has long-term effects on platelet aggretation, even though aspirin itself is rapidly metabolized and broken down in the liver. However aspirin is no longer given to children due to the risk of Reye's syndrome.
Ibuprofen is less irritating to GI mucosa than aspirin and is safe for children
Naproxen is longer acting
Indomethicin is often used for non-rheumatoid arthritis
Fenamates (meclofenamate) and Oxicams (piroxicam) have long half-lives, but GI toxicity is common.
Acetaminophen does not block COX 1 or 2 (though one study found it may block COX 3 in CNS which is not involved in inflammation) so is not considered an anti-inflammatory, but rather an analgesic & antipyrretic. Thus acetaminophen can be used in combination with NSAIDs or opiod analgesics (eg percocet).
As we mentioned above, COX inhibition can cause cause GI & renal toxicity, especially following long-term high dose NSAID administration. As you would expect drugs that irritate GI mucosa (eg alcohol) or affect renal function (uricosurics or diuretics) interact poorly with NSAIDs.

COX-2 Specific Inhibitors
The COX-2 isoform is induced by cell injury & stress and has less involvement in baseline functions. The rationale then behind COX-2 inhibitors is that selective inhibition of this isoform could specifically reduce inflammatory effects with fewer side-effects. Examples of selective COX-2 inhibitors are Celecoxib and Rofecoxib (Vioxx). Vioxx of course was recalled due to cardiotoxic effects, but the reason why Celecoxib is not as cardiotoxic is unclear - though celebrex still contains an FDA warning. Even though COX2 is considered inducible, it has some level of basal expression important in renal blood flow, so its inhibition still involves some risk of renal toxicity.

Slowly Acting Anti-Rheumatic Drugs (SAARDs)
Immunosuppressives such as methotrexate (a chemotherapeutic which inhibits DNA synthesis) can be used as anti-inflammatories because they can block turnover of WBCs. Anti-malarial drugs such as hydroxychlorquine are also effective against lymphocyte activity. Gold therapy can induce remission in some cases of arthrits. And D-penicillamine (a chelating agent used to treat heavy metal toxicity) can also reduce leukocyte chemotaxis & T-cell proliferation.

Opiod Analgesics
The term "opiates" refers to alkaloids found in opium and those drugs derived from them (eg morphine, heroin, codein), while the term opiods refers to all drugs that have opium or morphine-like pharmacological actions. Opiods function in pain relief by binding opiod receptors in the CNS, but also produce GI side effects (constipation) by binding receptors in the gut. Of course these receptors evolved to respond to endogenous peptides, it just so happens that opium alkaloids also activate the receptors (it's just so weird!!!)
Endogenous opiods include endorphins (μ-opioid receptors), enkephalins (μ and δ-opioid receptors), and dynorphins (κ-opioid receptors). Opiods can act on both c-fibres and Aδ's primarily through presynaptic inhibition.
Morphine is a μ-opioid receptor agonist. Morphine acts in presynaptic inhibition by binding μ receptors, causing Gi to inhibit adenylate cyclase, reducing cAMP and opening K+ channels while blocking Ca channels to reduce neurotransmitter release. Nothing is more potent than morphine for in patient reduction of chronic pain.
Codeine is more orally available than morphine, but less potent. Since codeine requires Cyp2D to produce active metabolites, it's effect is limited by the amount of enzyme available and so a ceiling effect occurs when all available Cyp2D is utilized. 5 - 10% of the population express very little Cyp2D so codeine is not as effective in these patients. Also some drugs that inhibit Cyp2D reduce codeine's effectiveness (eg SSRIs).
Oxycodone does not have the ceiling effect of codeine, and is not as addictive as morphine. It is often combined with other analgesics: percocet = oxycodone + acetaminaphen; percodan = oxycodone + aspirin; combunox = oxycodone + ibuprofen. Oxycontin is a sustained release version of oxycodone.
Fentanyl is a potent (80X morphine!), short-acting general anesthetic (often used when removing impacted wisdom teeth).
Dextromethorphan is the D-isomer (opposite) of codeine. Though it does not bind opiod receptors, it elevates cough threshold.
Meperidine (demerol) is a synthetic opiod with less peripheral side-effects, but otherwise similar to morphine.

Opiods interact with CNS depressants (BDZs, & barbiturates) and MAOIs. In cases of overdose, a broad opiod receptor blocker (naloxone) is used. Opiods do produce a lot of tolerance (except in constipation and pupillary constriction) so higher doses will be needed over time. So physical dependence develops (withdrawal), but so long as pain is present, psychological dependence is rare. Why is heroin more addictive than morphine? That has to do with it's high lipid solubility - it reaches the brain quickly to activate reward centers (nucleus accumbens & prefrontal cortex).

As an aside, one of the surgical residents doing a research rotation in our lab has studied opiod effects in GI motility, partly inolving alvimopan (entereg) - a peripherally acting μ opiod receptor antagonist designed to reduce GI side-effects while preserving central effects of opiod analgesia. However coming full circle to Vioxx, the alvimopan study was pulled in last month due to CV effects...

Today is the 2nd installment in the "study ideas" series:
We started with the idea in a nutshell, now what to do with the nuts?
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Once you've grouped the material for a lecture topic into 5 - 7 blocks of information and maybe a couple important figures...
...the next step is to take each one at a time, read that block (or figure), then without looking back write down (or draw) as many of the main points (or structures) as you can remember. It doesn't have to be verbatim, in fact you'll find that as you write you'll think of better ways to organize & condense the material.
Once you've written/drawn all you can remember, check it against the original - note what you remembered wrong or what you'd forgotten, then try again. If after 3 trials it's still difficult, it probably means either: 1. you have too much information in that block; or 2. the information in that block isn't sufficiently interrelated. In either case, it's best to stop and rework the block because you want to make sure you are reinforcing pathways that make intuitive & logical sense to your particular knowledge base & ways of thinking.
Once you've done one block, then do the next. Once you've finished each one, try doing them all together. And once you feel good about that topic as a whole, I'd practice problem sets (lesions, etc.) which are likely to appear on exams. Then you're done with that topic. Since you've built your base, you'll be able to review what you've got just before the exam and it should pop right in there.
Tomorrow I'll try to finish off study ideas with time management. That way we'll have covered the two major challenges of this class: the volume of material & the limited time.

And if all this studying has given you a headache, then you're ready for today's lectures...

Pain
Nociception is in the periphery, pain is in the brain (a sensory & emotional experience). Pain itself can be classed as acute or chronic. Chronic pain can be classed as nociceptive, or neuropathic (pain not due to nociceptors), mixed, or psychologically based. Complex regional pain syndrome is an example of chronic pain caused by injury to bone & soft tissue which may or may not show obvious nerve damage. The two hallmarks of chronic neuropathic pain are hyperalgesia (an exacerbated pain response to a painful stimulus) and allodynia (a painful response to a normally non-painful stimulus).
There are 4 steps in the pain pathway: transduction, transmission, modulation, & perception. A painful stimulus is transduced into an electrical signal typically via free nerve endings, but also by Pacinian corpuscles and/or muscle spindles if a certain threshold is exceeded. Transmission involves c-fibres, Aδ's (and in some cases Aβ's). These 1st order cells synapse in the dorsal horn on marginal cells (which are nociceptive-specific) or wide dynamic range (WDR) cells that can receive different types of inputs. WDR cells are capable of increasing their firing rate with increasing stimulation, and through a process known as WDR windup may eventually "take-off" and fire on their own. This is one mechanism underlying the sensitization characteristic of chronic neuropathic pain. 2nd order cells may also receive convergent input from different parts of the body, for instance cardiac afferents synapse at the same level as afferents for the arm so cardiac pain can be "referred" to the left arm (an even "cooler" example is brain freeze!). Fibres transmitting pain ascend to the thalamus (a stroke here can lead to thalamic pain syndrome). And from thalamus these signals are relayed to parietal cortex (for discriminative aspects of pain) and to frontal and limbic cortices (for affective aspects of pain).

Headache
Headache may be a primary conditon (most common) or secondary to another disorder (stroke, tumor, sinus...). Primary headache can be grouped as: migraine, tension-type, trigeminal autonomic cephalgias (cluster headache), and neuralgias (peripheral nerve disorders of the head & neck).

Migraine
Migraine is not technically a headache, though headache may be one possible symptom of migraine. Migraines affect women more than men, usually occur at day 0 of the mentrual cycle, and occur most frequently at awakening. Migraine may be experienced in phases, with about 1/3 of patients experiencing a prodrome phase where they can sense onset. 1/5 then have an aura phase in which they typically experience sensory paresthesias or scintillating scotomas. In the headache phase, pain is throbbing, and associated with hypersensitivity to stimuli (light, touch, movement) and dysautonomia (mainly nausea & sinus congestion). Finally recovery occurs during the postdrome phase.
Causes of migraine are uncertain, but may involve a wave of cortical spreading depression (CSD) that appears to originate in the occipital lobe and tracks with the movement of auras (if present). Genetic cases of migraine, such as familial hemiplegic migraine, suggest certain genetic mutations are important to the pathophysiology: FHM1 involves a P/Q calcium channel, FHM2 an Na/K ATPase, and FHM3 a voltage-dependent sodium channel. Though models based on these data are pretty vague, they center on hyperexcitability. More concretely migraine likely involves 5-HT because it can be treated by drugs acting at serotonergic receptors. IV administration of 5-HT itself relieves migraine. Triptans (5HT1B, 1D, & 1F agonists) block acute migraine. Methysergide (5HT2B antagonist) prevents migraine. Odansetron (5HT3 antagonist) prevents nausea. Unfortunately, substances which relieve migraine over time also lower the threshold for the next migraine. Drugs used in the prevention of migraine include β-blockers (propanolol), tricyclics (amitriptyline), anticonvulsants (divalproex), and Ca-channel blockers (verapamil). All of these appear to reduce cortical spreading depression.

Cluster Headache
Cluster headache has similar symptoms to migraine, but a more rapid onset and shorter duration of extremely intense pain. Cluster HA also shows a temporal periodicity, occuring predominantly in January & July and more often nocturnal (possibly at onset of REM). This periodicity forms the basis for one theory of cluster headache, because circadian rhythms are in part generated in suprachiasmatic hypothalamus and this structure shows alterations in form and function in patients with cluster headache. Other potential elements of pathophysiology involve cranial parasympathetics, trigeminovascular system, and internal carotid dilation. Acute treatment invloves high flow O2 or SQ sumatriptan. Preventitive treatment involves steroids (prednisone) and maintenance with verapamil or lithium. In refractory cases, surgical treatments may be required, with some promise from studies of deep brain stimulation of the posterior hypothalamus.

Serotonin
Serotonin (aka 5-HT, 5-hydroxytryptamine) is found in gut mucosa, platelets, and neurons of the CNS, ENS, & blood vessels. Serotonin functions to contract smooth muscle, induce platelet aggregation, and is important for intestinal motility and many CNS functions. Serotonin is degraded by monamineoxidase (MAO).
There are 3 serotonin receptors we discussed: 5HT1, 5HT2, & 5HT3. 5HT1 coupled to Gi (innhibits adenylate cyclase) is inhibitory in the brain and is vasoconstrictive so 5HT1 agonists are used to treat migraine (decreases pain signals & contracts vessels). These are the triptans sumatriptan and zolmatriptan (5HT1d agonists), and the ergot alkaloids ergotamine, ergonovine, and methysergide. Ergot alkaloids also affect dopamine and noradrenaline receptors. Ergonovine in particular is often used to treat postpartum haemorrhage because it preferentially causes uterine contraction. 5HT2 receptors are coupled to Gq (activate PLC) is excitatory in the brain & causes smooth muscle contraction. 5HT3 receptors are ionophores for Na+ and Ca++ (K+ too) and function in GI motility and nausea, which is specifically blocked by the 5HT3 antagonist odansetron.

