NBB 1 Part 2 Flashcards
Describe the ventricular spaces associated with each of the subdivisions of the brainstem
- Cerebral aqueduct of Sylvius between 3rd and 4th ventricles is in the midbrain
- 3rd ventricle is in the diencephalon
- 4th ventricle dorsal to pons, shared between pons and rostral medulla (which has choroid plexus on dorsal side at caudal end of 4th ventricle)
What are the exit points for CSF circulation in the brainstem?
Where does CSF go afterwards? What are the cisterns
- Foramen of Magendie (medial)
2 + 3. Foramina of Luschka (lateral)
Drains into cisterna magna (second place you can obtain CSF fluid, after spinal tap) –> subarachnoid space –> drained via arachnoid granulations –> venous sinus
Cisterns: magna, prepontine, interpeduncular, and quadrigeminal
Differentiate between the levels of the brainstem (medulla, pons, midbrain) and explain the basis for their gross anatomical differences:
1. Medulla
- Medulla:
A. Ventral side of rostral medulla: anteromedial fissure for anterior spinal artery
-Most medial - pyramid
- then olive - covers the inferior olivary nucleus (winding snake like appearance)
- then inferior cerebellar peduncle
B. Dorsal side of rostral medulla:
-4th ventricle, plus choroid plexus
C. Ventral side of caudal medulla:
-pyramidal decussation of corticospinal tract (motor tract for body from primary somatosensory cortex)
D. Dorsal side of caudal medulla:
-gracile tubercle (2nd order synapse of axons from lower limbs from sensory DCMLS)
-cuneate tubercle (2nd order synapse of axons from upper limb from sensory DCMLS)
Review DCMLS and STT pathways and where they pass through the medulla
DCMLS: vibration, proprioception, soft touch
1st order in DRG, 2nd is gracile and cuneate nuclei of caudal medulla, decussation as internal arcuate fibers of lower medulla, ascends via medial lemniscus, 3rd order is VPL of thalamus
-travels through medial medulla
STT: pain, temperature, crude touch
1st order in DRG, 2nd order is Lissauer’s tract in dorsal horn, decussates at anterior white commissure and ascends for 2 spinal cord levels, ascends via anterolateral system, 3rd order is VPL of thalamus
-travels through lateral medulla
- Name the motor and sensory pathway that synapse in the medulla
- Name the motor and sensory pathway that travel through the medulla
1A.Corticobulbar (synapse with CN LMNs)
B. DCMLS (ipsilateral cuneate/gracilis nucleus then decussates as internal arcuate fibers)
2A. Corticospinal (pyramidal decussation then synapse in anterior horn of spinal cord)
B. Spinothalamic (synapse in Lissauer’s tract and decussate at anterior white commissure of spinal cord)
- What is the difference between a nerve and a tract?
- Define functions of the types of motor nuclei:
A. Somatic efferent nuclei
B. Visceral efferent nuclei - general
C. Visceral efferent nuclei - special
3. Define functions of the types of sensory nuclei: A. Somatic afferent nuclei - general B. Somatic afferent nuclei - special C. Visceral afferent nuclei - general D. Visceral afferent nuclei - special
- Both are bundles of axons
Nerve is in touch with periphery, tract with CNS - A. Somatic efferent nuclei GSA: framework of body e.g. skeletal muscles that originate from embryonic somites
B. Visceral efferent nuclei- general GVE: parasympathetic fibers for smooth muscles (viscera)
C. Visceral efferent nuclei - special SVE: activates striated muscle (from embryonic branchial arches i.e. jaw, face, larynx, pharynx, trap, sternocleidomastoid) - Somatic afferent- info about changes in environment from framework of body (receptors)
A. General GSA- impulses that begin near the body surface e.g. pain, temp, touch pressure
B. Special SSA- highly specialized sensory systems e.g. vision (light) and hearing (sound)
Visceral - impulses arising in/around the viscera or organs
C. General GVA- receptors from mucous membrane or in organ walls - physical (distension) or chemical composition
D. Special SVA- specialized chemical stimuli i.e. smell, taste
Describe distribution of cranial nerves throughout the brainstem and medially/laterally
Rule = 2:2:4:4 (out:Md:Po:Me)
I and II - outside the brainstem
II and IV - in midbrain
V, VI, VII, VIII - in pons
IX, X, XI, XII - in medulla.
Motor CNs are more medial, sensory more lateral e.g. VIII is most lateral
Medulla - most medial is hypoglossal nucleus, then parasympathetic dorsal motor nucleus of X, then sulcus limitans line, then sensory nuclei (spinal trigeminal, nucleus solitarius, vestibular nuclei)
CN XII (Hypoglossal) I. Which part of the brainstem does it travel through? II. What are its functions? III. Lesion of UMN (corticobulbar tract) vs LMN (hypoglossal nerve) vs bilateral lesion
I. XII is between olive and pyramids in the medulla (ventral side)
hypoglossal trigone on the floor of the 4th ventricle (dorsal side) –> visual aspect of the hypoglossal nucleus, which is a cell column –> LMNs extend the full length of the medulla
II. Innervated by:
A. Voluntary movements/articulation
- UMNs form corticobulbar pathway from cerebral cortex –> crossed/contralateral innervation (e.g. R cortex to L hypoglossal nucleus)
-LMNs from hypoglossal nucleus innervate all extrinsic and all but one (palatoglossus - CN X) extrinsic tongue muscles
-GSE - ipsilateral tongue muscles –> controls movement of tongue, maintains muscle tone
B. Reticular neurons for automatic/reflex movements - control of movements while eating and swallowing
III. Corticobulbar tracts usually bilateral, BUT are contralateral for XII
UMN lesion –> tongue deviates to opposite side of damage (e.g. if you lesion L corticobulbar tract –> affects R hypoglossal nerve –> tongue deviates to R side)
LMN lesion –> tongue deviates to same side of damage (e.g. if you lesion L hypoglossal nerve –> tongue deviates to L side) + severe muscle atrophy
Bilateral lesion –> disability speaking, swallowing food; due to motor neuron disease, demyelination (ALS), bleeding, tumors of medulla / base of skull
CN XI (Spinal Accessory) I. Which part of the brainstem does it travel through? II. What are its functions? III. What happens with lesion?
I. Lateral to XII in the medulla, one part from medulla (Accessory nucleus), other part is ventral motor horn of cervical spinal cord
II. CN XI = motor
A. SVE Branchial motor part –> innervates ipsilateral sternocleidomastoid and trapezius muscles (neck and shoulder) Special visceral efferent
B. Visceral motor part –> control of larynx, joins CN X
III. Lesion:
- cannot rotate head towards healthy side (away from lesion) against pressure
- ipsilateral shoulder drop
- weakened voice or hoarseness
CN X (Vagus) I. Which part of the brainstem does it travel through? II. What are its functions? III. What happens with lesion?
I. Efferent fibers exit medulla between olive and inferior cerebellar peduncle on ventral side; vagal triangle is also on the floor of the fourth ventricle on dorsal side, overlies the dorsal motor vagal nucleus adjacent to hypoglossal nucleus
-Although LMNs from multiple nuclei inside brainstem – axons come together to form single bundle at CNX level of medulla
II. CN X is mixed
A. Motor components:
1. general visceral efferent (dorsal vagal nucleus)–> preganglionic parasympathetic –> ganglia for heart, lungs, GI to splenic fixture
2. special visceral efferent /branchial efferent (nucleus ambiguus) –> pharyngeal muscles (swallowing), laryngeal muscles (vocalization)
B. Sensory components:
- GSA (joins nucleus of CN V) - touch, pain, pressure from small parts of face –> pharynx, meninges, small region of external ear (conscious)
- SVA (rostral nucleus solitarius)- taste for small part of mouth –> epiglottis and posterior pharynx
- GVA (caudal nucleus solitarius)- from chemoreceptors and baroreceptors from aortic arch (subconscious)
III. bilateral lesion is fatal !
Unilateral lesion - motor affected first –> contralateral uvula deviation, ipsilateral vocal muscle paralysis
CN IX (Glossopharyngeal) I. Which part of the brainstem does it travel through? II. What are its functions? III. What happens with lesion?
I. Exits upper medulla rostral to vagus nerve (bw olive and cerebellar peduncle)
II. CN IX is mixed
A. Motor components:
1. GVE (inferior salivator nucleus in the pons) - pregang parasympathetics for parotid gland
2. SVE / branchial efferent (nucleus ambiguus) - stylopharyngeal muscle –> elevates pharynx during talking and swallowing
B. Sensory components:
- GSA- touch pain pressure from small parts of face –> pharynx, posterior 1/3 tongue, middle ear, small region of external ear (conscious)
- SVA (rostral nucleus solitarius)- taste from posterior 1/3 tongue
- GVA (caudal nucleus solitarius)- chemoreceptors and baroreceptors from carotid body (subconscious)
III. problems with coughing, saying “Aah”, blowing out cheeks; due to polio, ischemic lesions, motor neuron disease, etc.
Differentiate between the levels of the brainstem (medulla, pons, midbrain) and explain the basis for their gross anatomical differences:
2. Pons
- Pons
A. Ventral side - 2 corticospinal tracts on ventral side, one CN trying to reach cerebellum
B. Dorsal side - facial colliculus, 3 cerebellar peduncles - superior, middle (made of contralateral pontine nuclei fibers), inferior; 4th ventricle
CN V (Trigeminal) I. Which part of the brainstem does it travel through? II. What are its functions and motor/sensory nuclei? III. What happens with lesion?
CN V (Trigeminal) I. Small motor part exiting on dorsal side but large sensory part coming in through middle cerebellar peduncle
- innervations are ALL ipsilateral
- V3 includes anterior 2/3 tongue (taste for that region comes from VII
II. Mixed - 4 nuclei
A. Motor components:
1. SVE/branchial motor (trigeminal motor nucleus)- muscles of mastication + tensor tympani muscle + bilateral corticobulbar projections for voluntary chewing
*more medial to the principal sensory nucleus, fibers leave from dorsal side
B. Sensory components:
- GSA - crude touch, pain, and temp + noxious stimuli/ nociception from V1-V3 (spinal nucleus) –> trigeminothalamic tract
- GSA - fine touch and pressure from V1-V3 (chief/ principal sensory nucleus) –> trigeminal lemniscus tract e.g. afferent aspect of c
- GSA - unconscious proprioception and bite strength (mesencephalic nucleus) –> NO tract to thalamus; only primary sensory neurons already in CNS, in the mesencephalic nucleus –> goes from pons to the midbrain
III. Lesion
- atrophy and chin deviation on side of lesion
- trigeminal neuralgia - idiopathic, brief severe pain in V2-V3 but facial sensation normal
- loss of jaw jerk reflex
CN V.
Describe the trigeminothalamic pathway (i.e. Trigeminal Chemosensory pathway)
Trigeminothalamic pathway - conveys pain and temperature from the head and face to thalamus for CN V (general sensory afferent)
*conveys nociception / noxious stimuli detection (eg chili peppers, vinegar) - separate pathway from CN I
1st order neuron - trigeminal ganglion outside the pons
fibers go downwards from pons
2nd order neuron - ipsilateral spinal nucleus of V (medulla) or in the spinal cord
ascends and decussates at the pons and medulla (at 2 levels) –> create trigeminothalamic fibers
3rd order neuron - VPM nucleus of thalamus
*Spinal Nucleus V also receives afferents that enter brainstem with
IX - sensation for back of ear, posterior 1/3 tongue, upper pharynx
X - sensation for pharynx, larynx, external ear
CN V.
Describe the trigeminolemniscal pathway
Trigeminolemniscal pathway - conveys touch and pressure from head and face to thalamus for CN V (General sensory afferent)
1st order neuron - trigeminal ganglion outside the pons
fibers enter and synapse right away
2nd order neuron - principal sensory nucleus of V in the pons –> decussation only at pontine level
3rd order neuron - VPM of thalamus
CN VII ( Facial) I. Which part of the brainstem does it travel through? II. What are its functions and motor/sensory nuclei? III. What happens with lesion?
CN VII
I. Ventral pons - nerve exits laterally to VI at the ponto-medullary junction
Dorsal pons - facial colliculus on floor of 4th ventricle - consists of fasicles of facial nerve looping around abducens nucleus
II. CN VII - Mixed
A. Motor components:
1. SVE - muscles of facial expression - stapedius muscle and part of digastric muscle motor parts of corneal, sucking, and blinking reflexes
2. GVE - pregang parasympathetic for salivatory gland (lacrimal, sublingual, submandibular) EXCEPT parotid (IX)
B. Sensory components:
- GSA - sensation from small region near outer ear (also IX, X)
- SVA - taste from anterior 2/3 tongue (sensory is from CN V, posterior 1/3 is CN IX) –> joins other taste fibers (IX, X) at the nucleus solitarius
- GVA - mucous membrane of nasopharynx
III. Lesions
A. UMN (corticobulbar tract) lesions - bilateral for upper face and contralateral for lower face –> only lower face weakness
refers to voluntary facial paresis; emotional expression comes from anterior cingulate cortex and hypothalamus –> joins corticobulbar tract at facial nucleus LMNs
B. LMN (CN VII) lesion e.g. Bell’s Palsy - ipsilateral for upper and lower face –> unilateral facial weakness, dry eye, loss of taste
Differentiate between the levels of the brainstem (medulla, pons, midbrain) and explain the basis for their gross anatomical differences:
3. Midbrain
- Midbrain
A. Ventral side - cerebral peduncles (axons) with interpeduncular fossa in between (interpeduncular cistern) and CN III oculomotor nerve exiting *CN III between superior cerebellar artery (SCA) and posterior cerebral artery)
B. Dorsal side (back side) - trochlear CN IV exits; cerebral aqueduct; quadrigemina composed of paired superior (visual) and inferior (auditory) colliculi (collection of cell bodies) –> quadrigeminal cistern
Midbrain contributes one tract to medial motor system (superior colliculus –> tectospinal - head movement) and one to lateral (red nucleus –> rubrospinal - voluntary contralateral flexors)
Describe the vascular supply of the midbrain and conditions that arise if it is compromised
Posterior cerebral artery - covers the cerebral peduncles where all the motor pathways (corticobulbar, corticopontine), and sensory pathways (anterolateral, spinothalamic, trigeminal thalamic, trigeminal lemniscus) are together
-covers substantia nigra, red nucleus, descending sympathetic fibers
Describe the development of the eye.