Histamine
Histamine is synthesized from histidine, can be stored in & released from granules in mast cells, and like 5-HT is degraded by monamineoxidase. Histamine functions in two types of allergic response: type I and type II (which is complement-mediated), as well as functioning in gastric acid secretion & CNS neurotransmision.
There are 3 major histamine receptors: H1 acts via Gq to activate PLC leading to vasodilation (due to NO release by endothelial cells), but contraction of other smooth muscles; H2 coupled to Gs activates adenyl cyclase; and H3 coupled to Gi (possibly an autoreceptor providing negative feedback on histamine release).
How do you block an allergic reaction?
There are 4 examples of non-receptor mediated antagonists that prevent mast cell degranulation: epinephrine, cromolyn sodium, albuterol, and theophylline. Epinephrine also produces a physiological reversal of histamine action by inducing bronhial dilation & vasoconstriction.
Specific H1 receptor antagonists include diphenhydramine (benadryl which also has anti-muscarinic effects), and the 2nd generation drugs loratadine & fexofenadine which do not cross the BBB and therefore are not as sedating & have no central anti-muscarinic effects.
Specific H2 receptor antagonists include cimetidine (tagamet), ranitidine (zantac), and famotidine (pepcid) used to inhibit gastric acid secretion in treatment of ulcers (in students taking neural science!).

Tomorrow looks like motor systems and myotonic dystrophy...

Today is the third & final installment in the studying series, and covers two ideas about time management...
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The first idea is to use the "table of contents" (the list of that exam's topics, labs, modules) to pace yourself - if you know you how much time you have and how many topics you have to cover it's easier to get a sense of where you are. If at all possible it's nice to have everything together a day early - so you can "taper" the day before the test.
The second idea is to use lecture time as effectively as possible ; a day is often 4 to 6 hours of lecture so the more effeciently you can use that time the more you have for other things. Usually I take notes and try to pre-organize blocks during the lecture. Also you might note certain figures you want to include in your test guide for later. When possible it's easiest to put that material together that same day while it's fresh in your memory.
So that's all I can think of, if you have ways you like to keep material & time organized definitely feel free to post a comment - I'm sure they'd be helpful!!

Today's lectures cover organization of motor systems...

Vertical & Horizontal Organization of Motor Systems

Motor function is controlled at 3 vertical levels: spinal cord, brainstem, and telencephalon. Cortex can influence lower motor neuron (LMN) activity in two ways: directly (via corticospinal tract); or indirectly (via brainstem). There are 2 major internal loops: cortex - basal ganglia - thalamus; and cortico-ponto-cerebellar. And there are 2 major sources of somatic sensory inputs to motor pool function: vestibular nucleus & reticular formation.

Motor function is also organized horizontally within the ventral horn of the spinal cord: lateral MNs project to apendicular muscle largely for volitional movements; medial MNs project to axial muscle largely for postural control. Therefore descending inputs that terminate laterally are more important for volitional control, and those that terminate medially are more important for postural control. Two descending pathways primarily responsible for volitional control are 1. lateral CST from the cortex; and 2. corticorubrospinal tract from the red nucleus. Two major descending pathways to medial ventral horn come from: 1. the reticular formation; and 2. the vestibular nucleus

From the above I think you basically want to take a general picture of the structure of the motor system. We will look at each part in more detail over subsequent lectures. We've actually already covered a good bit at the spinal cord level...

Regulating Motor Function at level of Spinal Cord

Recall that transmission at the neuromuscular juntion is basically all-or-nothing, so the NMJ is not a major site of regulation. The "lowest" site of regulation is at the α-MN which receives many excitatory & inhibitory inputs. For an α-MN to fire it must have a convergence of excitatory input sufficent to build up an EPSP capable of spreading to the axon hillock and generating an action potential.

A single presynaptic neuron (eg a Ia afferent) can diverge sending multiple collateral branches to individual α-MN's. The area where converging inputs are sufficient to cause the α-MN to fire is called the discharge (or liminal) zone. The area where converging excitatory inputs are not sufficient to cause the α-MN to fire is termed the facilitated (or subliminal) zone. In spinal cord reflex circuits, the Ia is liminal to α-MNs to homonymous muscle (the origin of that Ia fibre); subliminal to α-MN to synergist muscles; and via interneurons, inhibitory to antagonists. So divergence and convergence of inputs to α-MN's in the spinal cord allow for graded reflex responses according to the number of α-MN's (motor units) in their discharge or subliminal zones (as we'll see next), and the same principle is used to grade descending inputs.
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For just about any motion you make, volitional or postural, you have to be able to regulate power of contraction and you have to monitor how contraction is proceeding so you can make adjustments to that power "on the fly".
Regulating Muscle Power
Each motor neuron and all the muscle fibres it innervates make up a motor unit. Some are large, some are small, but all fibres within a motor unit have the same contractile properties: slow twitch, fast fatigue-resistant, or fast fatigable. Slow twitch fibres develop little force, but can maintain tension for long periods. Fast-fatigable fibres generate more force, but cannot maintain tension for long. In general, postural muscles are predominantly slow twitch, and muscles involved in volitional movement are fast-twitch.
Muscle increases power in two ways, it can: 1. have each motor unit fire more frequently; or 2. recruit more motor units (smallest units are recruited first because smaller MNs have higher input resistance so a given current produces a greater change in voltage V = IR. The idea that it takes a greater synaptic input to recruit larger motor units is called the "size principle")
Monitoring Movements
Muscle stretch is monitored by muscle spindles and Ia afferent fibres. The Ia afferent spirals around the intrafusal fibre within the spindle. When lengthened spirals are extended and mechanoreceptors fire increasing AP frequency in the Ia afferent (there is a tonic discharge at rest). Two phases of stretch are sensed: the speed of the stretch (dynamic phase) and the magnitude of the stretch (static phase).

If you were to stretch your hamstring by touching your toes rapidly vs slowly, the faster stretch would have a larger dynamic phase, but the static phase would be the same for a given length. Now if you were to contract hamstrings say during a leg curl, the spindle would shorten and spirals close.
To keep spiral in working configuration, during a movement, you need parallel stimulation of intrafusal fibres. Otherwise during a contraction once the spindle had shortened enough for the spirals to close they would remain silent over succeeding series of contractions and extensions and you'd have no way of "knowing" how fast the muscle was stretching and how far it had gone. So descending inputs coactivate α-MN and γ-MN to cause movement & maintain sensitivity for sensory output necesary to coordinate muscle activity. In general, α-MN's receive both DRG afferent input (reflex) & descending inputs whereas γ-MN's receive only descending inputs.

We finish today with a look at one example of a disease of motor function...

Myotonic Dystrophy
Myotonia refers to delayed relaxation following contraction. In Myotonic Dystrophy myotonia appears clinically as percussion or grip myotonia and electrically as "dive-bomber" potentials in EMG.

Adult Onset Myotonic Dystrophy
Onset of adult MD typically occurs in the 20's to 50's and produces a characteristic pattern of weakness & atrophy in distal and CN innervated muscle (hatchet facies, wasting of hands, foot drop). Muscle biopsy will show: centralized nuclei; ringed fibres, and type I (slow twitch) fibre atrophy. Myotonic dystrophy (DM1) also shows cognitive effects associated with frontal lobe dysfunction (apathy, suspicion, and hostility are common), and widespread systemic abnormalities including, "christmas tree cataracts, balding, and cardio-respiratory effects. Arrythmias are due to disruption of the bundle of His leading to 1st degree block (pronounced PR interval) can lead to 2nd degree or 3rd degree complete heart block (no AV, ventricles beat independent of atria).

Neonatal Onset MD
DM1 is one cause of a floppy baby, and prenatally is associated with reduced fetal movements that lead to contractures (arthrogryposis). Note that floppy baby & arthrogryposis occur in other disorders besides myotonic dystrophy. Individuals show a gradual improvement in strength, but by their 20's muscle function deterriorates. Neonoatal onset MD is always maternally inherited because onset is related to genetic instability which is greater in the ovum than in sperm.

Cause of Myotonic Dystrophy
MD is a genetic disorder caused by a triplet repeat in an intron of the DMPK gene. Normally there are 40 stable CTG repeats, but DM1 will have 50 - thousands of unstable repeats. Within a range from 40 to 400 repeats, a higher number of repeats correlates with earlier onset and increased severity. It is thought that repeats act to sop-up/sequester RNA binding proteins such as muscle blind and CUG-BP1 which then become unavailable to function in transcriptional processing of other genes that rely upon them, thus leading to multisystem dysfunction.

Other types of myotonic dystrophy & related disroders.
DM1 is the major type of myotonic dystrophy, DM2 is similar but proximal muscles are affected, myotonia is less common, and there are fewer cognitive effects. DM2 comprises two conditions PROMM (proximal myotonic myopathy) and PDM (proximal myotonic dystrophy). Duchenne's muscular dystrophy (the most common genetic disorder in children) is similar in some aspects but X-linked recessive and does not show myotonia.

In honour of spring, we hop around a bit today from brainstem lesions, to post-infectious diseases of CNS/PNS, to local anesthetics, and then to motor systems.
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Brainstem Lesions
Brainstem lesions may result from: vascular events (stroke or haemorrhage), tumors (intrinsic or extrinsic), infections (eg fungal or TB), or demyelinating/neurodegenerative disease. Brainstem lesions typically cause mutliple CN deficits - the D's: dysarthria (slurred speech) VII, IX, X, XII "pa ka ta"; dysphagia (difficulty swallowing) IX, X, XI; diplopia (double vision) III, IV, VI & MLF; disequilbrium (vertigo) VIII & cerebellar tracts. The most common cause of a brainstem lesion is stroke, and since penetrating arteries supply ventroanterior brainstem and circumferential arteries supply more dorsolateral, lesions typically appear like the following:

How do you know you have a brainstem lesion?
You often see a crossed pattern with ipsilateral CN deficit & contralateral limb dysfunction. CN deficits may involve facial weakness/numbness, hearing loss, or internuclear ophthalmoplegia in which the eye ipsilateral to the lesion does not adduct, while the contralateral side develops a jerking nystagmus in the horizontal plane. Contralateral limb dysfunction may manifest as weakness, or a Babinski sign if CST is affected. Cerebellar dysfunctions are trickier becuase ascending fibres from cerebellum to cortex cross in caudal midbrain, while descending cortical efferents then recross at the pyramidal decussations, which is why they say that the cerebellum "double-crosses." That means cerebellar dysfunction produces ipsilateral deficits (eg heel to shin test, rapid hand movements (dysdiadochokinesia )).

hopping over to...