What are clinical implications of eye development?
Eyes form as an outgrowth the CNS (other sensory systems formed peripherally)
- Optic vesicle induces overlying ectoderm to differentiate into lens epithelium
- Optic vesicle folds in on itself and pulls in the forming lens
- Lens separates from ectoderm
- Outer layer differentiates into retinal pigmented epithelium; inner layer becomes neural retina –> retinal layer
- Surrounded mesenchyme becomes sclera (tough outer layer) and uvea (vascular layer)
optic nerve –> optic sheath –> subarachnoid space where CSF flows through –> dura
so increased intracranial pressure –> compresses optic nerve –> impairs venous return –> papilledema (optic nerve swelling that can be visualized through the pupil)
*swelling of optic nerve due to other causes = intraocular optic neuritis
What are the 3 distinct layers of the eye and their functions?
What are the segments of the eye?
3 layers (ie spheres lying inside one another):
I. tough outer layer –> sclera and cornea
II. vascular layer –> uvea with choroid posterior and ciliary body/lens and iris anterior
III. third inner layer –> retina, incomplete sphere with only posterior aspect
Fluid-filled segments:
1. Posterior segment - from retina to back of lens, filled with vitreous humor –> slow turnover
2. Anterior segment - from lens to cornea, filled with aqueous humor –> constantly replenished
A. Anterior chamber - in front of iris
B. Posterior chamber - behind iris
- Describe process of closing/opening eye
- Describe process of lacrimation
A. Dry eyes stimulation
B. lacrimation stimulation
1A. Opening eye - levator palpebrae superioris (CN III) and superior tarsal (sympathetic from superior cervical ganglion)
B. closing eye - obicularis oculi (CN VII) - orbital and palpebral portions motor limb of corneal reflex
- Lacrimation - lacrimal gland is superior and lateral –> produces tears which flow across eyes –> drain into lacrimal ducts near caruncle –> drain into inferior nasal meatus
sympathetic and parasympathetic (via CN VII) innervation:
A. dry eye signaled via afferent limb CN V to chief/principal sensory nucleus of trigeminal nerve
B. lacrimation stimulated via efferent limb of CN VII (parasympathetic fibers from superior salivary nucleus travel through greater petrosal nerve –> synapse on pterygopalatine ganglion –> innervate lacrimal gland)
I. Describe how the eye regulates light intensity.
II. Describe normal light and consensual reflexes
III. Differentiate bw light reflex results with II vs III lesion
I. Iris has 2 opposing muscle groups that regulate pupil diameter:
- Sphincter pupillae (parasympathetic via CN III; Edinger-Westphal nucleus) –> lesion leads to mydriasis “blown pupil”
- Dilator pupillae (sympathetic) –> dilates by pulling on sphincter muscle –> lesion leads to miosis
II. Light stimulus leads to constriction of stimulated (“direct”) and contralateral (“consensual”) pupils
Pathway: light –> afferent is II (i.e. optic nerve)–> information goes to prectal nucleus –> bilaterally to Edinger-Westphal nucleus (outer part of CN III nucleus)–> efferent limb is III –> synapses in parasympathetic ciliary ganglion –> postganglionic parasympathetic innervation to sphincter pupillae
III. Complete CN II lesion –> no direct or consensual reflex
Partial II lesion/ relative afferent pupillary defect / Marcus Gunn pupil –> decreased constriction in affected eye appears as dilation, use “swinging flashlight” test
III lesion –> no direct reflex, but consensual reflex still exists
Describe how the eye focuses light.
Describe role of lens in this process
What happens with presbyopia?
Light entering the eye is refracted by the cornea (bending) and the lens (fine tuning) to focus rays on the retina –> image is rotated 180 degrees
- myopia = image focused anterior to retina
- hypermetropia (far-sighted) = image focused posterior to retina
Lens changes thickness depending on object distance
- Distant objects: Ciliary muscle relaxed, Zonules (Suspensory ligaments) pull on lens –> lens is elongated and flattened (overcomes lens capsule force)
- Near objects: Ciliary muscle (parasympathetic innervation via Edinger-Westphal nucleus, part of ciliary body) contracts, Zonules relaxed –> lens capsule takes over and squeezes on the muscle –> lens becomes round
- -> this muscle tension during accommodation is why eyes get tired after reading
Presbyopia - lens hardens with age –> capsule still works but no matter how hard it squeezes, cannot get lens in rounder shape –> far-sighted
I. Describe the retinal layers
II. Describe the interdependence of retinal pigmented epithelium and photoreceptor cells
I. Retina began as 2 layers separated by actual space –> mature retina has 3 neural sub-layers and one epithelial outer layer
Retinal layers in order of looking in through pupil:
1. retinal ganglion cells (RGCs) –> only axons that leave the eye, form optic nerve
synapses on inner plexiform layer
2. inner nuclear layer (interneurons)
synapses on outer plexiform layer
3. outer nuclear layer (photoreceptors i.e. rods for B/w and cones for color)
4. Retinal pigmented epithelium (RPE)
II. Apex of outer segment of all photoreceptor cells is buried in the RPE –> crucial for function and survival
A. Rod outer segments contains stacked discs studded with photopigments that absorb light and convert into neural signals, these discs are pushed towards the apex and phagocytized by RPEs
B. Cones have sinusoidal plasma membrane with embedded photopigments
Eye pathology:
- Alport syndrome
- Wilson’s disease
- Corneal edema
- Alport syndrome - mutation in Type IV collagen genes –> affects basement membrane formation –> kidney failure, hearing loss (hair cell death), misshapen cornea and lens (anterior lenticonus); adult onset
“can’t pee, can’t see, can’t hear a bee” - Wilson’s disease (hepatolenticular degeneration) - recessive mutation that affects copper transporting ATPase –> inadequate copper excretion into bile and blood (decreased ceruloplasmin) –> copper deposits in body tissues –> liver fibrosis, neurological symptoms, Kayser-Fleischer ring in cornea, renal disease
- Corneal edema (hydrops): Cornea gets cloudy when fluid accumulates in connective tissue (normally pumped out by endothelium) –> solution is `cadaveric transplant to replace corneal epithelium don’t have to HLA match bc cornea is avascular
- Describe pathologies of the anterior segment of the eye and their role in glaucoma
- What are the two types of glaucoma?
- What are therapeutic options?
- Ciliary body epithelium produces aqueous humor and fills anterior/posterior chambers of the anterior segment –> flows toward junction between uvea and sclera (between middle and outer layer) –> collects in canal of schlemm and returns to venous system;
Imbalance leads to increased intraocular pressure in anterior chamber affects what is most vulnerable –> compresses the optic nerve (“cupping”) and compromises retinal ganglion cell (RGC) axons as they make a 90 degree turn leaving the eye –> RGCs generating the axons + downstream targets in LGN die –> glaucoma (vision loss)
2A. Open angle - fluid has unimpeded access to canal of schlemm but reabsorption is reduced –> slow onset
B. Closed angle –> lens moves anteriorly, displaces iris –> fluid cannot get resorbed –> rapid onset, acute loss of vision; use oral glycerol or IV mannitol
3A. Mechanical - insert stent in anterior chamber and reinforce connection to canal of schlemm; can only do this if having cataract surgery
B. Pharmacologic: first line is prostaglandin analog i.e. latanoprost - increases outflow
i. Beta blockers i.e. timolol reduce production of aqueous humor
ii. Muscarinic agonists i.e. pilocarpine, bethanechol- contract ciliary muscle to facilitate outflow of aqueous humor
more common in older age bc lens increases in size and can block pupil; other pathology common in old age is cataracts (clouding of lens)
Describe retinal pathologies:
- Macular degeneration
A. dry
B. wet - Stargardt disease
- Retinitis pigmentosa
- Diabetes
A. Nonproliferative
B. Proliferative - Retinoblastoma
- Macula - region of retina that encompasses fovea (Where we have best vision); degeneration of macula –> lose high quality vision in center of visual field, retain peripheral vision
A. Dry degeneration - drusen (debris) accumulation between choroid and RPEs - slow progression and no therapy
B. Wet degeneration - abnormal angiogenesis in choroid–> rapid progression and treatment with angiogenesis blockers (anti-VEGF i.e. bevacizumab) - Stargardt disease - genetic mutation –> buildup of Vitamin A on outer segment of photoreceptors –> passed to retinal pigment epithelial cells (RPEs) –> RPEs and photoreceptors killed –> fovea affected first so you lose central vision
- Retinitis pigmentosa - mutations in gene involved in signal transduction that affects rods first–> night blindness and loss of peripheral vision
- Diabetes - vision loss consequent to vascular changes leading cause of blindness
A. Nonproliferative - damaged vessels between retina and vitreous humor leak blood –> hemorrhages in retina and macular edema
B. Proliferative hypoxia –> new angiogenic factors and new vessels (which tend to burst)–> leaking leads to scar formation –> scar traction on neural retina –> separates photoreceptors from RPE; die if they are not reattached - Retinoblastoma - due to RB gene mutation (E2F no longer inhibited - keep going through cell cycle); tumor in eye glows; 1 eye is spontaneous mutation and 2 is inherited
What is the role of photoreceptors?
Describe actions of photoreceptors in dark vs light
Light comes down layers of retina to photoreceptors –> Photoreceptors convert light image into a neural signal –> electrical impulse then travels back up the layers of the retina to the thalamus –> visual cortex
- Dark: inflow of Na+ through cGMP gated channels > outflow of K+ –> photoreceptor cells depolarized “dark current” –> maximal neurotransmitter release
- Light: light acts as ligand and activates G-protein coupled receptors (opsin + Vit A) –> activate G-protein (tranducin) by removing repressors –> transducin activates phosphodiesterase PDE by removing repressors –> PDE cleaves and inactivates cGMP –> cGMP decreases –> Na+ channels close but still K+ efflux –> photoreceptors hyperpolarize –> neurotransmitter release diminished (graded in that more light lost –> larger decrease in glutamate)
* no action potentials - this cascade removes inhibition of ON bipolar cell and sends excitatory signal down neural pathway*
Describe the cell types of interneurons involved in signal compression in the inner nuclear layer of the retina
- Bipolar cells
- Horizontal cells
- Amacrine cells
- Bipolar cells - vertical transmission between photoreceptors and RGCs with graded response and glutamate neurotransmitter; minimal signal compression (1:50 rods, 1:4 cones)
- Horizontal cells - lateral inhibition of photoreceptor hyperpolarization and bipolar response –> involved in center-surround inhibition; primary point of signal compression – decide what to pass on and what to throw out
- Amacrine cells - also involved with lateral inhibition, double filter to reconsider information the horizontals let through
- Describe the center-surround receptor field concept of RGCs
- Differentiate 2 classes of RGCs
- Describe how the 2 RGC classes lead to 2 visual systems at the lateral geniculate nucleus LGN
- Visual system detects edges; Retinal Ganglion Cells (outermost layer of retina) have center-surround receptive fields
- stimulate just the center i.e. defined “Edge”–> retinal ganglion cell (RGC) is highly active (bc horizontal cells dont intervene)–> bipolar signals –> increased firing from RGCs
- stimulate center + surround –> not an edge so horizontal intervenes and bipolar blocked –> just above baseline firing
- stimulate surround but not center –> depresses firing, increased firing when stimulus is removed - P and M
P = precision; P cells have small receptive fields and small caliber axons; carry info on form and shape
M = motion; M cells have large receptive fields and large caliber axons; carry info on motion detectors (cannot detect the motion themselves but relay to cells in visual cortex that can) - LGN - relay center in thalamus for visual input from retina
Magnocellular - for movement (input from M cells); ancient system but gets to cortex faster bc larger axons –> important for reading
Parvocellular - for discrimination (input from P cells); newer system
Differentiate between histology of macula and optic disc
Both are areas of the retina
Central portion of macula is the fovea –> best vision bc overlying. intervening cells are pushed aside and light hits the cones directly
Macula is the larger region of high visual acuity –> central vision
Optic disc is where the axons from retinal ganglion cells RGCs coalesce and exit and w`here blood vessels enter –> no photoreceptors –> blind spot
- Describe segregation of sensory input from retina at LGN
- Describe effect of glaucoma on LGN
- Where do axons from LGN go?
- LGN - relay center in thalamus for visual pathway; signals leave retina as retinal ganglion cell RGC axons –> travel down optic nerve and tract –> 90% of axons from the eye go to LGN, where they segregate into 6 layers, each innervated by only one eye
Mnemonic: See I? I see, I see! for inner –> outer layers - LGN neurons die with glaucoma; can figure out which LGN is based on which layers atrophy
e. g. if layers 2, 3, and 5 die –> glaucoma on ipsilateral side - Axons from LGN travel through 2 divisions of optic radiations to V1 (i.e. primary visual cortex, striate cortex)
A. information from superior retina –> inferior visual field –> upper banks calcarine fissure
B. information from inferior retina –> superior visual fields –> lower banks calcarine through Meyer’s loop
- Describe the location and structure of the primary visual cortex (V1, striate cortex)
- Perfusion to V1 and clinical implication for cortex lesions
- Describe eye specific and orientation columns
- V1 (primary visual cortex; striate cortex) is in occipital lobe; encompasses calcarine fissure and contains retinotopic map; Cortex layers 4 & 6 prominent
A. Upper calcarine fissure –> information from superior retina –> inferior visual field
B. Lower calcarine fissure (Meyer’s loop) –> information from inferior retina –> superior visual field - Notched hemifield/ macular sparing with Posterior cerebral artery (PCA) infarct or V1 cortex lesion bc fovea can be supplied by middle cerebral artery; differentiates it from optic tract lesion
3.
A. Eye specific layer in LGN –> eye specific columns in V1
B. Orientation columns - simple V1 cells fire only if stimulus lines up at specific orientation column and in center of receptive field
Complex V1 cells fire with specific orientation but at multiple points in receptive field earliest cells that can detect and respond to motion
Describe visual cortex regions V1-V5 and effect of lesions
What is prosopagnosia?
V1 is primary visual cortex, V2-V5 are secondary visual cortex
V1 - raw data / all visual inputs –> cortical blindness (similar to severed optic nerve)
V2/V3 - form and shape –> aperceptive agnosia (acuity intact but cannot integrate visual input e.g. cannot draw a key by looking at the picture, but can draw from memory)
V4 - color –> achromatopsia (color loss)
V5 - motion –> akinetopsia (things disappear once the start moving)
Prosopagnosia - bilateral damage to fusiform gyrus (visual object recognition archives in the temporal lobes) –> inability to recognize faces; bilateral damage due to trauma/stroke
What is the significance of dorsal and ventral visual streams?
Dorsal and ventral are separate but interacting visual streams
Dorsal stream - vision for action “where” (subconscious)–> splits from ventral stream as early as V2 –> tap into stream by approaching object to interact
-lesions here: spatial disorders (e.g. akinetopsia, hemispatial neglect)
Ventral stream - vision for identification “what” (conscious)–> form a percept where all features (V1-V5) are integrated –> compare the percept to your archives
- lesions here: visual object agnosia –> see objects fully formed but cannot recognize them unless interacting with object
- unlike aperceptive agnosia (V2/V3 damage) - where objects are not fully formed*
- ID the site and function of autonomic receptors in the eye
- What are the effects of atropine and other antimuscarinic agents on the eye?
- Autonomic receptors lie on muscles that control the:
- dilator pupillae - alpha adrenergic receptors [sympathetic] –> increase pupil size
- sphincter pupillae - muscarinic cholinergic receptors [parasympathetic]–> decrease pupil size
- ciliary muscle - muscarinic receptors [parasympathetic]–> accommodation to near object, tension on trabeculae to facilitate aqueous humor outflow
- ciliary epithelium - beta adrenergic receptors [sympathetic]–> produces aqueous humor - Antimuscarinic agents block muscarinic receptors e.g. atropine (7-10 days), tropicamide (1/4 day)- induce mydriasis for optho exam, block accommodation
however, antimuscarinic excess –> dry as a bone, blind as a bat, mad as a hatter, hot as hell, red as a beet, and full as a flask
*alpha adrenergic agonist phenylephrine used to facilitate mydriases as well
CN III
I. Which part of the brainstem does it travel through?
II. What are its functions and motor/sensory nuclei?
III. What happens with lesion?
CN III - Oculomotor
I. exits through interpeduncular fossa ventrally at rostral midbrain; between PCA and SCA
II. Motor components:
A. GSE - motor to 4 extraocular muscles (MR, IO, SR, IR) and 1 eyelid muscle (levator palpebrae superioris)
B. GVE - preganglionic parasympathetic fibers to pupillary constrictor and lens ciliary muscle; come from Edinger-Westphal nucleus
III. Lesion - ipsilateral eye droops and moves down and out, “blown” or dilated pupil with loss of constriction and accommodation; diplopia
CN III susceptible to compression from aneurysms or ICP, GVE on outside so pupil changes are first symptoms
What is an uncal herniation?
What are the clinical signs of uncal herniation?
Uncus = on the parahippocampal gyrus of the medial temporal lobe, can herniate through tentorium cerebelli due to epidural hematoma, mass, hydrocephalus
Uncal herniation - type of transtentorial herniation:
- Ipsilateral CN III - Ipsilateral “blown” pupil (PNS fibers affected first), then down and out gaze
- Ipsilateral PCA (Posterior Cerebral artery) - Contralateral homonymous hemianopia with macular sparing
- Contralateral crus cerebri at the Kernohan notch (anterior portion of cerebral peduncles) - ipsilateral hemiparesis
If reticular formation in brainstem is compressed –> coma
Transtentorial herniation–> caudal displacement of brainstem –> rupture of paramedian branches of basilar arteries (midbrain) duret hemorrhages –> Death
CN IV
I. Which part of the brainstem does it travel through?
II. What are its functions and motor/sensory nuclei?
III. What happens with lesion?
CN IV - Trochlear
I. in caudal midbrain, decussates to contralateral side and exits on dorsal side
II. GSE - innervates superior oblique eye muscle –> depression in adducted position, abduction, intorsion (inward rotation)
III. CN IV palsy - due to lesion of right trochlear nerve or, less likely, nucleus –> extorsion (outward rotation) with hypertropia (one eye is on higher visual axis) –> patient tilts head to prevent diplopia
CN VI
I. Which part of the brainstem does it travel through?
II. What are its functions and motor/sensory nuclei?
III. What happens with lesion?
CN VI - Abducens
I. Nucleus is in pons surrounded by facial axons (below facial colliculus), exits in midline ponto-medullary junction ventrally
II. GSE - Innervates lateral rectus eye muscle –> abduction
III. CN VI lesion –> esotropia (eye sitting inwards), eye cannot move past midline
Can occur with increased ICP –> brainstem pushed downwards and VI is stretched
main central connection of II, IV, and VI is the medial longitudinal fasciculus (MLF) i.e. ascending medial vestibulospinal tract (descending for head movements)
Describe the 6 systems to control eye movements to place an image on the fovea
- Active fixation
- Saccadic system
- SPEM
- Vergence
- Vestibulo-ocular reflexes
- Optokinetic
- Active fixation - works best if eyes are still, those with nystagmus have poor vision
- Saccadic system - extremely fast movements to point eye to an object
- SPEM - smooth pursuit eye movement for following moving objects, convergence; requires moving object works with saccades when target moves
- Vergence - for targets at different depths, mediated by MR and LR muscles; vergence center in midbrain and thus convergence preserved with MLF lesion (–> INO)
- Vestibulo-ocular reflexes - hold images still on retina during head movements; elicited by vestibular inputs
- Optokinetic - hold images still on retina during translation/rotation; elicited by visual field movements e.g. watching trees go by when on the train
Describe horizontal gaze center of brainstem
PPRF = Paramedian pontine reticular formation in pons; produces excitatory burst to CN VI nucleus:
- CN VI LMNs –> lateral rectus
- interneurons in medial longitudinal fasciculus MLF –> contralateral CN III –> contralateral medial rectus
- see pictures for 6 possible lesions
Describe vertical gaze center of brainstem
What is Parinaud’s Syndrome
Diffuse areas cerebral cortex –> rostral interstitial nucleus of Cajal (midbrain vertical gaze center):
- CN III and IV
- posterior commissure –> CN III and IV for upwards gaze
Parinaud’s syndrome - -increased pressure on dorsal, rostral midbrain due to tumors, herniations, hydrocephalus:
- paralysis of upward gaze
- hydrocephalus (cerebral aqueduct), headaches (ICP) nystagmus (MLF - which extends to nucleus of cajal)
- large irregular pupils (because Edinger-Westphal fibers also go through posterior commissure)
- Describe pathways for vestibulo-ocular reflexes
- Conditions that affect VOR and symptoms
- Doll’s eye maneuver with coma patient
- Vestibulo-ocular reflexes (VOR) - gaze stabilization
detects brief head movements via vestibular system and generates eye movements in opposite direction
For example, if head turns left:
L vestibular inputs through VIII –> synapse on L medial vestibular nucleus –> stimulates R abducens nucleus and inhibits L –> R lateral rectus and L medial rectus (through MLF)–> Eyes turn right
- Conditions - injury to vestibular system (peripheral or central), cerebellar deficits, anxiety disorders, vestibular cortex lesions in parietal lobe prevent VOR suppression
- Symptoms - inability to read while walking or driving, oscillopsia (feeling that environment is moving) - Doll’s eye = oculocephalic reflex to test integrity of brainstem
- Vestibular input causes eyes to move in opposite direction of head turn if someone is in coma
- impaired doll’s eye reflex –> brainstem dysfunction
Describe cortical control of gaze. Types of lesions and their effects on eye movements: 1. Cortical lesion 2. Superior colliculus lesion 3. Brainstem lesion
Frontal eye field = Brodman Area 8; used for voluntary movements to the contralateral side
Projects through superior colliculus in midbrain to the contralateral PPRF (horizontal gaze center) in the pons
Lesions:
- FEF (cortical) lesion - transient loss of horizontal gaze to contralateral side
- -> eyes point towards the lesion e.g. eyes point L if there is a stroke in L cortex (would cause R paralysis) - Superior colliculus lesion - transient loss in accuracy, frequency of saccades; permanent loss of reflexive saccades
- PPRF (brainstem) lesion - longer lasting deficit in horizontal gaze to the ipsilateral side
- -> eyes point away from lesion e.g. eyes point R if there is a stroke in L pons (would cause R paralysis) *bc corticospinal fibers decussate in medulla
What are the components of the near response triad?