Post Infectious Disorders of CNS & PNS
Examples from this lecture are: Varicella Zoster, Bell's Palsy, Guillain Barre Syndrome (GBS), Transverse Myelitis, Subacute Sclerosing Panencphalitis (SSPE), and Acute Disseminated Encephalomyelitis (ADEM)
Herpes Zoster (or shingles) is due to reactivation of varicella zoster (chicken pox) and typically appears as vesicular dermatomal rash that follows a dermatome (often thoracic). A prodrome phase of acute burning pain precedes the rash, and during the course DRG neurons and fibres are lost. Zoster is treated with antivirals (aciclovir, valaciclovir, famciclovir) and the earlier the treatment the more likely pain & future outbreaks will be controlled.
Bell's Palsy (idiopathic facial paralysis) involves inflammation of CN VII typically in the labyrinth producing a compression of the nerve. Typically you will see unilateral upper & lower facial weakness (widened palpebral fissure in severe cases), decreased tearing, loss of taste from anterior 2/3 tongue, and hyperacusis. Though called "idiopathic", Bell's palsy has been associated with Herpes simplex, Lyme disease, tumor in the cerebellar-pontine angle, and Ramsay-Hunt Syndrome II (in which H zoster is reactivated in the geniculate ganglion). One of the more interesting outcomes of Bell's palsy involves sprouting of injured facial nerves to reinnervate aberrant muscles producing synkinesis.
Guillain Barre Syndrome (GBS) is the most common acute peripheral nerve disorder. GBS shows progressive weakness of more than one limb, areflexia, and sensory symptoms (numbness). History includes previous infection, and CSF has high protein but normal lymphocyte count. Treatment involves monitoring autonomic instability (respiratory, arrhytmia, hypo/hypertension).
Transverse Myelitis appears as an abrupt onset of a "hanging sensory level", commonly thoracic (eg back pain or paresthesia) often following an upper respiratory tract infection (URI). Signs & symptoms include UMN syndrome (hyperreflexia, spasticity, babinski) though in 1/3 of patients onset will be so rapid as to produce spinal shock. An important differential is a compressive lesion due to disc or metastatic tumor which requires immediate surgery. MRI is done to rule this out, then a head MR might be performed if there is a risk of MS, and if imaging shows no risks an LP is done to look for inflammation.
Subacute Sclerosing Panencephalitis (SSPE) is a chronic CNS infection due to a mutated measles virus that affects children 5 - 15; now rare due to vaccination. The disease follows stages from early behavioural changes, to rhythmic myoclonic jerking, to autonomic instability (and reduced myoclonus as the brain "burns out"), finally ending as a mute, quadriplegic patient. Anti-measles antibodies can be found in serum & CSF, MRI will show demyelination, As a side-note there may be some benefit to treatment with interferon and the antiviral inosine pranobex - from the above link.
Acute Disseminated Encephalomyelitis (ADEM) is a brief, monophasic attack of the brain & spinal cord commonly following previous viral infection or vaccination. Inflammation can be so abrupt as to cause seizure and coma. Commonly visual dysfunction, CN palsies, fever and head-ache are associated. The most important differential is MS; an MRI that shows larger contiguous lesions is more likely indicative of ADEM but no abnormality is pathognomonic. Treatment is with IV steroids (eg solumedrol).

hopping along to...

Local Anaesthetics
Local anaesthetics are used clinically for: topical application or local infiltration; peripheral nerve block; neuraxis (epidural & spinal) anaesthesia; and IV regional anaesthesia (Bier block).
There are 3 basic parts to the chemical structure of a local anaesthetic: 1. a hydrophobic benzene ring that allows entry across the lipid bilayer; 2. a hydrophyllic amine that juts into the sodium channel; and 3. an intermediate chain (with either an amide or ester bond) that determines potency, degradation, & immunogenecity. The prototypical ester drug is procaine (novocaine) and typical amides include lidocaine and bupivacaine (two "i's" are an amide). Esters have a slightly higher allergenic potential (related to their metabolites) and are metabolized by a relatively ubiquitous plasma cholinesterase (aka pseudo-cholinesterase) so these have a typically short half-life. Amides on the otherhand have to be transported to the liver for degradation.
All local anaesthetics are bases, and so have an uncharged form, and a protonated charged form. Recall that pKa is the pH at which half of the molecules are charged, and half uncharged. The charged form of the anaesthetic enters voltage-dependent sodium channels to block action potential propogation. In myelinated axons, when sufficient local anaesthetic is present to block 3 nodes in a row, the probability that neuron will stop conducting (known as the impulse extinction) is 100%. Larger axons are harder to block, but fortunately pain is carried by smaller Aδ's and c-fibres. The tricky thing is that local anaesthetics block channels from the inside. Since only the uncharged form can pass through the lipid bilayer, the closer a local anaesthetic's pKa is to physiologic pH, the larger the percentage of uncharged molecules, and the faster it works. Lidocaine is potent and fast with low cardiotoxicity. Bupivacaine has slower onset, longer duration and can potentially be highly toxic.
Serious toxicity occurs when bupivacaine is accidentally injected IV. Symptoms are initially "masked" because the anaesthetic is highly protein bound; but the next small amount of bupivocaine injected produces cardiac arrest and seizure. For this reason, epinephrine is mixed with locals, partly to cause vasoconstriction and "localize" the local, but also as a marker to produce symptoms of tachycardia and dizziness if accidentally injected IV. As a side note, safer alternatives to bupivocaine have been developed including at least ropivacaine (ROP). And bupivacaine toxicity has been overcome in some cases by flooding the system with IV lipids (Intralipid) to "sop up" the bupivacaine: Rosenblatt et al. Lidocaine, on the other hand, is not so highly protein bound (70%) and will show recognizable signs & symptoms of IV administration from dizziness, tinnitus, etc. long before cardiovascular toxicity. To get out of trouble with lidociane you maintin the ABCs, and administer a small dose anticonvulsant (BDZ or barbitturate) if necessary.

and landing at...

Descending Tracts of the Motor System
Corticospinal tract arises from Brodmann Areas 4, 6, 312, 5, and 7. The primary motor cortex is organized topographically into vertical columns of cells representing the contralateral body as the humunculus. This organization is maintained as fibres descend through corona radiata - internal capsule - cerebral peduncle - longitudinal fibres of the pons - pyramids - lateral & anterior corticospinal tracts - to lateral or medial ventral horn respectively. A small number of upper motor neurons called Betz cells make monosynaptic connections with lower motor neurons for fine movements of fingers (and maybe toes & tongue). In general UMNs coactivate both α MNs and γ MNs in order to maintain afferent sensitivity to movement required for active coordination (efferent modulation of afferent input). Primary cortex receives ascending somatosensory input via thalamus, input from basal ganglia & cerebellum via thalamus, and input from other cortical areas.
However not all descending fibres reach the spinal cord, many terminate in the brainstem (eg red nucleus and reticular formation) and lead to other descending tracts for motor control. To corticospinal tract we will add rubrospinal, tectospinal, reticulospinal, and vestibulospinal tracts:
Rubrospinal tract is a redundant pathway, parallel to CST, for control of head and upper limbs. From the magnocellular portion of red nucleus, axons cross and merge with the lateral CST to descend in lateral funiculus as far down as MN's to upper limb (where they synapse on interneurons & coactivate α MNs and γ MNs as per usual). The red nucleus itself receives major inputs from cortex and cerebellum (remember X/SCP?).
Rubrospinal is more of a lateral tract since it drives upper extremities (appendiular) but I'm going to move tectospinal tract (since it's head & neck) with the other medial descending motor tracts that function in postural control & righting: 2 reticular (pontine reticulospinal tract & medullary reticulospinal tract) and 2 vestibular (vestibulospinal & descending MLF).
Tectospinal tract arises from contralateral superior colliculus, crosses, and controls neck muscles for the startle response.Reticulospinal tracts arise from a diffuse distribution of nuclei in the pontine and medullary reticular formation. Interestingly they drive the same motor groups, but in opposite ways. Pontine reticulospinal tract descends uncrossed in anterior funiculus to drive extensors (postural muscles) while medullary reticulospinal tract provides counterbalancing inhibitory input to the same MNs. Recall that the ALT sent collaterals to reticular formation, and this "old" ascending afferent inputs to this "old" descending motor tract. Both reticulospinal tracts also receive input from cortex and cerebellum, but importantly the medullary reticulospinal receives an obligatory cortical drive - it will not work without cortical drive. If cortical input is removed from medullary reticulospinal tract it will remove that descending inhibition and produce spasticity.
Vestibulospinal Tract arises specifically from the lateral vestibular (or Deiter's) nucleus. The vestibulospinal tract is involved in tonic postural control and is driven by vestibular system & cerebellum but importantly not by cortex.
The vestibular apparatus itself has 2 fluid filled components: 3 semicircular canals that determine angular acceleration & deceleration; and 2 otolith organs (the saccule & utricle) that sense linear acceleration & deceleration and the position of your head in space. In both cases the receptor is a ciliated hair cell that increases or decreases firing of it's associated afferent depending on the deflection of sterocilia due to movement of fluid (semicircular canals) or calcium carbonate matrix (otolith). Afferent fibres within CN VIII diverge in the brainstem to input to various vestibular nuclei - Deiters (vestibulospinal tract), superior vestibular nucleus (ascending MLF), medial vestibular nucleus (descending MLF for righting reflex)...

....and to cerebellum which we'll have to catch up with tomorrow... I'm running a day behind!!

Cerebellum connects to all other motor systems so it is key to maintaining static posture & dynamic righting responses as well coordinating voluntary movements. Cerebellar lesions produce postural disturbances, ataxia, and discoordination.

Cerebellar Gross Structure
The cerebellum is divided into 3 lobes: anterior & posterior lobes are separated by the primary fissure, and the floculonodular lobe inferiorly. The anterior & posterior lobes are organized from medial to lateral into: vermis, paravermis, and lateral hemisphere. Embeded within each lobe are deep cerebellar nuclei: fastigial in vermis; interpositus in paravermis; and dentate in lateral hemisphere. Functionally, the vermis is associated with medial muscles and head (postural), while paravermis is associated with appendicular muscles (volitional). Together vermis and paravermis are known as spinocerebellum. The lateral hemispheres are called the cerebrocerebellum because most of their input is via corticoponocerebellar pathways. And the flocculonodular lobe is called the vestibulocerebellum because most of its input is vestibular. On the inferior surrface there are two cerebellar tonsils (see photo below) that can herniate thru foramen magnum, and a uvula in the middle.

Cerebellum Internal Structure
To go with its 3 lobes, cerebellum has 3 cortical layers: an inner "granule cell layer"; an intermediate "Purkinje layer"; and an outer "molecular layer". Within these layers there are 5 major cell types: In the GC layer you have granule cells whose axons ascend to the molecular layer & bifurcate to become parallel fibres running along the long axes of the folia like telephone lines, and golgi cells whose dendrites are in the molecular layer and axons provide negative feedback on incoming signals within glomeruli; Purkinje cells have their bodies in the Purkinje cell layer and parallel fibres contact their dendritic fields in the outer molecular layer; in the molecular layer itself you also have stellate cells and basket cells. All of these 5 cerebellar cells are inhibitory (GABAergic) except the granule cell which is excitatory.
Cerebellar Circuits
There are 2 types of neuronal input to cerebellum: one direct & powerful (climbing fibres); and one diffuse (mossy fibres). Climbing fibres, from the contralateral olive, synapse directly on 1 - 10 Purkinje cells (each PC receives input from only one climbing fibre). Mossy fibres, from everywhere else, synapse on 50 - 100's of granule cell dendrites whose parallel fibres contact: 1. Purkinje cells; 2. basket & stellate cells; and 3. golgi cells which initiate negative feedback of the mossy fibre-granule cell synapse at the "glomerulus". Climbing fibres & mossy fibres also send collaterals to the appropriate deep cerebellar nuclei. Purkinje cells are the outputs for these circuits, and except for a few Purkinje cells in the folocculonodular lobe that project directly to vestibular nuclei (for balance & to coordinate eye movements), most Purkinje cells synapse on deep cerebellar nuclei to dampen down tonic activity. In the spinocerebellum they synapse on fastigial & interposed nuceli for medial & lateral motor function. In cerebrocerebellum they synapse on dentate nucleus to contralateral thalamus & red nucleus to affect motor planning.

Cerebellar Peduncles
The physical connections between cerebellum & brainstem (ie the peduncles) reflect the role of the cerebellum in motor function: MCP is input of corticopontocerebellar tracts (carrying the copy of the motor plan down from cortex on its way to LMNs); ICP is mostly inputs from spinal cord, vestibular system, and inferior olivary nucleus (for comparison with the motor plan & motor learning); and SCP is mostly efferents to vestibular nuclei, reticular nuclei, red nucleus, and thalamus (to affect changes in motor plan for coordination).

I've posted Basal Ganglia to Day 24 where we go over pathologies related to BG - I think they're a bit easier to see together that way and saves space!

Netter's
Each eye receives input from both left and right visual fields. At the optic chiasm the visual fields separate and project back along optic tract to lateral geniculate to contralateral visual cortex (eg right visual cortex gets left visual field). Since each visual field has inputs from both eyes, it is important to keep the image from each eye superimposed on one another. This is accomplished in part by connecting occulomotor muscle CN nuclei III, IV, VI via ascending MLF.
If images are not superimposed you get double vision, diplopia. For instance, when you cross your eyes a distant object will appear double because the reflected light rays from the object now fall medial to the fovea of each eye. The object appears in the right eye field of the right eye, and the left eye field of the left eye, so covering the left eye removes the left image and vice versa.

The same type of thing occurs when occulomotor cranial nerves fail to coordinate eye movements:
Oculomotor Cranial Nerve Palsies
Looking only at horizontal eye movements, CN III palsy produces a horizontal diplopia especially when looking to the side contralateral to the lesion because the affected eye cannot adduct (medial rectus). Since the image now falls lateral to the fovea in the affected eye, the outer of the two images will appear on the same side you are looking. For example, if the lesion were to the right CN III when looking contralateral to the lesion (to the left), inputs from the contralateral (left) visual field fall lateral to the fovea (in the left visual field) because the right eye cannot adduct. Thus covering the affected eye removes the outer image on the same side you are gazing (left image is removed when gazing left). CN III palsy also produces dilated pupil (due to disrupted parasympathetic innervation), ptosis (due to levator palebrae superioris), and to some degree a "down and out" at rest (due to superior oblique & CN IV).
CN VI palsy also produces horizontal diplopia especially when looking ipsilateral to the lesion becuase the affected eye is unable to abduct to that side.
CN IV palsy produces a vertical diplopia especially when looking downward because the ipsilateral eye cannot depress as well without superior oblique. Additionally the eye cannot intort, so patients compensate by tilting their head in the opposite direction.

FEF & Vestibular Systems drive conjugate gaze via PPRF
The MLF which "yokes" occulomotor cranial nerves arises from the parapontine reticular formation (PPRF) that lies adjacent to VI in the pons. PPRF activates ipsilateral CN VI directly and contralateral CN III via ascending MLF. Therefore a lesion to one side of the PPRF will cause deviation to the contralateral side. Since descending corticospinal efferents have not yet crossed at this level, if they are affected on the same side as the PPRF lesion "you will look to the side of weakness".
PPRF receives both vestibular input (to maintain gaze during head movement) and cortical input (to direct volitional gaze). Cortical input comes from the contralateral frontal eye field (FEF, BA 8); left cortex drives right gaze. A lesion to the FEF then will cause ipsilateral deviation. If motor cortex is also affected then eyes will deviate to the opposite side of weakness. Vestibular input to PPRF occurs when the head is rotated and drives eyes in the contralateral direction to maintain gaze; left vestibular input drives right gaze. This can be used to assess brainstem (and vestibular occular reflex) integrity in comatose patients by evoking a doll's eye reflex (rapid rotation of the head will cause slow deviation contralaterally). Similarly a caloric test involving injection of cold water in one ear to cause vestibular hypofunction will produce conjugate eye deviation ipsilaterally. In an awake patient this later test produces nystagmus that can be quantified by electronystagmography.

Saccades, SPEMs, & Nystagmus
A saccade is just a darting eye movement, usually to find an object but a target itself is not required - one can just look to one side or the other. However smooth movements from one side to the other, called smooth pursuit eye movements (SPEM), do require a target. As an aside... SPEMs invlove many events including: visual cortex processing movement of a target image on the retina; initiation of an oculomotor response; integration of signals generated by movement of the eyes; and maintenance of pursuit by predictive and corrective eye movements (paraphrased from Avila et al.) When a peripheral or central lesion disrupts smooth pursuit you get nystagmus. Peripheral nystagmus occurs when vestibular input to PPRF is affected. Since vestibular input usually drives gaze contralaterally, a unilateral loss produces a slow drift towards the lesion and a quick corrective saccade (jerk nystagmus). In the Hallpike maneuver, moving the head down and rapidly rotating to the ipsilateral side will increase the nystagmus. Nystagmus may also appear as "pendular" or "see-saw" movements (see see-saw video here) only 50 cases of this in literature! Central or pathological nystagmus by contrast is more common, and is a CNS condition.

That's it for today. See you all tomorrow!!
photo

Today we look at diseases of basal ganglia function - Parkinson's, Huntington's, et al. - and consider mechanisms & current treatments...

Basal Ganglia Circuits & Parkinson's Disease

Normally, input from substantia nigra pars compacta (SNc) drives dopamine receptors in the putamen to increase cortical activity via two routes, one direct and the other indirect. The neurons receiving SNc DA input are both inhibitory (GABAergic), but the first inhibitory neuron in the direct pathway has substance P and is driven by the excitatory D1 dopamine receptor, while the first inhibitory neuron in the indirect pathway has enkelphalin & endorphins and its firing is reduced by DA activation of the inhibitory D2 dopamine receptor.
Thalamic excitatory inputs to cortex are modulated by basal ganglia circuits. The direct pathway increases cortical activity by disinhibiting thalamus - D1 receptor activation (via Gs) drives firing of inhibitory input to the inhibitory output from GPi to thalamus. By contrast, if the indirect pathway were activated it would reduce cortical activity indirectly - by disinhibiting STN excitatory input to the inhibitory output from GP to thalamus - D1 receptor activation (via Gi) reduces firing of this indirect pathway and thus increases cortical activity.
In Parkinson's Disease, the dopaminergic input from the SNc is progressively lost, so less and less DA is available to drive the direct and inhibit the indirect. So thalamus is now no longer disinhibited and in fact STN is now free to drive inhibition of thalamus from GPi.
Motor Manifestations of Parkinson's
The reduced cortical facilitation results in motor manifestations such as: resting tremor (one that usually lessens with movement); rigidity (increased resistance to passive stretch) with cog-wheeling (related to tremor); akinesia or bradykinesia (inability or delay in initiating movements); and altered gait (shuffling). Tremor in Parkinson's may involve the lips and jaw, but rarely the head (head tremor is more commonly an essential tremor). Parkinson's tremor is strongly associated with the nucleus ventralis intermedius (aka ventral lateral nucleus) of thalamus because neurons here oscillate at the same frequency, and lesions here abolish tremor. Recall that ventral lateral VL receives input from globus pallidus, 1° motor cortex & cerebellum, and projects out to 1° motor cortex (BA 4).
Pathology of Parkinson's
The classic histopathological findings are loss of DA neurons in SN, Lewy bodies partly consisting of α-synuclein & ubiquitin proteins, and extra-neuronal melanin. But it turns out PD does not start in SN, but rather is found first in dorsal motor nucleus of vagus & locus coeruleus (starting in the hindbrain and marching anteriorly) Braak I couldn't get the PDF, but thought it was interesting that if locus coeruleus is hit early and that L-DOPA feeds into catecholamine synthesis in general I wonder if norepinephrine replacement has any role in L-DOPA efficacy??
Treatment of Parkinson's
The standard approach is to increase the amount of dopamine (DA) released presynaptically by giving Levodopa (L-DOPA) which bypasses the rate-limiting (tyrosine hydroxylase) step in catecholamine synthesis. L-DOPA crosses the blood-brain-barrier, is taken up by DA transporter and converted to dopamine (DA) by DA decarboxylase. Often L-DOPA is given in combination with carbidopa as a mixture (eg Sinemet). Carbidopa is an inhibitor of DA decarboxylase but cannot cross the BBB so it blocks L-DOPA conversion to DA only in the periphery to reduce side-effects.
However, if patients have lost too many DAergic neurons, there will not be enough left to make DA even with added L-DOPA. In this case a D2 agonist (eg bromocriptine) can be used to drive post-synaptic receptors, but eventually you get down-regulation and lose efficacy. Alternatively you can reduce DA breakdown by inhibiting MAO-B which is expressed primarily in striatum (eg selegeline). Lastly, since the balance between cholinergic and dopaminergic signaling is tilted due to loss of DA, another alternative is to reduce ACh signaling with the muscarinic ACh antagonist trihexyphenidyl to restore the balance. But perhaps the most striking treatment of Parkinson's involves deep brain stimulation. I'm sorry I missed this talk at lunch, if anyone has a comment (or left-over bagels) let me know!

Whereas Parkinson's is a hypokinetic disorder, Huntington's Chorea is a hyperkinetic disorder...

Huntington's Disease

Huntington's Chorea is characterized by twitches, jerks, and chorea ("dance-like" movement) as well as major cognitive problems which may either precede or follow motor dysfunction. Genetically, Huntington's involves a trinucleotide CAG repeat in the HD gene: normally there are fewer than 30 repeats, but with 40 or more there is complete penetrance of the disease; and earlier onset with larger repeats (Huntington's is prone to expansion). The disease is heavily in the striatum and shows profound atrophy of caudate. Basically, loss of striatum leads to less inhibition of thalamocortical projections and increased movement. Indirect pathways are affected earlier in the disease. Presumably, direct pathways remain early to disinhibit thalamus, and when they are later lost more Parkinsonian symptoms would arise. Treatment of Huntington's is difficult due to involvment of multiple neuronal systems. In terms of motor symptoms treament may involve DA depeleting agents or D2 antagonists.

Tics
Tics are repetitive or sequential movements or utterances that often mimic normal behaviours in a stereotyped pattern. These can be semivoluntary in that they can be suppressed for a short period, but the drive builds until it is irresistable (as if you are trying not to swallow or not to blink). As such, patients often experience a premonitory sensation that drives the tic which often is linked to OCD. Simple motor tics can be clonic (blink, twitch), dystonic, or tonic (tense & relax). Examples of more complex motor tics are head shaking, copropraxia (lewd gestures), and echopraxia (imitating gestures). Phonic tics can be simple throat clearing or vocalizations including coprolalia (cursing), echolalia (repeating another person's words), and pallilalia (repeating your own words/syllables, similar to stuttering).

Tourette's is a condition of multiple motor tics and at least 1 phonic tic. Typically these tics wax and wane, so when evaluating efficacy of treatment this cycling becomes an important consideration. There first onset usually appears 3 - 5 yo, and a high percentage spontaneously remit by age 18. Adults with Tourette's by definition have more severe disease. Pathogenesis may involve dopaminergic system, but remains relatively unknown. Treatment may involve an α-agonist such as clonidine, and later clonazepam. If symptoms remain refractory then atypical antipsychotics or haloperidol but risk chronic extrapyramidal effects. Botox treatments can also be effective in eliminating motor tics, as can surgical ablation and deep brain stimulation. Treatment of comorbid OCD is with SSRI's (paroxetine) and TCAs, and of ADHD is with destimulants (eg methylphenidate).

Alzheimer's Disease
Pathology of Alzheimer's involves neuritic plaques containg β-amyloid, and neurofibrillary tangles. Since there is a loss of cholinergic neurons in basal forebrain, the focus of treatment has been on boosting cholinergic signaling. Tacrine has been superseded by donepezil (Aricept) (which has fewer side-effects) but both are centrally-acting ACh esterase inhibitors that function to increase ACh levels, though neither has been shown to slow progression of the disease.

Tomorrow, Dr. Hamill brings us home with the last lecture of this exam block!!

The cerebellum in action!

Here's a slow motion video of the final shot.