Near response to moving eye to see a near object:
- Convergence (controlled by neurons in midbrain near oculomotor nerve)
- Accommodation (increased curvature of the lens)
- Constriction (increase depth of field)
Describe the types of gliomas including key characteristics and histology: 1. Astrocytoma A. Pilocytic astrocytoma B. Diffuse astrocytoma C. Glioblastoma *role of MGMT
- Astrocytoma - tumor arising from astrocytes (BBB, physical support, removes neurotransmitter, reactive gliosis; GFAP marker positive)
A. Pilocytic astrocytoma - Grade I (potentially curable with surgery), usually suprasellar or cerebellar
- most common CNS tumor in children
- Classic MRI = cyst with mural nodule
- histology: elongated cells with hairlike processes, tumor makes eosinophilic Rosenthal fibers
B. Diffuse astrocytoma - Grades II, III, or IV; infiltrate normal brain
- histology: irregular, elongated, crowded darkly-stained nuclei; fibrillary background
C. Glioblastoma - Grade IV astrocytoma; Glioblastoma multiforme (GBM) is most common malignant CNS tumor in adults
- histology: microvascular endothelial cell proliferation, palisading necrosis
- frequent amplification of receptor tyrosine kinases
- classic gross autopsy “butterfly lesion”
- classic ring-enhancing lesion on MRI
- patients with methylated MGMT promoter do better bc MGMT is not transcribed (MGMT can remove chemo drug from tumor DNA)
Describe the types of gliomas including key characteristics and histology:
- Oligodendroglioma
- Ependymoma
- Oligodendroglioma - tumor of oligodendrocytes
- Grade II or III (III called anaplastic), usually cerebral hemisphers and often hemorrhagic
- genetics - co-deletion of 1p and 19q
- histology: “fried egg” nuclei (artifact of fixation), chickenwire vasculature, heavily calcified - Ependymoma - tumor of ependymal cells (epithelial lining of ventricular system of CNS)
- Grade II or III
- most commonly in 4th ventricle (in kids, aggressive) or spinal cord (in adults, treatable)
- histology: perivascular pseudorosettes (tumor cells surrounding blood vessels)
Describe the following including key characteristics and histology:
- Pituitary adenoma
- Craniopharyngioma
- Pituitary adenoma - low grade neuroendocrine tumor
- most common doesnt produce hormone (null cell)
- most common hormone-producing type os prolactinoma
- symptoms: bitemporal hemianopsia (lose peripheral vision bc tumor squishes optic chiasm), prolactinomia (amenorrhea, galactorrhea) - Craniopharyngioma - tumor of very young kids, from rathke pouch –> supratentorial mass –> bitemporal hemianopsia
- histology: squamous epithelium, wet keratin, cholesterol clefts w/out tumor in them
Tumor predisposition syndromes with CNS manifestations:
- NF1
- NF2
Tumor predisposition syndromes - mutant gene (either inherited or de novo)
- NF1- Neurofibromatosis Type 1
- lose neurofibromin, which normally negatively regulates Ras
- bodies covered with neurofibromas, cafe au lait spots; nerve sheath tumor is usually cause of death - NF2 - Neurofibromatosis Type 2
- lose merlin, which normally negatively regulates pro-proliferation signal with actin cytoskeleton
- hallmark bilateral vestibular schwannoma
- tumors surgically treatable but there are so many / recurrent –> not good prognosis
Tumor predisposition syndromes with CNS manifestations:
- Schwannoma
- Meningioma
- Schwannoma - tumor of Schwann cells
- Grade I
- bi-allelic inactivation of NF2 –> bilateral vestibular schwannoma (tinnitus, deafness)
- histology: spindle-shaped cells with rod-like nuclei, hyper (Antoni A) and hypo (Antoni B) cellular areas, and Verocay bodies (nuclei lined up) - Meningioma - dural-based tumor of meningothelial arachnoid cells
- Grade I-III
- 50% have NF2 mutation; more common in adult females
- Classic MRI sign = dural tail –> does NOT invade the cortex
- histology: whorls and psammomatous calcifications (layering of calcium)
Tumor predisposition syndromes with CNS manifestations:
- Tuberous sclerosis complex (TSC)
- Von Hippel Landau (VHL)
- TSC - multiple benign tumors grow in multiple systems
- SEGA - subependymal giant cell astrocytoma - see tumors jutting out into the ventricles (most commonly lateral)
- inactivation mutation in TSC1 or TSC2 - normally negatively regulate mTOR - Von Hippel Landau (VHL)
- associated with hemangioblastoma (Grade I) - blood vessel tumors in cerebellum
- histology: foamy stromal cells and dense capillary network
- also get retinal angiomas, renal cell carcinoma
- inactivation mutation in VHL - normally negatively regulates HIF –> too much angiogenesis
Tumor predisposition syndromes with CNS manifestations:
- Medulloblastoma
- Metastasis
- Medulloblastoma - malignant tumor of primitive neurons (from neuroectoderm) that affects young children
- Grade IV - poor prognosis and spreads via CSF
- only arises in cerebellum
- synpatophysin positive (normal neurons don’t normally make this)
- form true rosettes (wrap around neuritic processes, not bv like the pseudorosettes from ependymoma) - Metastasis - most common reason for neoplastic lesion / tumor in CNS
- most common primary cancers - lung
- most likely to go to brain - melanoma, breast, renal
- most likely to go to grey-white junctions
- well circumscribed, usually several of them
Describe the vascular supply of the medulla
Contrast to vascular supply of pons
- Medulla
- Anterior spinal artery –> midline (pyramids, medial lemniscus, hypoglossal nucleus)
- Vertebral artery –> medial olivary nucleus
- PICA –> lateral (anterolateral system, nucleus solitarius, ambiguus, vestibular nuclei) - Pons
- Basilar artery –> median parts of pons –> corticospinal tract, pontine nuclei, abducens nuclei, facial nerve fascicles, MLF, PPRF, medial lemniscus
- AICA –> lateral pons –> motor V, spinal V, auditory nerve, vestibular nuclei, middle cerebellar peduncle, VII nucleus/nerve,
Describe lateral medullary syndrome including lesion and associated symptoms
Lateral medullary syndrome = Wallenberg’s, due to infarct of PICA
Symptom (lesion):
1. contralateral loss of pain and temp on body (spinothalamic anterolateral tract)
2. ipsilateral loss of pain and temperature on face (spinal nucleus of V)
3. nystagmus, vertigo, ataxia (vestibular nuclei)
4. ipsilateral ataxia, nystagmus (inferior cerebellar peduncle)
5. ipsilateral Horner’s (descending autonomics)
- ipsilateral decreased taste (bc of n. solitarius)
- hoarseness and dysphagia (trouble swallowing), contralateral uvula deviation (n. ambiguus)
Describe medial medullary syndrome including lesion and associated symptoms
Medial medullary syndrome = Dejerine, due to infarct of ASA (anterior spinal)
Symptom (lesion):
- contralateral loss of position and vibration sense (bc medial lemniscus is composed of internal arcuate fibers post decussation of DCMLS)
- contralateral hemiparesis/hemiplegia (bc fibers of lateral CST decussate after pyramids)
- ipsilateral tongue weakness/same side tongue deviation (LMN lesion of hypoglossal nerve)
* pain and temperature spared (bc STT is on lateral side)
Describe lateral pontine syndrome including lesion and associated symptoms
Lateral pontine syndrome, due to AICA infarct
Symptom (lesion): vary depending on level
- contralateral loss of p/t on body (STT)
- ipsilateral loss of p/t on face (spinal tract of CN V)
- vertigo, nystagmus, ataxia (vestibular nuclei/nerve)
- ipsilateral ataxia, nystagmus (middle cerebellar peduncle)
- ipsilateral Horner’s (descending autonomics)
- ipsilateral deafness, tinnitus (auditory nerve)
- ipsilateral facial weakness (facial nucleus/nerve)
- jaw weakness, dysarthria (motor nucleus V)
Describe medial pontine syndrome including lesion and associated symptoms
Medial pontine syndrome, due to infarct of paramedian branches of basilar artery
Symptom (lesion)
- contralateral loss of touch, vibration, position (DCMLS)
- contralateral hemiparesis of face AND body (but not forehead, since its UMN); dysarthria/ trouble speaking bc of UMN effects on IX, X (CST, corticobulbar)
- contralateral ataxia (pontine nuclei and pontocerebellar fibers)
- ipsilateral facial weakness (facial nerve fascicles)
- ipsilateral horizontal gaze palsy, diplopia (PPRF, abducens nucleus/nerve)
- Internuclear Ophthalmoplegia INO (MLF) - conjugate horizontal gaze palsy with normal convergence
Describe types of midbrain syndrome and including lesion and associated symptoms:
- Midbrain base (Weber’s)
- Red nucleus (Claude’s)
- Midbrain syndrome (Benedikt)
- Midbrain base (Weber’s) - infarct of paramedian branches at top of basilar artery
Symptom (lesion):
- contralateral hemiparesis (UMN syndrome) of body and face (CST, corticobulbar)
- ipsilateral CN III palsy (oculomotor nerve and fascicles) - mydriasis, eyes down and out - Red nucleus (Claude’s) - infarct of proximal PCA
- contralateral tremor and ataxia (Red nucleus)
- contralateral loss of position vibration (DCMLS) - Weber + Claude = Benedikt syndrome
- all symptoms combined
Where is the cerebellum located?
What are the main subdivisions of the cerebellum and their functions and deep cerebellar nuclei ?
What is the somatotopy
Cerebellum located in posterior fossa, covered by tentorium cerebelli , and is the roof of the fourth ventricle (the floor being pons and medulla)
Functions - motor planning (feedforward), execution (feedback), and learning (adjustments)
Subdivisions:
- Cerebrocerebellum (dorsal lateral) –> lateral hemisphere –> planning, cognition execution of skilled and complex spatio-temporal sequences e.g. speech
- dentate nucleus
- superior cerebellar peduncle connects to midbrain - Spinocerebellum (dorsal medial) –> midline vermis + intermediate hemisphere –> gross limb movement e.g. touching nose; vermis in particular is eye movements, proximal muscles
- intermediate hemisphere –> emboliform + globusus nuclei (= interposed nuclei)
- vermis –> fastigial nucleus - Vestibulocerebellum (ventral) –> flocculonodular lobe –> posture, equilibrium affected by alcohol
- Vestibular nuclei
- fastigial nucleus
Deep cerebellar nuclei: “Don’t Eat Greasy Food” (lateral to medial)
Somatotopy = midline/vermis represents midline structures (eyes) whereas intermediate hemisphere is the limbs
Role of red nucleus and tectum in conveying cerebellar output pathways
Both contain pathways from the midbrain
- Red nuclei are within midbrain tegmentum (ventral part of midbrain)
A. caudal magnocellular red nucleus is origin of rubrospinal tract –> voluntary contralateral upper arm flexor muscles
-lateral motor system that runs with the lateral CST
-ventral tegmental decussation in midbrain
B. rostral parvocellular red nucleus is origin of central tegmental tract to inferior olivary nucleus, which feeds back to cerebellum
-Guillan Mollaret triangle - Superior and inferior colliculi are within the tectum (“roof,” dorsal part of midbrain) –> tectospinal tract (coordinates head and eye movements)
- Fastigial nucleus in vermis –> superior colliculus –> immediately decussates –> tectospinal tract
*inferior colliculus has to do with hearing
Describe and identify the cerebellar peduncles and the types of inputs and outputs for each of its functions:
Superior Cerebellar Peduncle
1. Output - Motor learning, cognition, planning
2. Output - Motor coordination
Information leaves cerebellum via peduncles, each associated with one part of the brainstem –> Superior cerebellar peduncle SCP = midbrain
SCP decussates at roof of 4th ventricle (level of inferior colliculus)
- Motor learning, cognition, planning
Dentate nucleus (lateral hemisphere) –> crossed outputs via superior cerebellar peduncle to contralateral:
A. VL ventral lateral nucleus (thalamus) –> motor cortex
B. Parvocellular red nucleus (midbrain) –> central tegmental tract –> inferior olivary nucleus (medulla) –> inferior cerebellar peduncle –> crosses back to cerebellum/dentate nucleus where info is stored this is called Guillan-Mollaret triangle - Motor coordination
Interposed nuclei (intermediate hemisphere) –> crossed outputs via superior cerebellar peduncle to contralateral:
A. VL nucleus (thalamus) –> motor cortex –> pyramidal decussation –> lateral corticospinal tract
B. Magnocellular red nucleus (midbrain) –> ventral tegmental decussation –> rubrospinal tract, runs next to lateral CST and corrects movement
Describe and identify the cerebellar peduncles and the types of inputs and outputs for each of its functions:
Middle Cerebellar Peduncle
1. Inputs from cortex
Middle cerebellar peduncle MCP = pons (on dorsal aspect); afferents ONLY
- largest input to cerebellum from cerebral cortex (frontal and parietal) –> corticopontine axons travel through cerebral peduncles in midbrain –> pontine nuclei –> cross to contralateral side as pontocerebellar fibers –> coalesce to form middle cerebellar peduncle –> cerebellar cortex/deep nuclei
deep nuclei - e.g. dentate, interposed - send info back up to cortex via SCP/VL –> one big loop!