Cerebellar Ataxias
Cerebellum analyzes and coordinates movement and maintains balance and muscle tone. To do so it receives a tremendous amount of afferent input; 40 X as many afferent inputs as efferent outputs. Corticopontine fibres input primarily to lateral hemispheres (dentate nucleus) for apendicular arm movements. Spinal & trigeminal fibres are primarily associated with vermis & paravermis (fastigial & interposed nuclei) for posture. And vestibular afferents input to flocculonodular lobe for balance. People tend to fall to the side of the cerebellar lesion, as opposed to the opposite side of a cortical motor lesion, because the cerebellum double-crosses (X/SCP to thalamus and cortex, then cross again on the way back down to leg extensors, etc. as corticospinal.
Cerebellar dysfunction that alters the coordination of maintaining and executing movements is referred to as ataxia. Typically cerebellar dysfunction can appear as: dysmetria (overshoot target), dysdiadochokinesia (impaired rapid alternating movements), dyssynergia (break-down of complex movements), and dysarthria ("telegraphic" speech) Due to the somatotopic organization of cerebellum, lesions to superior vermis produce gait ataxia (legs are considered axial here), and lesions to lateral hemispheres produce ipsilateral hypotonia and ataxia. Cerebellar dysfunction is also associated with intention tremor (an action tremor that increases as you approach target) as opposed to the tremor at rest commonly associated with Parkinson's.

We all have physiologic tremors to some extent, usually in the 8 to 12 Hz (cycles/sec) range. But pathological tremors are generally half that frequency (3 - 6 Hz).

Essential Tremor
Essential tremor is the most frequent movement disorder. It is a monosymptomatic condition characterized by shaking during movement especially of the hands or head. Generally what happens is the patient will move, there will be a slight delay, then tremor will build. Essential tremors can be reduced with alcohol (or BDZs like lorazepine or clonazepine) taken at times when tremor would be a problem. But the "drug(s) of choice" for treating essential tremor are primidone (an anticonvulsant) and propanolol (a β-blocker). On the subject of medications, tremors can be pharmacollogically induced as well.

On that note I'm off to get a cup of coffee...
Enjoy your weekend of study!

including the Circle of Willis!!

Blood is delivered to Mr. Willis' brain by two routes - internal carotids and vertebrals that form an anterior circulation and a posterior circulation respectively - which's why his character Dies Harder...

Anterior Circulation
Internal carotids enter the skull via carotid canal, give off branches to ophthalmic, posterior communicating (part of Circle of Willis), and anterior choroidal arteries (to hippocampus, amygdala, and basal ganglia) before dividing into their terminal branches: anterior cerebral artery (ACA) and middle cerebral arteries (MCA). MCA travels in lateral Sylvian fissure and is the primary source of lenticulostriate arteries to basal forebrain and basal ganglia. ACA travels through the interhemispheric fissure, wraps around corpus callosum and splits into pericallosal and callosal marginal arteries. The anterior communicating artery connects the paired ACAs. The recurrent artery of Huebner is another supply to basal ganglia.
Posterior Circulation
Vertebral arteries enters the skull via foramen magnum, give off branches to anterior and posterior spinal arteries, penetrating branches to supply lateral medulla, and posterior inferior cerebellar arteries (PICA). The two vertebrals join anteriorly near the pontomedullary junction to form the basilar artery. Branches from the basilar (from caudal to rostral) include: anterior inferior cerebellar arteries (AICA), penetrating arteries to pons, and superior cerebellar arteries before its terminal bifurcation into posterior cerebral arteries (PCA). Note that in the interpeduncluar fossa, superior cerebellar artery lies caudal to CN III and PCA lies rostral to CN III. Posterior communicating arteries from the first part of the PCA connect the vertebral-basilar posterior circulation with the carotid anterior circulation, forming the...

...Circle of Willis

Here the anterior circulation from carotid and posterior circulation from vertebral-basilar come together at the circle of Willis. Normally there is little blood flow through communicating arteries forming this circle, but with obstruction collateral flow can occur. Berry aneurysms, congenital dilations of arteries, frequently occur in the Circle of Willis and represent the primary cause of non-traumatic subarachnoid haemorrhage.

Vascular Territories

MCA supplies almost the entire lateral surface of the cortex. PCA supplies occipital lobe (including primary visual cortex) and inferior part of temporal lobe. Looking at motor and sensory humunculus: ACA supplies the trunk & lower extremity, MCA supplies the arm hand & face regions. Watershed infarcts (border zone) occur where boundaries of two vascular regions meet (eg ACA-MCA) , because these regions are particularly susceptible to decreased blood flow (hypotension).
Aneurysms & arteriosclerotic (atherosclerotic) plaques often occur at branch points. Microaneurysms occur due to hypertension and primarily involve small penetrating arteries (eg lenticulostriate to basal ganglia). Cerebral ischaemia involves a reduction in blood flow, due possibly to a thrombotic or embolic or haemorrhagic event. Examples of Anterior and Posterior circulation syndromes are given in lecture notes.

Brainstem Circulation
Blood supply to the brainstem and cerebellum derives from the vertebral-basilar system.
Cerebellum is supplied by PICA (from vertebrals), AICA (from basilar), and superior cerebellar arteries.

Caudal medulla is supplied by penetrating branches from vertebral artery (laterally), anterior spinal artery (ASA), and posterior spinal artery (PSA) - however in rostral medulla PICA replaces PSA in supplying dorsal regions. An ASA lesion in rostral medulla would affect CN XII (tongue deviation toward lesion) and the pyramids (contralateral weakness, spasticity...) A PICA lesion would affect: vestibular nuclei (dizziness), DMV & nucleus ambiguus (vomitting & dysphagia), spinal nucleus of trigeminal (ipsilateral facial numbness), ALT (contralateral P&T), and ICP.
Pons is supplied by AICA, perforating branches from basilar, and superior cerebellar artery. A lesion involving pontine arteries (eg a lacunar infarct) could affect abducens (CN VI palsy) and longitudinal fibres of the pons (contralateral weakness...).
Midbrain is supplied by superior cerebellar and posterior cerebral arteries. As we've seen, a lesion affecting midbrain could produce a CN III palsy (ptosis, pupillary dilatation, down-and-out...) and contralateral weakness (if cerebral peduncles are affected).

And a basilar stroke??
...Zed's dead baby.

The Strokes

A little music to study by...Is this it?

Terminology of Cerebral Vascular Disease
Cerebral vascular disease is a pathologic term for a "brain lesion caused by a vascular abnormality of the brain." Stroke is a clinical term for the signs and symptoms resulting from such a brain lesion. A TIA is transient ischaemic attack, by definition lasting less than 30 min and not producing permanent damage. RIND is a reversible ischaemic neurologic deficit similar to a TIA but lasting ~ 48hrs. Ischaemia is a reduction in blood supply, hypoxia is a reduction in Air Supply; usually the two occur together. Ischaemia can be occlusive (eg due to a thrombus) or non-occlusive (eg cardiac arrest, shock. WIth ischaemia/hypoxia, it is thought that increased glutamate release lead to overstimulation of NMDA receptors, excessive Ca++ entry, and excitotoxicity causing cell death secondary to the ischaemic event.
The two major risk factors for stroke are aging and hypertension. Hypertension can be evidenced by four features during a retinal exam: "copper wiring"; AV nicking; haemorrhage; and exudates (of serum).

There are six conditions that account for ~ 90% of all cerebral vascular disease, four involving infarcts (thromotic, embolic, border zone, lacunar) and two involving haemorrhage (intracerebral, subarachnoid). An infarct is "An area of tissue death due to a local lack of oxygen {blood supply}."

Thrombotic Infarct
Thrombotic infarcts are often associated with atherosclerosis of the carotid at the junction of the internal and external carotid areteries. Since 80% of the blood flow from internal carotid is destined for MCA territory, and since 80% of us have some anomaly in the Circle of Willis (often an absence of a posterior communicating artery), that leaves MCA territory somewhat more vulnerable to infarct. By the same token, if someone has a TIA in MCA territory, look to the carotid for the source.
Immediately following an infarct, a patient may actually get worse as swelling develops either due to fluid accumulation in vessels (vasogenic edema) or tissue (cytotoxic edema). If the person survives the initial stroke and secondary edema, the ensuing time-course can be divided into three phases: an acute phase of cell death & neuronal loss; a subacute phase of macrophages & phagocytosis; and a chronic phase of residual glial scarring.
Embolic Infarct
Emboli differ from thrombus by: 1. tending to be haemorrhagic (because they eventually lyse, and with reperfusion you get bleeding thru the necrotic area); and 2. tending to affect multiple distributions (because they can spread, into ACA & MCA for example). In this case you need to look for the source, and the three most common are : heart, aorta, and carotid. Hence Dr. Pendlebury's clinical pearl: cerebral vascular disease = coronary vascular disease until proven otherwise, and vice versa.
Border Zone Infarct
Sometimes referred to as a watershed (probably the analogy fits better in terms of venous drainage). These occur where vascular distributions of cerebral arteries meet (eg ACA-MCA, or ACA-MCA-PCA in a Gerstmann syndrome). In these zones, blood flow through the capillary beds is most sensitive to low flow or no flow (eg with cardiac arrythmia leading to hypoperfusion) leading to cell death distributed along the border zone.
Lacunar Infarct
Lacunar infarcts occur in small vessles coming off at right angles to larger vessels to supply deeper structures (eg lenticulostriate, pontine perforators, etc.). In cases of chronic hypertension, these small arteries undergo a physical change to increase resistance (as part of an autoregulatory reponse to maintain steady cerebral blood flow). The vessels become hypertrophied, and then lipoproteins leak into the vessel wall, the lumen narrows and weakens. Then one of two things can happen: 1. the vessel totally occludes giving you a lacunar (Lake Champlain) infarct (potentially silent clinically); or 2. the vessel ruptures and you get a haemorrhage...
Intracerebral Haemorrhage
Intracerebral haemorrhages tend to occur in the same distribution as lacunar infarcts for the same reasons as above. But instead of a small infarct, you have bleading into the brain. Basal ganglia and thalamus are most commonly involved, but may also occur in pons and cerebellum.

Subarachnoid Haemorrhage
A congenital malformation of the Circle of Willis called a Berry aneurysm, is one potential cause of bleeding into the subarachnoid space (see Thursday's lab for an example of this). These are congenital defects, not due to chronic hypertension. They often occur at junction points, possibly due to gaps in endothelial smooth muscle, and usually are in the anterior circulation (90%). Patients (if conscious) will describe "the worst headache ever" and may have no other findings on neurologic exam except possibly meningismus (neck flexion causes pain) Berry aneurysms are detected by angiogram, and treated by clipping the base.

I'll probably put visual system on Day 28...
...a final "clip" of the Strokes Last Night

Sensory systems transduce the outside world into electrical signals that are conveyed along various pathways to the level of cortical "awareness".
Today we look at two senses: vision & hearing.

In order to "See the Light" you have to:
1. get that light to your retina;
2. turn the light into a neural signal; and
3. send that signal to your visual cortex.

The First Step in Enlightenment - getting light to the retina

1. Light passes through the cornea. The cornea is the most refractive structure in the eye for focusing light onto the retina, so defects in corneal shape can produce: astigmatism (blurring due to differences in corneal curvature); near-sightedness(myopia) if the cornea is too sharply curved (or the eye is too long) the image falls in front of the retina; or far-sightedness (hyperopia) if the cornea is too flat (or the eye too short) the image falls behind the retina. Myopia is treated with a concave lens, hyperopia is treated with a convex lens. The conjunctiva assists the lacrimal gland in keeping the cornea moist; lack of lubrication can cause dry eye (keratoconjunctivitis sicca).
2. Light passes through the aqueous humor. Aqueous humor produced by the ciliary body in the posterior chamber bathes the avascular cornea in the anterior chamber and drains through a trabecular meshwork to the canal of Schlemm. Debris or infection can obstruct reuptake (open angle glaucoma), or the angle between the iris and the cornea can narrow or close and block flow (closed angle glaucoma). Resultant building pressure in anterior chamber pushes the lens against the vitreous body and retina which can block blood flow through retinal vessels and potentially lead to blindness.
3. Light passes through the pupil. The pupil is the aperture in the iris that controls the amount of light entering the eye. Normally the size of the pupil is set in reponse to the presence or absence of light by two smooth muscles within the iris: a circular constrictor pupillae (parasympathetic); and a radial dilator pupillae (sympathetic).
4. Light passes through the lens. The lens is able to stretch and contract in response to tension applied by suspensory ligaments (aka the Zonule of Zinn ...this has to be the best name in all anatomy!). Contraction of the ciliary muscle within the ciliary body reduces tension in the ligaments and increases convexity of the lens (accomodation for near vision). Elasticity of the lens decreases with age loses (presbyopia), and cataracts can obscure light passage through the lens.
5. Light passes through the vitreous humor. Unlike aqueous humor, the vitreous is not replenished. Vitreous humor consists of a collagen-hyaluronan matrix (aka goo or the closely-related goop). Floaters are often small bits of matrix/etc. that can sometimes be seen, though "floaters" actually tend to sink...
6. Light passes through layers of the retina.

The retina has 5 major cells arragned in layers: light first passes through the ganglion cell layer; then amacrine, bipolar, and horizontal cell layer; to the photoreceptor layer (rods for B/W or cones for color). At the fovea cell bodies are shifted to the side, so photoreceptors here receive the least distorted visual input. Converseley, at the optic disc (where optic nerve fibres from retinal ganglion cells leave the eye) there are no photoreceptors so you have a blindspot. In retinal detachment mechanical stimulation of the retina can generate phosphenes which you can also get by rubbing your eyes. Disruption of blood flow to retina can produce visual loss which may be: transient (eg amaurosis fugax ) or progressive/permanent (eg diabetic retinopathy).
Deep to the retina you have the retinal pigment epithelium (RPE, attached to underlying choroid) whose cells produce black melanin to prevent light rays from ricocheting back to the retina and confusing the visual image. RPE also is involved in the vitamin A cycle to isomerize trans- back to cis- retinal (see below). A deficiency in vitamin A can cause nyctalopia

Step 2 in Enlightenment - changing light to an action potential
The outer segment of a rod or cone (the part of the cell nearest the RPE) is composed of a series of discs containing photopigment. In rods the pigment rhodopsin consists of opsin and the light absorbing protein retinal (a derivative of vitamin A). In cones, 3 different opsins are linked to retinal in such a way that they preferentially detect red, green, or blue wavelengths of light. In the first step of transducing light into a neural signal, light hitting these photopigments isomerizes cis retinal to trans retinal which dissociates from opsin. Opsin activates the G-protein transducin which in turn activates cGMP phosphodiesterase to reduce cGMP levels, leading to closure of sodium channels and photoreceptor hyperpolarization. That means light hitting the photoreceptor reduces glutamate release onto its postsynaptic bipolar cell.

Each photoreceptor synapses on two types of bipolar cell, an off-center (depolarized by glutamate), or an on-center (hyperpolarized by glutamate). If the photoreceptor is not illuminated, it remains depolarized and continues to release glutamate to depolarize the off-center and hyperpolarize the on-center bipolar cell. Converseley, when light hyperpolarizes the photoreceptor, reduced glutamate release depolarizes the on-center and hyperpolarizes the off-center bipolar cell. For cones in the fovea there is a one-to-one relationship between photoreceptor and bipolar cell, but over much of the retina each bipolar cell receives convergent inputs from rods.
Bipolar cells converge on a retinal ganglion cell (RGC) of the same type, on-center or off-center. So the receptive field of an RGC covers the roughly circular area of photoreceptors associated with its bipolar cell inputs. The RGC receptive field can be divided into a center and a surround; in fact the name on-center or off-center is derived from the fact that an on-center RGC fires strongest when only the center of the receptive field is illuminated (and not the surround), and an off-center RGC fires strongest when the light is removed from the center but directed at the surround.

Photoreceptors in the center of the RGC receptive field synapse directly on bipolar cells. Photoreceptors in the surround of the RGC's receptive field synapse on an inhibitory interneuron called an horizontal cell. When driven by glutamate release by photoreceptors in the surround, the horizontal cell inhibits photoreceptors in the center. Conversely, when light hits the surround reduced glutamate release in the surround reduces drive on the horizontal cell thus depolarizing cones in the center. So there are 4 possibilities for the receptive field of an RGC : 1. if all photoreceptors are lit, the center is hyperpolarized directly by light but depolarized indirectly by the surround; 2. if none are lit, center remains depolarized but is indirectly hyperpolarized by the surround; 3. if only the center is lit it will be direclty hyperpolarized by light and also indirectly hyperpolarized by the horizontal cell from the dark surround; 4. if only the center is dark it will remain depolarized and be indirectly depolarized by reduced inhibition from the horizontal from the lit surround. Thus the greatest depolarization of an on- or off-center retinal ganglion cell will occur when there is contrast between center and surround. Rather than the graded potentials of the photoreceptor-bipolar cell, the RGC conveys this information about contrast by increasing or decreasing firing frequency.
The same idea of center-surround occurs for black-white, red-green, and blue-yellow in comparing object to background. RGCs with large receptive fields are called M-type (magnocellular) and those with smaller receptive fields are P-type cells (parvocellular). A parvocellular ganglion cell detects color and form - "what" an object is. A magnocellular RGC detects motion and orientation - "where" an object is. Half of the RGCs are "W-type" (they do not have a center-surround) and function in visual reflexes (pupil constriction, visual tracking).
One caveat here, understanding center-surround inhibition was problematic and I had to turn to the book-of-last-resort: Kandel & Schwartz
. It made sense after reading the chapter (for the 3rd time) but they focus more on the horizontal than amacrine cell, probably they function similarly, but you should definitely follow lecture notes - based on these the correct response for what cell is responsible for center-surround will be amacrine. May the Schwartz be with you!!

Step 3 in Enlightenment - from retinal ganglion cell to visual cortex
Each eye receives input from both visual fields. Most peripheral vision is monocular (light from the outer visual field strikes only the ipsilateral nasal retina but cannot reach the contralateral temporal retina), while central vision is binocular (L/R visual field hits both ipsilateral nasal retina and contralateral temporal retina). As information leaves the retina on bundles of RGC axons as the optic nerve, fibres from the temporal retina remain ipsilateral at the optic chiasm and travel in the ipsilateral optic tract. Conversely, RGC fibres from the nasal retina cross at the optic chiasm to the contralateral optic tract.
Most fibres synapse in lateral geniculate nucleus (LGN), though 20% synapse in superior colliculi (W-type RGCs) and others may synapse in suprachiasmatic nucleus of hypothalamus. Within the LGN there are 2 layers for magnocellular information (the "where") and 4 layers for parvocellular ganglion cells (the "what") and the layers are divided for right vs left visual field information. LGN neurons send their axons posteriorly via optic radiations to synapse in primary visual cortex (layer IV). Optic radiations have an upper loop (carrying lower visual field information) and a lower loop (Meyer's loop, carrying upper visual field information).
So... If you lose optic nerve you get blindness of that eye. If you lose central chiasm you lose peripheral inputs (tunnel vision). If you lose optic tract you lose that whole visual field. If you lose an upper / lower (Meyer's) optic radiation you get a quadrantanopia (loss of upper or lower quadrant of a visual field). Interestingly, since cones in the macula are one-to-one with bipolar cells there are a relatively high number of fibres from the macula and unless damage is extensive macular vision is often spared (safety in numbers).

Left visual cortex receives right visual field, and vice versa. Optic radiations synapse first on a circular symmetric cell, these converge onto simple cells (still just dots), which in turn synapse on complex cell (now lines). The complex cell (a pyramidal cell) also receives input from the contralateral visual cortex via the corpus callosum, so it is the first to receive binocular information. The visual cortex is divided into occular dominance columns that process information from either the right or left eye.

As a prereq for proper vision, your left and right eye must be aligned
In strabismus the eyes are misaligned. If strabismus is left untreated in children, the brain (being still plastic) can learn to ignore the faulty input and you get amblyopia. A Hirschberg is a quick test for strabismus; light should reflect of the cornea at the same location in front of the pupil. If it doesn't you have either: exotropia (turned out), esotropia (in), hypertropia (up), or hypotropia (down).

Speaking of strabismus...

Isn't it strage that people "see" into the future, possess "sight" or look to the beyond! but no one ever "hears" into the future??

Auditory System

Like the visual system the auditory takes a peripheral stimulus (sound), transduces it to an electric signal, and routes it to the cortex.

Sound frequency
Sound is produced when vibration causes changes in air pressure that travel outwards as a waves of alternating high and low pressure. Peak-to-peak amplitude is loudness, frequency (# waves/sec) is pitch. The range of hearing for humans is described by the Decibel scale, where 0 is undetectable and values increase logarithmically such that a 20 dB change is a 10-fold change in sound intensity. Sounds above 100dB can be damaging.

How is a pressure wave transduced into an action potential?
Pressure waves cause alternating inward and outward movements of the tympanic membrane that are amplified and communicated by the bones of the middle ear to the cochlea at the oval window. Within the middle ear, the tensory tympani (V) and stapedius (VII) function to damp down ossicle movements, so loss of stapedius can cause hyperacusis.

The cochlea itself is a fluid filled canal, and as the stapes moves in the oval window it causes pressure waves within the fluid. There are three fluid filled chambers within the cochlea: scala vestibuli, scala media, and scala typmani (plus the helicotrema). Scala vestibuli and scala tympani contain perilymph. Scala media contains endolymph which has a very high potassium K+ concentration (higher even than intracellular levels). Within the scala media a relatively pliable basilar membrane coils up the cochlea.
The sensory transduction apparatus called the organ of Corti sits atop the basilar membrane. Hair cells in the organ of Corti have the tops of their cilia embedded in a stiff tectorial membrane above, so when part of the basilar membrane moves it bends the cilia in that region. Two classes of hair cell are arranged in rows along the length of the basilar membrane: one row of inner hair cells, and three rows of outer hair cells. Each row contains approximately 5000 hair cells, so throughout the entire cochlea you have 20, 000 hair cells but only 5000 inner hair cells to transduce auditory signals. The outer hair cells set the intensity (receptivity of the inner hair cells) by way of the efferent component of the vestibulocochlear nerve.

The cell bodies of hair cells lie in perilymph, but their cilia lie in the high K+ environment of the endolymph. When pressure waves toss the cilia in one direction they hyperpolarize and when they move the other way the depolarize. The cilia are connected to each other by tiplinks which attach to individual channels within the membrane. When cilia stretch, the tiplinks pull the channels open and K+ enters and depolarizes the cell. Depolarization opens voltage dependent Ca channels for vesicle release, but also opens Ca-gated K channels so that as K+ travels into the cell body it now diffuses out into low K+ perilymph to repolarize the cell. With continual stimulation, the hair cells are capable of adaptation, by translocating the tip hook down the membrane to take tension off of the channel.

How do you distinguish pitch?
Different regions of the basilar membrane oscillate at different frequencies because compliance changes along its length; high frequency waves resonate close to the oval window, and low frequency waves resonate farther away. Also each hair cell has individual electrical properties for edge detection that impart a "cone" of sensitivity for a given frequency; such that 1 Hz above or below that point produces a surround inhibition. Part of this tuning also comes from efferent drive to the outer hair cells from vestibulocochlear neurons with cell bodies in the superior olivary complex.