Describe and identify the cerebellar peduncles and the types of inputs and outputs for each of its functions:
Inferior Cerebellar Peduncle
1. Dorsal spinocerebellar tract
2. Cuneocerebellar tract
Inferior cerebellar peduncle ICP = medulla
*No decussation - these pathways are ipsilateral
- DRG have inputs from leg/lower body proprioceptors –> gracile fasciculus –> synapse on nucleus dorsalis of Clark (C8-L3)–> 2nd order neurons ascend via dorsal spinocerebellar tract –> inferior cerebellar peduncle –> cerebellar cortex/deep nuclei
- DRG have inputs from arm/upper body proprioceptors –> cuneate fasciculus –> synapse on external cuneate nucleus –> 2nd order neurons ascend via cuneocerebellar tract –> inferior cerebellar peduncle –> cerebellar cortex/deep nuclei
- Afferents - climbing fibers from olivocerebellar tract from contralateral inferior olivary complex
- Efferents from flocculonodular lobe and fastigial nucleus - to vestibular nuclei
I. Describe the general cellular characteristics of the molecular, Purkinje cell and granular layers of the cerebellar cortex
II. Differentiate between climbing and mossy fibers in stimulating Purkinje cells
III. Describe how overall cerebellar output is excitatory if Purkinje cells are GABA inhibitory
I. Cortex of cerebellum is folded into folia and can be divided into 3 layers:
- Outer - molecular layer –> contains stellate and basket cells
- Middle - Purkinje cell layer –> contains purkinje cells that integrate sensory inputs with motor outputs only output of cerebellar cortex
- Inner - granular layer –> contains granule and golgi cells
IIA. Climbing fibers arise from contralateral inferior olivary nucleus in medulla –> innervates one Purkinje cell but makes multiple connections on it
B. Mossy fibers are pontocerebellar fibers that arise from contralateral pontine nucleus –> synapse with many granule cells (T-shaped axons) –> each granule cell innervates multiple Purkinje cells via glutamate
III. Deep cerebellar nuclei are inhibited by the Purkinje cell output BUT stimulated directly by the mossy and climbing fiber axons –> net output is excitatory
Describe vascular supply of cerebellum
Anterior lobe - above primary fissure, perfused by superior cerebellar artery SCA
Cerebellar peduncles (all 3) - perfused by AICA
Flocculonodular lobe - perfused by both AICA and PICA
- Common signs of cerebellar disease
2. Common causes of cerebellar disease
- Common signs of cerebellar disease lesions produce ipsilateral symptoms
- hallmark = ataxia –> disturbance of voluntary movement esp truncal, appendicular but also speech, eye movements
- hypotonia
- disturbance of reflexes
- nystagmus –> fast phase pointing to side of lesion
- dysarthria –> difficulty talking
- dysdiadochokinesis - inability to perform rapid alternating movements
- gait disturbance –> wide stance, staggering quality, fall towards side of illness - Common causes of cerebellar disease
- congenital agenesis/hypoplasia
- neoplasms
- trauma
- infections
- thrombosis of cerebellar arteries
- degenerative disorders
Describe the following cerebellar syndromes incl symptoms and causes:
- Anterior lobe syndrome
- Posterior lobe syndrome
- Flocculonodular lobe syndrome
- Anterior lobe syndrome - general ataxia, esp of legs incl staggering “drunken” gait; memory impairment, confusion
- also nystagmus/oculomotor disorders (Eyes represented on the somatotopy)
- due to toxins, B1 deficiency (Wernicke-Korsakoff) - Posterior lobe syndrome - more severe hypotonia –> Cerebellar ataxia with postural instability that manifests as rebound phenomenon (patients arm can hit them in face when released)
- dysdiadochokinesis (inability to perform rapid alternating movements)
- due to cerebellar agenesis, dysplasia, cerebellar stroke or tumor, trauma - Flocculonodular lobe syndrome - most commonly pediatric
- truncal ataxia with poor balance and titubation (trunk tremor upon standing still)
- walk with wide base gait
- nystagmus
- due to medulloblastoma, pilocytic astrocytoma
Describe symptoms of the following cerebellar injuries:
- Superior cerebellar peduncle
- Middle cerebellar peduncle
- Inferior cerebellar peduncle
- Fastigial nucleus
- Dentate nucleus
- Superior cerebellar peduncle - cerebellar ataxia with falling to side of injury; cerebellar tremor
- Middle cerebellar peduncle - cerebellar ataxia (but not falling), hypotonicity of limbs and facial muscles
- Inferior cerebellar peduncle - cerebellar ataxia, falling to side of injury, hypotonicity, marked cerebellar tremor
- Fastigial nucleus - cerebellar nystagmus
- Dentate nucleus - unilateral cerebellar tremor and ataxia of the limb
Describe the components of consciousness: 1. Content 2. Level A. Alertness B. Attention C. Awareness
- Content - contribution by all other systems e.g. sensory, motor, limbic (emotional), and others (visual)
- Level
A. Alertness - arousal due to neurotransmitters (HANDS - histamine, acetylcholine, norepi, dopamine, serotonin)
B. Attention - choosing what information to further process –> both sustained (i.e. concentration) and selective (ignoring background noise)
*same systems involved in arousal and awareness
- increased activation of areas processing the info
- right hemisphere is more important
C. Awareness - ability to combine different info into efficient summary that can be remembered later
- most poorly understood
Describe the abnormal posturing in the following lesions:
- Metabolic encephalopathy
- Upper midbrain
- Upper pontine
- Metabolic encephalopathy - brainsterm preserved, lesion in cerebral cortex –> patient responds to painful stimuli or brush you off even though unconscious, Babinski reflex
- Upper midbrain - decorticate –> flexed upper limbs bc rubrospinal (Red nucleus) preserved, extended lower limbs
- most common in gunshot wounds - Upper pontine - decerebrate –> both upper and lower limbs extended bc lesion is below red nucleus
- most common in motorcycle accidents
- can have changes in posturing if lesion progresses
Define coma and possible lesions and causes
Describe neurologic exam of coma patient
Coma - unarousable unresponsiveness in which patient lies with eyes closed; minimum 1 hr but not permanent (patient either deteriorates into brain death or recovers within 2-4 weeks)
Can be caused by dysfunction of:
1. Ascending Reticular Activating System (ARAS)
2. Bilateral cerebral cortex
3. Bilateral thalamus (medial)
Neurologic exam:
- Locomotion
- Cardiorespiratory - breathing
- forebrain (brainstem spared) - Cheyne-stokes respiration with waxing/waning depth and apnea
- upper brainstem - hyperventilation
- medulla - respiratory arrest - Eyes - Pupils
- pontine lesion - small pupils bilaterally response to light
- midbrain lesion - blown pupil
- opiate overdose - pinpoint pupils bilaterally
- brain death - large, fixed pupils unresponsive to light - Brainstem reflexes e.g. Vestibulo-ocular
- Doll’s eye movement
- caloric test - brainstem intact = eyes move towards cold water side - Motor/sensory responses
Define:
- Brain death
2. Vegetative state
- Brain death - irreversible form of coma
- no evidence of forebrain or brainstem function
- no brainstem reflexes, but may be spinal cord reflexes e.g. Lazarus reflex - where you turn their head and they put up their arms
- no EEG activity
- NO cerebral perfusion nor metabolism
Exams: caloric test, apnea test; if they have posturing reflexes –> NOT brain death - Vegetative state - follows coma where patient regains sleep-wake cycle and other reflexes but remains unconscious
- sometimes open eyes and arouse (NOT coma)
- may turn towards stimuli
- may produce sounds / move limbs (NOT meaningful)
- low level of metabolism - patient is still alive
- persistent state > 1 month
Define:
- Minimally conscious state
4. Locked-in Syndrome
- Minimally conscious state - visual tracking - early sign of recovery from vegetative state
- minimal responsiveness eg says words, holds objects but no reliable communication or functional use of those objects - Locked-in Syndrome - consciousness is preserved but all voluntary muscles except eyes are paralyzed
- due to lesion in ventral brainstem motor pathways at pons or below OR peripheral neuromuscular blockade
- most common is basilar artery infarct but also TBI, hemorrhage
- no treatment or cure
What are the brain regions involved in the consciousness system?
What are the outputs?
- Cortical
A. Medial and lateral frontoparietal association cortex
B. Cingulate gyrus
2. Subcortical (THUB): A. Thalamus B. Hypothalamus C. Upper brainstem D. Basal forebrain (n. accumbens, diagonal band of Broca, medial septal nuclei, nucleus basalis of Meynert --> Acetylcholine)
Outputs dependent on normal functioning of cortex AND its arousal by brainstem and diencephalon
What is the reticular formation and its function
Reticular formation
- clustered neurons in diffuse white matter nerve pathways that are arranged through central core of all 3 brainstem segments - connect spinal cord, cerebrum, cerebellum
- sensory information goes into reticular formation –> it focuses us on the stimulus
All of its functions: influences everything
- maintains consciousness [ROSTRAL]
- control of skeletal muscle via reticulospinal, reticulobulbar tracts [CAUDAL]
- control of somatic and visceral sensations [CAUDAL]
- control of ANS
- control of endocrine nervous system
- influence on biological clocks (hypothalamus)
- activates cortex - influences all three levels of consciousness –> Alertness, attention, awareness
- damage leads to coma or death
What is the pontomesencephalic reticular formation and its function and inputs
Pontomesencephalic (i.e. rostral) reticular formation = consciousness system, part of the reticular formation that sends continuous stream of impulses –> diffuse/ widespread projection systems
- rostral part involved in consciousness
- caudal part of reticular formation more involved with controlling muscles, pain perception (focused on spinal cord) –> premotor coordnation of lower somatic and visiceral motor neuron pools
- innervates thalamic intralaminar nucleus, basal forebrain, hypothalamus, and directly into cortex
- part of ARAS (Ascending Reticular Activating System)
Inputs:
- mental activation e.g. learning (fronto-parietal association cortex)
- emotional activation e.g. anger (limbic and cingulate cortex)
- sensory inputs e.g pain (visual, auditory, olfactory, somatosensory)
Which neurotransmitters are associated with which diffuse systems - origins + projection sites
Pontomesencephalic reticular formation has diffuse projection system –> innervates many structures
Monoamine nuerotransmitters of diffuse projections: H- histamine A- acetylcholine N- norepi D- dopamine S- serotonin
affect on one neurotransmitter doesn’t lead to coma, but rather altered state of reality
For each neurotransmitter, describe function, origins, and projections: Acetylcholine
Acetylcholine: Neuromodulation –> arousal
Originates in:
1. Basal forebrain:
A. Nucleus basalis of Meynert –> projects to entire cerebral cortex –> cortex/limbic system (emotional state and cortical responsiveness)
B. Medial septal nuclei and nucleus of diagonal band of Broca –> projects to hippocampus (memory)
2. Tegmental nuclei (junction of midbrain and pons)–> project to thalamus + others further down
For each neurotransmitter, describe function, origins, and projections: Dopamine
Dopamine: Neuromodulation
Originates in midbrain:
- Nigrostriatal pathway: substantia nigra –> projects to dorsal striatum (putamen + caudate) i.e. motor basal ganglia–> control of movement
- Mesolimbic pathway: ventral tegmental area –> projects to limbic structures - nucleus accumbens i.e. emotion basal ganglia –> reward, emotional response
- Mesocortical pathway: ventral tegmental area –> projects to prefrontal cortex (dorsolateral PFC) –> working memory
- Tuberoinfundibular pathway: arcuate nucleus (tuberal region of hypothalamus) –> projects to pituitary gland –> regulates secretion of prolactin from anterior pituitary
For each neurotransmitter, describe function, origins, and projections: Norepinephrine
Norepinephrine / Noradrenaline: Neuromodulation
Originates in:
- locus ceruleus (rostral pons) –> go to virtually every brain and spinal cord region
- highest when awake + new sensory stimulus (especially scary/noxious) –> associated with panic disorders/PTSD - lateral tegmental area (only in pons + medulla) –> projects more towards spinal cord region
For each neurotransmitter, describe function, origins, and projections: Serotonin
Serotonin: Attention, arousal, mood regulation, feeding
Originates in all levels of the brainstem, top producers are in midbrain:
- Dorsal raphe nucleus
- Medial raphe nucleus
- project virtually everywhere, from cortex to spinal cord
- rostral more associated with psychiatric disorders (depression, anxiety, OCD)
- caudal associated with pain modulation, breathing, temperature, motor control
For each neurotransmitter, describe function, origins, and projections: Histamine
Histamine: Neuromodulation both excitatory and inhibitory
Originates in posterior hypothalamus: tuberomammilary nucleus –> projections to forebrain (cortex, thalamus)
- associated with cognitive deficits and insomnia
Describe hemineglect syndrome
Right hemisphere more important for attention- monitors both hemifields, while L hemisphere monitors just R
Lesion to L hemisphere - no deficits because R is still monitoring R nad L
Lesions to R hemisphere –> L is still monitoring R, but no monitoring of L side –> neglect whole left side
- most severe –> claims half of the body is not their own
- test by asking them to draw an object e.g. clock and left side is missing, but can copy perfectly
In addition, Right hemisphere more relevant for processing emotional and facial information
Basal Ganglia
- Anatomy
- Pathways
- Functions
- Dysfunctions
Basal ganglia - group of subcortical nuclei:
- striatum - dorsal (caudate + putamen) and ventral (nucleus accumbens + olfactory tubercle)
- globus pallidus
- ventral pallidum
- susbtantia nigra
- subthalamic nucleus
4 parallel pathways:
- Motor - movement
- Oculomotor - eye movement
- Prefrontal - cognition
- Limbic - emotions, addiction
Functions: regulates frontal lobe, motor, + limbic functions –> initiates, sequences, and automates movement and habits NOT sensory
Dysfunction: movement disorders (PD, Huntington’s), addictions, OCD, tics (Tourette’s), schizophrenia
- Describe basal ganglia motor loop
2. Describe the inputs and outputs of the basal ganglia and the excitatory and inhibitory connections
- Motor loop: Frontal cortex (Premotor + primary motor) –> caudate and putamen (dorsal striatum) –> thalamus (VA + VL nuclei) –> feedbacks to the cortex
- VA/VL nuclei in thalamus excite motor cortex via glutamate
- GPi (globus pallidus internus) inhibits VA/VL via GABA –> tonic inhibition at rest
- GPi in turn can be excited (subthalamic nucleus) –> overall inhibition of cortex/movement
or inhibited (by dorsal striatum) –> overall disinhibition/excitation of cortex and movement
Explain the direct and indirect motor pathways, including the influence of disinhibition
Describe the role of the substantia nigra pars compacta and dopamine on the direct and
indirect pathways
- Direct pathway: facilitates movement through disinhibition
Frontal cortex excite dorsal striatum –> striatum inhibits GPi (globus pallidus internus) –> GPi is not able to inhibit thalamus –> VA/VL nuclei excite motor cortex –> corticospinal tract –> LMN –> movement - Indirect pathway: inhibits movement
Frontal cortex excites dorsal striatum –> striatum inhibits GPe (globus pallidus externus) –> now GPe can no longer inhibit subthalamic nucleus (STN) –> STN excites GPi –> GPi inhibits VA/VL –> no cortical excitement for movement - Substantia nigra pars compacta makes dopamine –> nigrostriatal pathway –> dopamine receptors on medium spiny neurons
A. D1 receptor binding –> activates striatum –> facilitates direct pathway –> facilitates movement
B. D2 receptor binding –>inhibits striatum –> inhibits indirect pathway –> facilitates movement
Positive and negative motor symptoms caused by basal ganglia disorders
- Positive symptoms (hyperkinetic) - occur at rest, ranked slowest –> fastest:
- dystonia - slow, twisting postures
- athetosis - slow, writhing movements in hands and fingers [cerebral palsy]
- chorea = continuous rapid movements of face, limbs [Huntington’s]
- hemiballismus - spontaneous, involuntary movements [lacunar infarcts in subthalamic nucleus]
- tics [Tourette’s]
- tremor [unilateral - Parkinson’s; essential - cerebellar]
* tardive dyskinesia [hyperkinetic smooth tics due to using dopamine antagonist meds] - Negative symptoms [Parkinson’s]
- akinesia - no initiation/freezing of gait
- bradykinesia - slow movement
- hypokinesia - too little movement
- decreased postural adjustment
- “lead pipe” rigidity - with interrupted “cog wheel” movement
Parkinson’s Disease:
- Pathology
- Cardinal signs to diagnose
- Other signs
- Pathological features
- Treatment
Parkinson’s
- Pathology - progressive neurodegenerative –> cell death in substantia nigra –> decreased dopaminergic terminals in dorsal striatum
- increased risk - genetics, age, environment (pesticides), oxidative stress (MPTP)
- decreased risk - coffee and cigarettes - Cardinal symptoms - begin unilaterally
A. bradykinesa - slowed movement
B. resting tremor - pill-rolling
C. rigidity - lead pipe, with cog-wheeling
D. postural instability –> later symptom - Other symptoms:
- hypomimia (lack of facial expression)
- festinating (shuffling then speeding up)
- loss of automaticity
- non-motor: personality changes, paresthesias, dementia - Pathological features:
- neurons in substantia nigra contain Lewy bodies (aggregations of alpha-synuclein proteins ) - Treatment:
- pharmaceuticals
- surgical lesions (thalamus or globus pallidus)
- deep brain stimulation (globus pallidus internus, subthalamic nucleus) –> normalize output and block action potentials, but increased rate of post-op events
- How is Parkinson’s diagnosed?