All roads eventually lead to cortex - Auditory Pathways
The primary afferents, spiral ganglion neurons, are truly bipolar (the entire cell is myelinated). Their terminals form calyces to maximize their input to second order neurons in the ipsilateral cochlear nucleus. From this point onward all information is bilateral. One example of an auditory circuit leads from cochlear nucleus to superior olivary complex to inferior colliculus (via lateral lemniscus), then on to medial geniculate, then primary auditory cortex, then secondary association cortices. You can start to distinguish ipsilateral from contralateral for sound localization at the level of the superior olive. Connections between inferior and superior colliculi give you the first map of auditory and visual space. And within primary auditory cortex frequency is mapped as a tonotopic map.
Deafness
Deafness may be conduction or sensorineural. Conduction deafness involves an impaired ability of tympanic membrane and ossicles to transmit sound, commonly due to middle ear infections or otosclerosis (fixation of stapes in oval window). Sensorinural deafness involves a problem along the auditory pathway after the middle ear, and may be acquired (loud noise, infection, presbyacusis (wear & tear with age)) or congential. Most genetic disorders related to deafness involve membrane channels (especially connexin 26) required for the transfrer of potassium back to stria vascularis which makes endolymph.
Conduction and sensorinueral deafness can be differentiated by Rinne's test or Weber's test. In Rinne's test a tuning fork is held at the mastoid process until it cannot be heard (lower limit of conduction) then placed by the ear. Normally the middle ear will amplify vibration so the fork can still be heard, but if compromised then no sound is heard. In Weber's test the tuning fork is placed on the middle of the skull. Normally sound is heard equally in both ears, but if there is a sensorineural deficit sound localizes to side of hearing, whereas a conduction deficit will localize sound to the affected side because the organ of Corti has been tuned-up/amplified by efferent modulation.

Here is a preview of the latest technological-advance in Weber's testing...
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Last year I'd emailed an anatomy professor at Columbia med school to ask him for some study ideas, and he suggested the best ways to learn these things is to draw them, check your drawing against an atlas, and redraw until you can do it from memory - then go to the real thing and ID it there. I found it worked really well, so if you like to try it out on this set of labs that'll be...

Blood Supply

Arteries:
vertebral, basilar, AICA, PICA, superior cerebellar, posterior cerebral, posterior communicating, anterior cerebral (A1-horizontal/A2-vertical), middle cerebral, anterior communicating, Circle of Willis, lenticulostriate, pericallosal, callosomarginal

Veins:
superficial cerebral, internal cerebral, thalamostriate (terminal), septal, Great Vein of Galen

Visual System

Eye histology & Fundus
macula, fovea, optic disc, optic nerve, sclera, choroid, retina, retinal pigment epithelium (RPE), central retinal vessels

Optic structures
optic nerve, optic chiasm optic tract, lateral geniculate, superior colliculus, optic radiation, primary visual cortex (BA17), calcarine sulcus, dorsal pathway (where), ventral pathway (what)

in a Sheep's Eye

Wet specimen
cornea, sclera, optic nerve, viterous, retina, optic disk, choroid, ciliary body, iris, lens, extraoccular muscles (answers)

Eye figures
conjunctiva, aqueous humor, anterior/posterior chamber, fundus, retinal blood vessels, choroidal blood vessels, macula, fovea, ciliary body/processes/muscle, zonular fibres, sphincter/dilator pupillae, canal of Schlemm

Can't see??

Most blindness is due to posterior segment causes related to aging or microvascular disease. In this lecture we start with 3 examples of posterior segment diseases: glaucoma, macular degeneration, and diabetic retinopathy.

Glaucoma
The hallmark of glaucoma is the progressive excavation of the disk, usually due to increased intraocular pressure (though there is also a low-tension form of glaucoma). A typical cup to disk ration is 1/3. With cupping you tend to get visual field loss, but there is already a lot of tissue damage before you start to see deficits. There are two general types of glaucoma: open-angle and closed-angle. Primary open-angle glaucoma (POAG) is the second leading cause of blindness in the US. In open-angle glaucoma there's a problem with the reuptake of aqueous humor. In the case of closed-angle glaucoma, as you age and lamellae are added to the lens, it pushes the iris against the cornea and causes angle-closure (particularly in an hyperopic eye, and especially in mid-dilated position). Glaucoma is treated by either decreasing aqueous humor production (β-blockers, carbonic anhydrase inhibitors, or in combination as cosopt) or by increasing outlfow (eg pilocarpine to constrict pupil, or prostaglandin agonists)

Age-related Macular Degeneration (AMD)
AMD is a leading cause of blindness in older patients in the US. There are two forms, wet and dry. Dry AMD is most common (90%) but only accounts for maybe 10% of blindness associated with AMD. The hallmark of dry AMD is drusen, which likely indicate problems in RPE metabolism. Wet AMD is less frequent but accounts for 90% of the blindness of AMD. The standard treamtent for wet AMD is lucentis (Ranibizumab), an anti-VEGF antibody by intravitreal injection.

Diabetic Retinopathy (DR)
DR is characterized by intraretinal microvascular abnormalities that leak exudate. When they reach the fovea vision goes down. Vessels can grow into the vitreous, and with age the vitreous shrinks and can rupture the vessels. The goal of treatment is to save macular function, and the current standard uses a thermal "laser".
However the "giant laser" cannot be used near the fovea, and produces side-effects of inflammation and edema. The best treatment here would be prevention and rigorous management of the disease.

Diseases of the anterior segment of the eye include:

Diseases of eyelids & margins
Staphylococcal blepharitis characterized by hyperemia and scaling at the eyelid margin, this usually goes away with hygenic care.
Trichiasis is a posterior misdirection of eyelashes (as opposed to entropion where eyelashes are anterior but curve back into the eye). Either disorder can lead to corneal ulceration.
Meibomitis occurs when meibomian (tarsal) glands become blocked, and can go on to become chalazion.
Chalazion is an inflammation of the margin that eventualy forms a nodule. *An important consideration with chalazion is sebaceous gland carcinoma, especially if madrosis (loss of eyelashes) is also present.
Basal cell carcinoma (BCC) is the most common malignancy, and 10% of the cases involve the eyelids. There are three types of BCC: nodular BCC; nodulo-ulcerative BCC; and sclerosing BCC (which can mimic blepharitis).
Cellulitis has 2 types, preseptal and orbital. Preseptal cellulitis is an infection anterior to the orbital septum. Orbital cellulitis is infection behind the orbital septum, and commonly causes proptosis and ophthalmoplegia. *An important consideration is mucormycosis which can be a serious condition especially in AIDS or immunocompromised patients.

Lacrimal system disorders
Nasolacrimal duct obstruction occurs in cases of congenital, non-patent lacrimal ducts in newborn.
Dacryocystitis is infection of the lacrimal sac, and can produce obstruction of the lacrimal duct. * An important consideration is a lacrimal sac tumor, but these occur above the medial canthal tendon.

Corneal & Conjunctival Disorders
Thyroid orbitopathy involves eyelid retraction such that the superior 1/3 of the cornea is not covered as is usual. Thyroid orbitophathy is the most common cause of proptosis (bulging eyes) and can lead to corneal defects. The cause is edema and fibrosis of occulomotor muslces, interestingly up to 1/4 of these patients do not have abnormal thyroid function.
Conjunctivitis can be allergic (itching) or bacterial (discharging) and is by definition inflammation of the conjunctiva. Gonococcal conjunctivitis in particular progresses quickly to corneal ulceration and potentially perforation. Chlamydia infection often accompanies.
Epidemic keratoconjunctivitis is usually viral and shows corneal abrasions * an important consideration is to look for a retained foreign body if the abrasions are vertical.
Herpes simplex keratitis shows a characteristic dendritic-shaped ulcer
Herpes zoster ophthalmicus (HZO) is zoster affecting V1 division of trigeminal

We'll finish with the time-honored method for preventing eye injury...

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That's it! Have a nice (hopefully) sunny Memorial Day!!

I thought I might try taking the learning objectives for the lecture and turning them into questions with a block of notes below each question. Then one could review by scanning the title questions, trying to answer them in their head, and if not refer back to notes. We'll see how it goes...

Hypothalamus

We start with hypothalamus whose primarily job is to maintain set-points for the body. The hypothalamus is a small region bounded anteriorly by (anterior commissure)-(lamina* terminalis)-(optic chiasm) and posteriorly by (interventricular foramen)-(hypothalamic sulcus)-(mammillary bodies).
*stria was an earlier mistype...

What are the functions of the hypothalamic nuclei?
Hypothalamus contains 7 major nuclei: medial preoptic (containing LHRH, aka the sexually dimorphic nucleus); suprachiasmatic nucleus (circadian clock); supraoptic & paraventricular nuclei together projecting to posterior pituitary to release oxytocin (smooth muscle contraction, esp uterine.) & vasopressin (ADH, water balance); arcuate & paraventricular nuclei together project to median eminence; mammillary body (target of fornix in Papez circuit); dorsomedial (stimulate feeding); and ventromedial (satiety).

What pathways connect to hypothalamus?
Hypothalamus receives inputs from basal forebrain via the medial forebrain bundle (an unmyelinated tract and so basically invisible in lab); this bundle continues on to autonomic centers of the brainstem. Inputs from amygdala arrive on stria terminalis. Inputs from from hippocampus take the fornix-express. Inputs from habenula come in on stria medullaris thalamicus. Medial forebrain bundle, stria terminalis, fornix, and SMT are "two-way streets" carrying outputs from hypothalamus as well. Mammillothalamic tract however is a "one-way street" from mammillary body to hmmmm thalamus (specifically anterior nucleus). Tuberoinfundibular and hypothalamohypophyseal tracts are also one-way to the pituitary:
Neurons from arcuate and paraventricular nuclei to the median eminence are small so they're called the parvocellular system. In the median eminence they release "releasing hormones" into the hypophyseal portal system that flows into the adenohypophysis (anterior pituitary) to cause release of tropic hormones: the "FLAT PEG" in anterior pituitary (FSH, LH, ACTH, TSH, Prolactin, Endorphins, GH).
Neurons from supraoptic and paraventricular carrying oxytocin & vasopressin to the neurohypophysis (posterior pituitary) are large so they're called the magnocellular system.
I think there is maybe a little confusion in the handout here: the chart on p.7 refers to "hypothalmohypohyseal control of neuroendocrine function" and diagrams the "FLAT PEG" in the anterior pituitary. But the "hypothalmohypohyseal tract" was referred to as projecting to neurohypohysis (posterior pituitary). Also, looking up tuberoinfundibular tract seems to refer specifically to dopaminergic projections from the arcuate... Based on Fig 6 & 7 on p. 6 I would be tempted to say that hypothalmohypophyseal refers broadly to connections between hypothalamus and pituitary, and that parvocellular refers to those projections to median eminence and on via hypophyseal portal system to anterior pituitary, and that magnocellular refers to the oxytocin/ADH from supraoptic & paraventricular to posterior pituitary. You might want to ask Dr. Jaworski about it though to be sure...

What are the 7 circumventricular organs and what do they do?
We have just seen two CVO's: the median eminence (monitors endocrine functions) and the neurohypophysis (containing vasopressin and oxytocin). Other CVOs are the area postrema (emesis), pineal gland (circadian), organosum vasculosum of lamina terminalis (OVLT) and subfornical organ (involved in osmoregulation), and subcommissural organ (UNK) ...

How do suprachiamatic nucleus and pineal function in circadian rhythms?
Certain retinal ganglion cells containing melanopsin project to suprachiasmatic nucleus whose fibres then project to thoracic spinal cord. From the intermediolateral gray, pre-ganglionic sympathetics travel back up to synapse in superior cervical ganglion, and post ganglionic sympathetics from SCG innervate pineal to influence melatonin release. You wake up when this sympathetic drive decreases.