- Difference between PD and Parkinsonism Plus diseases
- Progressive supranuclear palsy
- Huntington’s
- Diagnosis: clinical diagnose (80% accurate)
- bradykinesia + one other symptom (Resting tremor, or cog wheel rigidity, postural instability)
- rule out other causes e.g. strokes, TBI, encephalitis
- supportive evidence - e.g. dopamine response - Parkinsonism Plus: same 4 major symptoms BUT
A. Lack of resting tremor
B. symmetrical symptoms
C. early postural instability
D. lack of response to dopamine
*Parkinson’s disease most common form of Parkinsonism - Supranuclear palsy - most common form of atypical Parkinsonism
- affects multiple regions of rostral midbrain (looks like mickey mouse ears on MRI)
- symptoms 50+ and progress more rapidly than PD –> trunk rigidity, swallowing changes, decreased vertical eye movement, dementia - Huntington’s - also progressive and neurodegenerative
- due to cell loss in caudate nucleus, then putamen + cortex
- chorea and dementia
- Define tic disorders
2. Provide examples of the different types of tics: A. Simple motor B. Complex motor C. Simple vocal D. Complex vocal
- Tic disorders - rapid, recurrent, non-rhythmic movement or vocalization, often involuntary or response to irresistible urge; onset before 18 yo
2A. Simple motor - eye blinks, grimacing, jaw snaps
B. Complex motor - slower, orchestrated
- echopraxia - imitating others movements
- copraxia - obscene gestures
- self-injurious - tongue biting, head whipping
C. Simple vocal - throat clearing, spiting, screeching
D. Complex vocal - alterations in pitch
- echolalia - repeating others words
- palilalia - repeating own words
- coprolalia - obscene words
Tourette’s Disorder
- Criteria
- Course incl. brain activity
- Factors impacting symptom severity
- Treatment
Tourette’s
- Criteria: multiple motor and vocal tics
- several times/day >1 year
- onset before 18 yo
- not due to physiological effects or medical condition
- more common in whites, males - Course
- decrease in intensity, severity worse 9-12 yo
- location, frequency, and severity of tics changes over time
- starts with hyperactive behavior, simple motor tics
- Brain activity - lag to deactivate prefrontal and cingulate cortex seen in fMRI - Factors impacting symptom severity
- stimuli (illness, fatigue, stress)
- familial inherited component
- infectious disease (PANDAS - associated with Group A Strep)
- inability of basal ganglia to suppress motor neural areas that initiate tics potential etiology
- comorbidity - those without comorbid disorders (OCD, attention problems, learning disability, anxiety) –> smarter, more athletic - Treatment
- treat comorbid conditions first and tic severity will usually decrease
- educational and extracurricular interventions, psychotherapy
- medication e.g. clonidine (alpha adrenergic)
For the following Parkinsons drug - Levodopa
- MOA
- Pharmacokinetics
- Side effects - GI, cardio, CNS
L-dopa = most effective agent
1. MOA - synthesized from L-tyrosine, inert, can travel through BBB, and is metabolized into dopamine (or melanin)
- Pharmacokinetics - absorbed rapidly from small intestine, plasma 1/3 life 1-3 hours
- competes with dietary protein for transport to brain
- only 1% of dopamine actually enters CNS, other 99% metabolized in peripheral tissues via L-AAD and COMT - Side effects:
A. GI: anorexia, nausea, vomiting (stimulates emetic center); reduced when in sinemet (combo with carbidopa)
B. Cardio: arrhythmia, postural hypotension; aggravated with MAO inhibitors
C. CNS: dyskinesias (abnormal involuntary movements), psychological (anxiety/confusion)
For the following Parkinsons drug - Levodopa
- Long-term effects - response fluctuations
- Drug interactions
- Contraindications
- Long-term effects - Response fluctuations:
A. End-of-dose deterioration - predictable; buffering effect of levodopa on dopamine system that wears off –> dyskinesia (difficulty performing voluntary movements result in smooth tics, athetosis of face/extremities)
B. On-off phenomenon - unpredictable; fluctuate between med effects (mobility) and no effects (dyskinesia)
afterwards, have to administer secondary therapy
5
A. Pyridoxine - B6 enhances peripheral metabolism
B. MAO-A inhibitors accentuate levodopa effects –> hypertensive crisis
- Contraindications
- psychotic patients - psych meds aim to decrease dopamine in CNS
- closed-angle glaucoma –> increased intraocular pressure
- active peptic ulcer –> GI bleeding
- history of melanoma –> levodopa precursor of melanin
For the following Parkinsons drug - Carbidopa
- MOA
- Use
Carbidopa - increases fraction of L-dopa that remains unmetabolized and available to enter CNS
1. MOA - inhibits decarboxylase, which is one of the peripheral metabolizers of L-dopa into dopamine (other is COMT) –> longer 1/2 life and plasma concentration of L-dopa
- Pharmacokinetics - cannot cross BBB
- sinemet = levodopa + carbidopa in fixed concentrations
- less L-dopa can be given –> reduces side effects
- active peptic ulcer
Describe MOA and pharmacokinetics for the following Parkinson’s drugs:
- Dopamine agonist - ergot derivative
i. bromocriptine - Dopamine agonist - non-ergot derivative
i. ropinirole
ii. pramipexole
iii. rotigotine
iv. apomorphine
- Dopamine Agonist: Ergot derivative
i. bromocriptine
A. MOA: D2 dopamine receptor agonist –> inhibits indirect pathway –> facilitates motor movement
B. Pharmacokinetics: well-absorbed orally, 3-7 hr 1/2 life, used in combo with levodopa for on/off phenomenon - Dopamine agonist - non-ergot derivatives, used as monotherapy or adjunct for smoothing response
i. ropinirole - D2 agonist, metabolized by CYP1A2
ii. pramipexole - D3 agonist, excreted largely unchanged in urine
iii. rotigotine - once-daily transdermal patch for continuous absorption –> less serum fluctuation
iv. apomorphine - subcutaneous injection to treat “off” episodes, rapidly taken up in the brain w/in 10 min
Describe MOA and pharmacokinetics for the following Parkinson’s drugs:
- MAO-B inhibitors
i. selegiline
ii. rasagiline - COMT inhibitors
i. tolcapone
ii. entacapone - Anti-cholinergics e.g. trihexyphenidyl, benzytopine
- Antiviral - amantadine
MAO-B metabolizes dopamine in the brain to DOPAC; MAO-A metabolizes norepi, serotonin, dopamine
- MAO-B inhibitors - used in combo for late PD
i. selegiline: irreversible - retards breakdown of dopamine in dorsal striatum without inhibiting peripheral metabolism
ii. rasagiline: more selective than selegiline, may progression of disease in early PD
COMT metabolizes dopamine in the periphery + brain to 3-OMD (longer half life, competes with L-dopa for transport into brain)
- COMT inhibitors - adjunct to reduce levodopa dose
i. tolcapone - central and peripheral effects; more potent, hepatotoxicity
ii. entacapone - peripheral effects; less potent but no hepatotoxicity –> more preferred - Anti-cholinergics - 20% of striatal neurons have ACh –> excite indirect pathway –> increase inhibition
- anticholinergics –> decrease inhibition –> more movement
- improves tremor and rigidity but not dyskinesias
- restore dopamine:cholinergic balance - Antiviral - amantadine
- unclear MOA, antidyskinesia (anti-cholinergics do not affect dyskinesia) plus less rigidity and tremor
- enhances effect of endogenous dopamine
Limbic system:
- Describe the Papez circuit
- Modern view of limbic system - emotional processing anatomy
- Anatomy of the limbic system - specifically, memory formation
Limbic system involves emotional processing and memory formation
- Papez circuit: Originally thought to be emotional experiences, now more linked to learning and memory formation:
Medial temporal lobe (hippocampal formation) –> fornix –> mammillary body –> anterior nucleus thalamus (via mammillothalamic tract) –> cingulate gyrus –> entorhinal cortex –> hippocampal formation - Emotional processing - through limbic system outputs to the hypothalamus and brainstem reticular formation –> motor circuits to laugh, cry, chew, vomit, etc
- cingulate gyrus
- orbital and medial prefrontal cortex (association cortex)
- ventral striatum (basal ganglia)- nucleus accumbens and olfactory tubercle –> reward pathway
- amygdala –> emotional center
- mediodorsal nucleus of thalamus
Memory - process by which knowledge and experiences are encoded, stored, and retrieved
- anterior nucleus of thalamus
- mammillary body
- hippocampus (bidirectional connections to cortical regions –> memory formation)
- basal forebrain - nucleus basalis of Meynert, septal nuclei
- fornix (main output of hippocampus, projects to mammillary bodies, septal nuclei, and anterior nucleus)
[Limbic system] - Amygdala
- Describe location and function and structure
- Describe, generally, the inputs and outputs of the amygdala
1A. Location: Almond-shaped, posterior to uncus and anterior to the C-shaped hippocampus in the temporal lobe
B. Function: emotional center- assigns value to positive and negative stimuli (e.g pleasant vs aversive) and helps us choose the appropriate visceral/behavior response e.g. activated when viewing untrustworthy faces
C. Structure: 12 nuclei divided into 3 groups -
i. Medial - olfactory and autonomic actions
ii. Basolateral - inputs
iii. Central - outputs
2A. Inputs
- basal forebrain (Attention)
- thalamus - short pathway (for subconscious fear recogntiion)
- sensory cortices - visual, auditory, olfactory (via piriform cortex) *can go straight to amygdala without processing
B. Outputs: prepare body for action
- via stria terminalis to hypothalamus –> endocrine changes in bloodstream
- brainstem –> signals to muscles in face and limbs; autonomic signals, neurotransmitters
C. Bidirectional (all previous are also bidirectional)
- frontal (limbic) and temporal association cortex –> deciding on behaviors; implicit motor actions
- hippocampus - emotional charging of memories
[Limbic system] - Amygdala
- Describe fear conditioning in the amygdala
- Explain the deficits associated with lesions of the amygdala incl symptoms and conditions - Kluver Bucy syndrome
- PTSD
- Experiment: Animals subjected to innocuous tone + painful input –> changes at synaptic level using NMDA receptors = synaptic plasticity –> increased responsiveness in neuron and amygdala in response to input –> animals quickly learn to fear the tone
- Kluver-Bucy syndrome - bilateral amygdala lesions
- fearlessness - cannot experience or recognize fear!
- disinhibition - hyperphagia (eating), hypersexuality, hyperorality (examining everything orally)
- Associated with HSV-1 encephalitis (can produce hemorrhages in temporal lobe) - PTSD - initial trauma input into amygdala enhanced by norepi from locus ceruleus –> CNS sensitization –> fear response with autonomic activity (flashbacks, rage, increased heart rate)
- hyperactivation of amygdala
- hypoactivation of prefrontal cortex (helps us extinguish memories)
- Describe basal ganglia mesolimbic loop pathway
- What is the role of dopamine in this pathway
- How do addictive drugs fit into this system?