How do hypothalamus, SFO and OVLT function in osmoregulation?
Supraoptic and paraventricular nuclei work in concert with two CVOs: OVLT & subfornical organ. Supraoptic and paraventricular release ADH to cause distal convoluted tubule to increase water reabsorbtion. SFO monitors angiotensin II to increase drinking. OVLT turns off supraoptic and paraventricular. So damage to SO/PV leads to diabetes insipidus: polyuria (pee a lot) & polydipsia (drink a lot).

How does hypothalamus regulate food intake?
Ventromedial region decreases intake, dorsomedial increases appetite (down (ventral) decreases, up (dorsal) increases). Leptin seems to decrease intake, and the diabetes gene is a leptin receptor.

How does hypothalamus regulate temperature?
Posterior hypothalamus responds to cold by heating (eg. shivering), Anterior hypothalmus responds to heat by cooling (eg sweating). So lesions of anterior hypothalamus can produce hyperthemia (temperature greater than 101). Fever is a change in set point that can occur when cytokines contact the OVLT which activates COX to produce PGE2 which inhibits warm sensitive neurons in anterior hypothalamus to raise set point. "Fever differs from hyperthermia, which is an increase in body temperature over the body’s thermoregulatory set-point (due to excessive heat production or insufficient thermoregulation, or both)."

What are the S&S of hypothalamic syndrome in pituitary adenoma and craniopharyngioma?
Hypothalamic syndrome involves amenorrhea, galactorrhea, somnolence, diabetes, adiposity. If tumors such as pituitary adenoma or craniopharyngioma (a congenital tumor) impinge on hypothalamus they can produce a hypothalmic syndrome. Tumors may also impinge on optic chiasm (tunnel vision) or cerebral aqueduct (obstructive hydrocephalus).

Hypothalamus has extensive connections with the limbic system which we consider next...

Limbic System

WebMuseum

What are the cortical and subcortical parts of the limbic system?
The limbic system functions in emotion, memory, and emotional memory (and possibly memorable emotions). The limbic system has both cortical and subcortical components. Subcortical components include the amygdala (functions in fear & aggression) and basal forebrain nuclei (septal nucleus, nucleus accumbens, and nucleus basalis of Meynert). Cortical limbic components include prefrontal cortex, cingulate gyrus, hippocampal formation, and entorhinal cortex. Hippocampal formation includes hippocapmus (aka Ammon's horn), dentate gyrus, and subiculum. The hippocampus and dentate gyrus are 3 layered cortex (archicortex) while the subiculum is a transitional region called paleocortex (from 3 to 6 layered cortex).

What are the parts of the Papez circuit?
The Papez circuit connects limbic structures. Starting with hippocampus, most input arrives via an indirect pathway called the perforant pathway which first terminates in dentate gyrus, then granule cells in the dentate gyrus project to pyramidal cells in hippocampus. But there are also direct inputs to hippocampus. Pyramidal cell axons project out of hippocampus directly, or by synapsing in subiculum, to form the fimbria and fornix. Fornix projects to mamillary body, mammillothalamic tract projects to anterior nucleus of thalamus, thalamocortical fibres project to cingulate, cingulum bundle projects full circle back to entorhinal cortex, subiculum & hippocampus.

"In 1937, Papez described a circuit for the processing of emotions, which has subsequently proved to be critical for memory function." R SPERLING

What are the three elements of declarative memory?
Declarative memory can be divided into 3 stages: acquisiton, storage, retrieval. Acqusition depends on context and significance of the information. Storage involves long-term potentiation (LTP) that is thought to involve NMDA receptors of hippocampal neurons. Retrieval may be immediate, short-term, or long-term. The hippocampus functions in immediate recall and in consolidation (the process of converting short- into long-term memory).

What are the symptoms of Kluver-Bucy, Wernicke's encephalopathy and Korsakoff's syndrome?
Loss of limbic structures, as you'd expect, affects emotional behaviour and memory. Bilateral removal of temporal lobes and amygdala can cause Kluver-Bucy syndrome which is characterized by hyperorality, hypersexuality, visual agnosia, and docility. Bilateral removal of hippocampus can cause anterograde amnesia in which prior events are remembered, but no new memories are formed, however procedural memory remains (which is why Drew Barrymore could still paint in 50 First Dates). Memory deficits also occur in Wernicke's encephalopathy (thiamine deficiency (alcoholism) leads to lesions in mammillary bodies) and Korsakoff's syndrome (due to chronic thiamine-deficiency, untreated Wernicke's). Korsakoff's patients who lose short-term memory may invent memories of events, called confabulation.

From amygdala to, the smell (and taste) of fear...

Olfaction & Gustation

What is the basic neuroanatomy & physiology of olfaction?
In olfaction, the primary sensory receptor is itself a neuron. In order to detect the 1000 or so different odors, that means there are 1000 different neurons spread out over the olfactory epithelium. However by some unknown mechanism, all neurons expressing a receptor to a given odor all converge on the same second order neuron, called a mitral cell, in a structure within the olfactory bulb called a glomerulus. From mitral cell, signals pass back along the olfactory tract to olfactory tubercle, amygdala, perirhinal, entorhinal and piriform cortices. Thus olfactory signals input directly to limbic system, which is different from other sensory systems that first synapse in thalamus.

Sense of smell is closely related to gustation.

What is the basic physiology of taste and a potential clinical application?
Gustation involves sensations of sweet, bitter, salt, sour, and umami. The receptors for taste (taste buds) open to the surface of the tongue through a taste pore. Gustatory receptor cells are very short-lived, and are replaced by basal cells ~ 10 days. Transduction of sour and salt occurs when H+ and Na+ direclty alter membrane conductance, other tastes are transduced via second-messenger pathways. Signals are passed on to the special sense afferents of cranial nerves VII, IX, and X, but really VII along chorda tympani accounts for 90% of taste. Inputs from VII, IX, and X come together in the nucleus tractus solitarius )NTS). Interestingly, sweet taste has an analgesic effect. For those interested in pediatrics this field of research sounds really interesting... Blass E M J and Hoffmeyer L B (1991) Sucrose as an analgesic for newborn infants. Pediatrics 87, 215-218.

Finally we go from taste to ophtalmology ...

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Ophthalmology

What are elements in taking an ophthalmic history?
Sudden or gradual onset? Sudden events are usually vascular (eg stroke, CRAO). Events that occur over hours-days may be inflammatory or involve rential detachment or angle-closure glaucoma. Events that occur over months to years include cataracts, open-angle glaucoma, and retinal degeneration.
What are some elements assessed during the exam?
Assess visual acuity: from 20/20 to 20/400 and beyond that to count fingers (CF), hand movement (HM), light perception (LP), no light perception (NLP). To assess pupils: if not equal that's anisocoria if difference greater in bright light, the larger pupil is abnormal, if dim light then the smaller pupil is abnormal. Swinging flashlight test can be used to identify a Marcus Gunn pupil (relative afferent pupillary defect) If the optic nerve is damaged, when the light is swung over to that eye that pupil acutally dilates from its prior constricted state. Assess intraoccular pressure (nromally 10 - 21 mmHg). Assess confrontational visual fields
What data can be gathered prior to consult?
To localize the deficit "from tear film to occipial lobe" systematically "factor in the factors"
Starting from the outside and working in, you can assess: face (symmetry), eyes (proptotic or enophthalmic), lids (ptosis), lashes (trichiasis, distichiasis), conjunctiva (injection, discharge), cornea (abrasion, perforation), anterior chamber (shallow due to glaucoma/perf, WBC hypopyon, RBC hyphema), iris (neovascularization), lens (centered & clear?), vitreous, optic nerve (cup/disc > 0.3 = glaucoma?), retinal vessels (hypertension), macula (exudate with diabetes, macular degeneration).

Next up frontal-subcortical circuits & eating disorders...

Frontal-Subcortical Circuits
In addition to external (motor) behaviours, frontal lobes also function in internal behaviours primarily in prefrontal regions. The prefrontal cortex includes three basic yet overlapping functional regions: the dorsolateral circuit (for executive function); the anterior cingulate (for motivation); and the ortbitofrontal cortex (for social behaviour). Note that there is some difference in definitions of the functionality of these regions among lecturers... Nevertheless, all of these areas participate in loops with thalamus and basal ganglia forming frontal-subcortical circuits.

Dorsolateral Circuits & Working Memory/Executive Function
Referred to as "executive" in this lecture because it delegates tasks. This is how you maintain an agenda that allows you to do tasks in an organized sequence, suspending certain activities as needed in response to the demands of the current environment (would that be sleep in our current context?). As such the dorsolateral region is a working memory, but it's applied to internal behaviours. If these circuits are imparied as in dementia, or damaged by removal of a frontal astrocytoma, we lose the ability to plan and instead show perseveration. We can function if the environment furnishes structure, but cannot create structure for ourselves. As a correlate to this, damage to dorsolateral circuits lead to difficulty retrieving memories, though memories themselves are intact.

Anterior Cingulate & Motivation
Anterior cingulate receives input from brainstem "activating" centers via thalamic midline nuclei as well as from other limbic structures (Papez circuit). The anterior cingulate functions in motivational drive, affect, and attention. Parietal inputs are especially important in adding emotional import to attention. So lesions to anterior cingulate produce apathy (lack of interest, action, or concern) and aboulia (lack of will) as well as impairments in verbal fluency

Orbitofrontal Circuit & Emotional Decision Making
Orbitofrontal cortex provides inhibitory inputs to amydgala. Orbitofrontal cortex functions in activating "emotional" memories (internalized rules) in order to regulate impulsive or aggressive behaviours, ie to recognize the consequences of one's actions. So lesions to the orbitofrontal region produce a lack of judgement and empathy, and impulsivity. "Patients with... orbitofrontal lesions... do not show the normal pattern of risk aversion..."

video
"Nut job" or orbitofrontal hypofunction??

Orbitofrontal and anterior cingulate are "hubs" for inputs from limbic structures, basal ganglia, and association cortices. As such they may play important roles in frontal lobe dysfunction. A hyperactive cingulate motivational circuit (with nucleus accumbens) can function in addiction. A hypoactive cingulate converseley can function in apathy and depression. A hyperactive orbitofrontal cortex (with caudate) can function in OCD.

We'll end this section with part of Dr. Black's quiz.
What structure is associated with:
A deficit in initiative?
A deficit in concentration?
A deficit in judgement?

Now on to eating disorders...

Both anorexia and bulima involve preoccupation with becoming fat, because a patient's self-worth is tied to "how they look". And both anorexia and bulimia have subtypes that may be restricting or purging. The difference between anorexia and bulimia is apparently just weight; DSM IV criteria are 85% of expected body weight (by age) and amenorrhea (3+ consecutive cycles). Anorexia predominates in female patients (90%). Onset is generally mid-late adolesence, with half of the cases resolving, 30% wax and wane, 10% are severe and the upper range of estimates for mortality is as high as 10%. Bulimia however is not as associated with mortality. Most of the morbidity associated with ED's are due to electrolyte and metabolic imbalance; food deprivation itself will cause secondary symptoms. Eating disorders are also frequently associated with anxiety disorders, either preceding or concomitant.

There is evidence for genetic inheritance functioning in combination with environmental interactions. Empirically certain personality features are associated with anorexia: high functioning perfectionistic, overcontrolled, and emotionally dysregulated. Cognitive behavioural therapy is one approach to treatment, which requires generating motivation, and challenging patient's beliefs, which can definitely be difficult. Initial treatments usually focus on preventing medical complications, and associated depression or anxiety.

Next up, limbic system disorders - Dr. Hudziak always gives a most excellent lecture!