- Mesolimbic dopamine system - enabling behaviors, emotional expression, and habit formation reward pathway
Cortical input (amygdala, orbitofrontal cortex, hippocampus) --> activates ventral striatum (medium spiny neurons of nucleus accumbens) --> inhibits Ventral pallidum + substantia nigra pars reticulata via GABA--> now the medial dorsal nucleus of thalamus is disinhibited --> activates amygdala, anterior cingulate cortex, orbitofrontal + medal prefrontal cortex
- Dopamine is an input, just as with the nigrostriatal pathway for movement
GABA –> Dopaminergic release from ventral tegmental area [midbrain] through median forebrain bundle –> nucleus accumbens
- dopamine binds to receptors, endorphins bind to opiate receptors
- taken up by postsynaptic receptors on nucleus accumbens - Abused drugs increase dopamine effect –> ventral tegmentum (more release) or n accumbens (longer action) –> reinforces pleasurable effects of drugs
- e.g. opiates, alcohol, cocaine, meth (highest high), nicotine, cannabinoids
- stimulated by music, attractive facial expressions, good food, money
- nucleus accumbens lights up in anticipation of reward
Distinguish between short, recent, and long-term memory and describe the general brain areas
involved in each.
- Short-term declarative memory - more about attention than memory formation *cortical neurons activated repeatedly show short-term increases in firing rate (due to longer after-depolarization bc of more open Ca2+ channels)
A. Immediate memory - register information (“repeat these 3 words immediately”) –> brainstem and cortical areas
B. Working /short-term memory - hold info long enough to use (“repeat phone number” digit span test) –> brainstem and dorsolateral prefrontal cortex - Recent memory - remembering minutes-days ago (“repeat these 3 words in 5 min”) –> medial temporal cortex and diencephalon limbic
- Long-term memory - basic historical facts (“what year were you born?”) –> medial temporal and specific cortical regions
Describe the memory deficit that occurred in the patient, HM, and the importance it had to understanding the neuroscience of memory
HM - had bilateral medial temporal lobe (where the hippocampus is) resection as epilepsy treatment –> anterograde amnesia = inability to form new memories
also had retrograde amnesia = inability to retrieve old memories, for the 10 years before the surgery
- speech, IQ, social skills normal
- emotions blunted bc most of amygdala removed
- could not recognize anyone, remember what he just ate or read or said
- BUT he could learn new motor tasks –> procedural memory in a different location from declarative memory
- AND he had preserved memories –> they live in the cortex
Hippocampus:
- Anatomy
- Histology
- Connections
- long-term potentiation
Hippocampus in the medial temporal lobe - memory formation, spatial memories, memory storage
- Anatomy
A. dentate gyrus in the tip –> cells here can undergo neurogenesis
B. surrounded by hippocampal formation (CA1-CA3 of pyramidal cells) –> important for spatial orientation - Histology
A. Dentate gyrus has outer molecular layer, granule cells, then inner polymorphic layer
B. Hippocampal formation has outer molecular layer, pyramidal cells, then polymorphic - Connections - Receives projections from different cortical regions and integrates, sends back outputs (bidirectional) –> CA1 pyramidal neurons are major output, exhibit long-term potentiation
- long-term potentiation - CA1 neurons respond more to repeated inputs (i.e. high frequency tetanic stimulation) via bigger EPSPs –> increases responsiveness of post-synaptic neurons to subsequent inputs
- this strengthening of synapses is an example of synaptic plasticity (Hebbian synapse “neurons that fire together wire together”)
- due to more open Ca2+ channels –> more NMDA receptors
- Describe consolidation, retrieval, and reconsolidation of memories.
- Why/how are memories forgotten?
- Experience –> consolidation into long-term memory (hippocampus/amygdala)
When triggered –> reconsolidation (retrieval) OR extinction
Retrieval: neuron that created the memory is activated again during recall –> labile model of memory recollection
Reconsolidation: Period of lability during memory retrieval - can be influenced by bias, mood, suggestions –> even false memories !
- Memories forgotten to remove confusion from our thought processes
- prefrontal cortex inhibition of the hippocampus retrieval systems (prefrontal cortex hypoactivated in PTSD)
Describe the following memory conditions:
- Alzheimer’s
- Wernicke-Korsakoff’s
- Alzheimer’s - degeneration of neurons in hippocampus and parahippocampus + loss of cholinergic cells in basal forebrain nuclei (decreased ACh)
- forgetfulness, disorientation
- anterograde + retrograde amnesia
- also degeneration of entorhinal cortex (medial temporal lobe) - Wernicke-Korsakoff’s - damage to mammillary bodies and medial nuclei of the thalamus –> anterograde + retrograde memory losses
- also confabulation with anosognosia (make up memories and don’t realize it)
- caused by alcoholism and B1 thiamine deficiency
- 3 major signs: ataxia, nystagmus, confusion [Wernicke delirium - reversible]
- progression to learning and memory problems [Korsakoff dementia - irreversible]
- Describe the brain similarities among species that allow for animal studies of addiction
- Describe the animal models of drug addiction
- Animals also have ventral tegmental area, nucleus accumbens, and prefrontal cortex –> hard-wired reward pathway but for natural rewards e.g. food, water, sex
- natural rewards increase dopamine levels, but not to same high as drugs
2A. Conditioned place preference - prefer to spend time in environment where drug is present
B. Self-administration - tests rewarding properties of drug –> potential to be addicting
C. Relapse to drug self-administration, stimulated by drug or stress
D. Intracranial self-stimulation - want to electrically stimulate brain reward regions (nucleus accumbens)
Drugs addictive to humans are also addictive to lab animals!
- Which route of drug administration is fastest?
2. Why is addiction a chronic brain disorder?
- Fastest is inhalation (shorter distance from lung –> L heart –> brain), then injection, then snorting, then oral ingestion
greater dopamine release –> greater the high *why some drugs e.g. Ritalin (ADHD) are taken orally, to reduce addiction potential
- 50/50 Genetic/environmental factors in addiction; psychiatric condition is significant comorbidity
Lower dopamine D2 receptors ability in addicts –> addiction less about reinforcement and more about negative reinforcement (avoid stimuli that is bad/negative i.e. withdrawal/negative affect)
-striatal dopamine declines in addiction, rises slowly during convalescence
Intensity spectrum for: 1. MRI T1W T2W FLAIR DWI
- CT
- When do you use CT vs MRI?
- MRI - intensity
T1W- CSF and edema are hypo, white matter and fat are hyperintense
T2W- CSF and edema are hyper, white matter is hypointense
FLAIR - type of T2 but CSF is hypointense –> use for multiple sclerosis to look for bright tumors
DWI - blood is hyperintense –> use for stroke - CT - density in Hounsefield Units
Fat, tumor, edema = dark (negative HU)
Blood = light (50-100 HU)
calcification = v bright (1000 HU) - For subacute issues use head CT (blood stays bright/hyperintense for up to 3 days, isodense ~1 weeks, then hypodense compared to brain tissue >2 weeks)
- for chronic issues use MRI - good at looking at brain in detail e.g. for tumors
[Olfaction]
- Describe basic anatomy for olfaction including Olfactory epithelium and Olfactory bulb
- Describe how odorants are picked up
- Odor desensitization
- Anatomy of olfaction
A. Olfactory epithelium - contain olfactory receptor neurons (ORNs), supporting cells, bowman’s gland
- ORNs replaced every 30 days from basal stem cells
- axons easily sheared - easy to lose olfaction
- ORN have thresholds for some odorants - pleasant at low concentrations but bad when you pass threshold
B. Olfactory bulb - contain glomeruli where there is convergence of axons of many ORNs expressing same olfactory receptor –> synapses with mitral, tufted, and granule cells which relay output via olfactory tract - ORNs have cilia that protrude into mucous environment and transduce odorants
Odorant binding to 7 transmembrane receptor –> G protein binding –> elevated cAMP –> cation channel opening –> depolarization - Desensitization with repeated stimulus –> important to prevent receptor saturation and be able to respond to other odors
- uncoupling of receptor from G proteins, internalization of cell surface receptors, or down-regulation of receptors
Describe Central olfactory pathway
Central olfactory pathway:
Axons of ORNs go from olfactory epithelium –> through olfactory nerve/CN I and cribriform plate –> to olfactory bulb
–> make excitatory glutamatergic synapses with mitral and tufted cells in the glomeruli of the olfactory bulb–> pattern of odor recognition depending on glomeruli activation (based on which receptors are activated/how strongly) –>
transmitted through anterior olfactory nucleus (nuerogenesis occurs here) –>
through olfactory tract to olfactory areas:
-piriform cortex
- olfactory tubercle
- amygdala
- entorhinal cortex
no thalamic relay - goes directly to cortical regions e.g. orbitofrontal cortex
Differentiate:
- Conductive vs sensorineural hearing loss
- Unilateral vs Bilateral anosmia
- Conductive vs sensorineural hearing loss
A. Conductive due to obstruction of nasal airflow e.g. allergic rhinitis, polyps, tumors
B. Sensorineural due to damage of olfactory nerves along central olfactory pathway e.g. head trauma, toxins, dementia, Alzheimer’s, MS
- Weber lateralizes left + Rinne AC>BC –> sensorineural loss R ear
- Weber lateralizes left + Rinne BC > AC –> conductive loss L ear - Unilateral vs Bilateral anosmia
A. Unilateral compensated by contralateral nostril - can be localized to olfactory epithelium, nerve, bulb, tract
B. Bilateral - destruction of olfactory cortex or pathways posterior to trigone
*most patients who report taste/chemosensory loss actually have anosmia, true gustatory loss RARE
Describe Kallman Syndrome incl etiology, symptoms and treatment
Kallmann - congenital hypogonadotropic hypogonadism
A. Etiology - defective neuronal migration from olfactory placode –> ORNs to olfactory epithelium and GnRH-releasing neurons to hypothalamus –> lack of GnRH synthesis in hypothalamus + underdeveloped olfactory bulbs
B. Symptoms - anosmia, decreased FSH LH testosterone
-low sperm count in males
-amennorhea in females
C. Treatment - testosterone replacement in males, estrogen replacement in females to rescue sexual characteristics, fertility
- anosmia is permanent
[Taste]
- Describe basic anatomy for taste
- Neural pathways for taste
Taste - contact of water-soluble compounds with tongue papillae; less sensitive than olfaction
1. Anatomy: Taste cells clustered into taste buds, which are embedded in lingual papillae
A. Fungiform (anterior 2/3)
B. Circumvallate (posterior 1/3)
C. Foliate (posterior edges)
- open onto lingual epithelium via taste pore
-replaced from basal stem cell population (As with ORNs)
- A. Anterior 2/3 tongue –> chorda tympani branch of VII
B. Posterior 1/3 tongue –> lingual branch of IX
C. Posterior pharynx/epiglottis –> superior laryngeal branch of X
ABC –> rostral nucleus solitarius in medulla –> VPM of thalamus –> insula and frontal cortex –> amygdala
- Anatomical correlates of distinct taste modalities
- Describe taste transduction
- 2 Taste processing pathways
A. Labeled line
B. Ensemble
1. Sweet - sugar, aspartame Sour - protons Bitter - variety Salty - Na+/K+ Umami - MSG/free AA
- Taste transduction
Taste cells are NOT neurons but can generate action potentials, innervated by sensory neurons
-Na/K (salty) - Na+ influx and H+ (sour) - H+ influx - act directly on ion channels;
-bitter, sweet, umami tastants act via G-protein mediated cascades –> depolarization –> transmitter release to primary sensory neurons via serotonin –> action potential - Neural encoding of taste
A. Labeled line code - specific receptor neuron type directly transmitted
B. Ensemble coding - pattern of responses to stimulus processed
Pheromones including anatomy, processing
Pheromone - substances secreted via urine/glandular secretion (sweat) and received as signals for gender ID, mating, bonding, etc
Vomeronasal organ (VMO) - found in oral cavity of animals and mediates pheromone process, vestigial structure in humans –> our pheromone signaling is thought to be olfactory (evidence via syncing of periods, etc)
Processing in amygdala, doesn’t reach cortex so no consciousness of pheromones
- Describe language lateralization and localization
- Contribution of non-dominant hemisphere to language
A. result of damage to Wernicke’s area
B. result of damage to Broca’s area
1A. Language lateralized to left hemisphere in 98% of people - considered dominant hemisphere
B. Language localized to perisylvian fissure area in ALL people - whether R or L dominant
-newborns born with ability to process language - speech preferentially activates left hemisphere
- Non-dominant hemisphere is usually R –> involved in emotional content of speech
A. damage to Wernicke’s area equivalent (temporal lobe) in non-dominant hemisphere –> can’t tell if someone is mad, sad, etc
B. damage to Broca’s area equivalent (frontal lobe) in non-dominant hemisphere –> monotonic speech
- Define language and aphasia
2. Detail vascular perfusion of language areas and equate stroke to specific aphasias (global, non-fluent, fluent)
1A. Language = ability to understand AND produce spoken and written language
B. Aphasia - loss of ability to comprehend AND produce spoken and written language; acquired
-naming objects first thing affected and last to recover
- Most aphasias due to vascular accidents; perisylvian area (i.e. language core) perfused by middle cerebral artery
Global aphasia –> MCA before branch point –> both comprehension/expression impaired
Fluent (Wernicke’s aphasia) –> inferior division of MCA
Non-fluent (Broca’s aphasia) –> superior division of MCA
Describe characteristics of different types of aphasias: 1. Wernicke's (fluent) 2. Broca's (non-fluent) A. Big Broca's B. Little Broca's 3. Conduction aphasia
- Wernicke’s (fluent) aphasia - comprehension compromised but expression intact; damage to temporal/parietal lobe (primary and secondary auditory cortex)
- fluent speaking but unintelligible, patient unaware they have a problem - Broca’s (non-fluent) aphasia - comprehension/input intact but expression/output compromised –> labored speech, naming difficulties but automatic speech (1234) preserved
A. Big Broca’s - initially global aphasia, then regain understanding; permanent aphasia, more extensive frontal lobe damage + insula –> repeats one word e.g. Tan
B. Little Broca’s - affects Broca’s area (inferior frontal gyrus), full recovery w/in 1 yr - Conduction aphasia - both reception and expression intact BUT communication between temporal and frontal lobe compromised
- patient makes paraphrasic error (substitutes related work e.g. arm for leg) and iterates until they correct error
Differentiate transcortical aphasias from B/W aphasia
A. Transcortical motor
B. Transcortical sensory
Transcortical aphasias - damage outside of perisylvian area so language core is intact
- could be due to systemic problem (Eg hemorrhage) that affects watershed areas
- information can get from temporal lobe to frontal lobe –> repetition is intact
- patients can repeat a “low frequency statement” eg “Mets are World Series Champions”
A. Transcortical motor - resembles Broca’s (expression compromised)
B. Transcortical sensory - resembles Wernicke’s (comprehending compromised)
I. Define:
1. Abscess
2. Encephalitis
3. Encephalopathy
II. How does bacteria end up in the brain and cause an abscess?
III. What are the most common locations for an abscess?
- Abscess - collection of pus that is walled off in tissue
* pus = liquid produced in infected tissue, with dead WBCs, bacteria, tissue debris, serum - Encephalitis - inflammation of brain, not necessarily walled off
- Encephalopathy - altered brain function
II. Bacterial spread methods:
A. Contiguous spread most common - pus in sinus breaks through thin walls and enters brain
B. Hematogenous seeding - bacteremia e.g. staph
C. Post-traumatic (or surgery)
D. Cryptogenic - they don’t know
III. Most common locations:
otitis media –> temporal
sinusitis/dental –> parietal lobe
bacteremia –> multiple locations
- Most common infecting organisms for brain abscess
- Clinical manifestations for brain abscess
- Diagnosis
- Treatment
- Streptococci strains, Gram-negative bacteria (bacteroides + enterobacteriaceae), fungi (more common in cancer patients)
* S. pneumonia and H. influenza are main pathogens for meningitis but negligible for abscess - Clinical manifestations: more subtle than meningitis
- indolent - slowly progressive
- headache - most common symptom
- seizures
- nuchal rigidity is V uncommon - Diagnosis: MRI preferred but CT scan more common approach for headaches, blood cultures or biopsies
* do NOT do lumbar puncture if you suspect brain abscess to avoid herniation
- CSF shows increased neutrophils/WBCs, increased protein normal glucose (bacteria are in brain and do not have access to consume the glucose in the CSF) - Treatment: antibiotic that can cross BBB, surgical drainage, surgery
Differentiate between:
- Cranial epidural vs subdural abscess
- Spinal epidural vs subdural abscess [paraspinal]
1A. Cranial epidural abscess - related to frontal sinus disease and osteomyelitis
B. Cranial subdural abscess - neurologic emergency, usually with seizures and bacteremia
- Paraspinal abscess - Staph aureus most common cause; can lead to paralysis if missed
Cord compression –> radicular pain then urinary retention, constipation, leg weakness, hyperreflexia
A. Spinal subdural abscess -MRI or CT essential; treat with steroids, antibiotics, surgical decompression
B. Spinal epidural abscess - most common in thoracic (bc more fat), posterior > anterior; with vertebral osteomyelitis; positive blood culture but negative CSF analysis
Describe the infectious etiologies of chronic meningitis: 1. TB 2. Crypotococcus 3. Lyme disease 4. Syphilis 4A. Meningovascular syphilis 5. Neurocysticercosis
List noninfectious etiologies of chronic meningitis
Infectious etiologies of chronic meningitis
1. TB - most common etiology of chronic meningitis; usually have to treat empirically bc hard to diagnose (PPD and smears negative)
2. Crypotococcus - immunodeficient, use india ink to diagnose
3. Lyme meningitis - occurs at any stage of lyme, glucose normal + high protein; only time you see bilateral Bell’s palsy
4. Syphilis - commonly asymptomatic; common in HIV patients, most frequently manifestation of tertiary syphilis (give test for any psych hospital admission and do lumbar puncture if result is positive)
4A. Meningovascular syphilis - infarction of small vessels –> stroke, seizures
5. Neurocysticercosis - calcified cysts, presents with seizures, associated with dealing with horses
Noninfectious - neoplasms, sarcoidosis (growth of inflammatory granulomas), vasculitis, drug-induced
Define parenchymatous neurosyphilis.
List symptoms that would suggest neurosyphilis
List pattern of CSF findings expected on lumbar
puncture
Parenchymatous neurosyphilis - tertiary neurosyphilis due to chronic meningitis –> destruction of nerve cells in the cerebral cortex (Cerebral atophy esp of frontal lobes)
- Psychiatric and neurologic problems:
A. General Paresis - personality changes, social dysfunction, defects in speech, mania/depression, Argyll Robertson pupils (accommodate but do not react)
B. Tabes dorsalis - much less common
- shooting pains
- ataxia
- sphincter disturbance
- peripheral neuropathy - profound decrease in vibratory sense
- cranial neuropathy
CSF findings - high WBC count, normal glucose, elevated protein + positive VDRL test
Explain the difference in clinical presentation of
encephalitis vs meningitis
- most salient difference* Encephalitis has altered mental status (although both encephalitis and meningitis can lead to coma)
- CSF exam similar - increased neutrophils and lymphocytes (WBCs), increased proteins
- Encephalitis rarely have neck stiffness, but even adults with meningitis rarely have neck stiffness
- fever, headache, confusion most related to encephalitis
Viral Encephalitis: 1. Diagnosis 2. Types A. HSV B. Eastern equine encephalitis EEE C. West Nile 3. Post-infectious encephalitis [non-viral]
Viral encephalitis - caused by eastern equine (highest mortality), west nile, HSV, colorado tick fever, california, etc. –> hard to differentiate clinically
- Diagnosis: not culture but rather PCR of CSF, serology for West Nile, EEG for HSV, MRI or CT
- brain biopsy is last resort - Types
A. HSV - frontal-parietal localization, RBCs in CSF findings; HSV is only treatable encephalitis so patients usually started on acyclovir
*HSV-1 associated with Kluver-Bucy (amygdala damage)
B. EEE - highest mortality; basal ganglia and thalamus localization, polys in CSF findings
C. West Nile - avian reservoir, self-limited illness; low grade fever + altered mental status, hallmark is muscle weakness with flaccid paralysis (post-infectious Guillan Barre) - Non-viral: most common are bacterial pathogens (Listeria, Salmonella, Nocardia) – will see the bacteria on the lumbar puncture
- Post-infectious encephalitis - ADM –> demyelination and inflammation in the white matter (no direct infection)
- multifocal neurologic symptoms; requires steroids
Describe the function of the Heteromodal (Tertiary) Association Cortices
Describe function and location of Parietal HAC
Describe role of synesthesia
- Primary cortices - motor, somatosensory, auditory, visual
- Secondary - unimodal (e.g. only visual)
- Tertiary = Heteromodal Association Cortices –> global view, unites different information from environment
Parietal HAC - inferior parietal lobes (junction of temporal/parietal/occipital –> supramarginal and angular gyri
-function - takes discrete sensory inputs and assembles unified sensory percept –> sends information to prefrontal cortex in frontal lobe –> assess situation and decide what you want to do (pick one plan and inhibit others; with input from limbic system) –> motor output
Synesthesia - aberrant binding of sensory information in parietal lobe –> perceived sensation in non-stimulated sensory system
- most common - sounds or letters evoke visual colors
Describe role of inferior parietal lobes in dominant and non-dominant hemispheres and effects of lesions
Inferior parietal lobe in dominant hemisphere (usually Left) - language functions
- Gerstmann’s syndrome: math difficulties (acalculia), writing difficulties (agraphia); finger agnosia (usually ring/index fingers), L-R confusion
Non-dominant hemisphere (usually Right) - spatial awareness (limits of intrapersonal space, beginning of extrapersonal space), spatial attention (shifting attention between objects), spatial orientation
- Hemineglect - lose monitoring of intrapersonal space on one side of the body –> usually L
- Extinction - can only recognize stimulus e.g. only recognize L side stimulus in isolation
Describe functions of specific regions of the prefrontal cortex and effects of damage to the region:
1. Orbitofrontal
Prefrontal cortex is the anterior most region of frontal lobes, which mature (by creating connections) slowly –> social maturity; majority of action is subconscious
- Orbitofrontal - personality
- emotions, social interactions
- ethics, morals
- empathy, recognizing emotions
- theory of mind –> concept of self (recognize your thoughts are separate from others)
* primary role is to filter / inhibit actions (influenced by reward and punishment)
* medial PFC also involved in emotions, social information processing
Damage - often due to closed head injuries (coup-contrecoup damage)
- personality changes / apathy
- social dysfunction
- poor anger management
- compromised inhibition / lack of filtering –> usually many thoughts never reach level of consciousness before they are inhibited
Describe functions of specific regions of the prefrontal cortex and effects of damage to the region:
- Dorsolateral
* describe steps of executive function
- Dorsolateral - cognition
- making and executing plans
- adapting to new situations
- focus
- Executive function - engaging in current behavior to achieve future goal (more activity required with longer time frame between behavior and reward) - Initiation - input from medial prefrontal cortex
- Follow plan
- Working memory - know where you are to go to next step
- Inhibition - ignore internal and external distractors
- introspection - monitor progress, compare plan to reality
- Adaptability - fix if broken; feelings of guilt recruited from orbitofrontal prefrontal cortex
Damage leads to executive dysfunction
- failure to launch
- poor planning
- compromised working memory
- lost focus
- poor adaptation
Describe types of frontal lobe injury
- Utilization behavior
- Frontotemporal dementia (FTD)
- Signs of Frontal Cortex Association lesions
- Utilization behavior - behavior influenced by objects in environment; damage of orbitofrontal PFC
- act out normally subconscious plans (of interacting with the object) that should be suppressed –> lack of frontal lobe inhibition means the plans reach level of consciousness and are carried out
e. g. flipping light switch on/off continuously - Frontotemporal Dementia - neurodegenerative disease of frontal and temporal lobes; age of onset ~55; “Pick” inclusion bodies
A. Dominant lobe - progressive aphasia first
B. Non-dominant (Pick;s Disease)- behavioral issues first, aphasia later
i. Orbitofrontal PFC- disinhibition, antisocial acts
ii. Medial PFC (anterior cingulate gyrus) - apathy, loss of drive - Signs of Frontal Cortex Association lesions
- perseveration - get stuck when pattern changes
- impersistence - loss of sustained movement (Eg holding arm out) even though no motor problems
- frontal release signs (e.g. grasp reflex)
- gegenhalten - involuntary hypertonia e.g. tense up when touched
- abulia - lack of motivation
- mood changes (Left - depressed; Right - manic)
- magnetic gait - shuffling
- incontinence - BILATERAL medial
Describe branches of the Anterior cerebral artery ACA, major structures supplied, and major deficits from occlusion
- L problems = aphasia; R problems = hemineglect
Anterior circulation - from internal carotid
A. ACA supplies medial portion of frontal and parietal lobes –> lower limb and sensory
Deep branches = recurrent arteries of Heubner (supply anterior limb internal capsule, head of caudate nucleus)
B. Damage:
i. Contralateral hemiparesis/leg weakness (UMN weakness) –> larger infarcts may cause hemiplegia
ii. contralateral leg cortical-type sensory loss
ii. frontal lobe behavioral abnormalities
iii. grasp reflex
+
iv. L sided ACA strokes: transcortical motor aphasia (expression compromised but comprehension and repetition intact)
iv. R sided ACA stroke: left hemineglect
Describe branches of the Middle cerebral artery MCA, major structures supplied, and major deficits from occlusion:
A. Middle cerebral artery stem
B. Lenticulostriate
MCA = largest cerebral artery, most likely to stroke out; supplies lateral surface of frontal and parietal lobes
Branches –> Structures supplied –> Deficits
A. Middle cerebral artery stem (MASSIVE) –> face/arm/leg contralateral sensorimotor deficit +
L - global aphasia (Wernicke + Broca)
R - neglect (parietal association cortex)
Visual field deficits (optic radiations)
Transient paralysis of horizontal gaze; preference towards lesioned side (frontal eye field)
B. Lenticulostriate –> basal ganglia and internal capsule –common site of lacunar infarct
- contralateral hemiparesis (can be pure motor or pure sensory bc of the anatomical separation of face/arm/leg areas in internal capsule)
- hemiballismus - spontaneous, involuntary movements (if subthalamic nucleus affected)
Describe branches of the Middle cerebral artery, major structures supplied, and major deficits from occlusion:
C. MCA Superior division
D. MCA Inferior division
Branches –> Structures supplied–> Deficits
C. MCA superior division –> region anterior to central sulcus:
- contralateral face and arm weakness (UMN)
- contralateral face and arm cortical-type sensory loss (agraphesthesia, astereognosis)
- contralateral horizontal gaze (transient)
L - Broca’s aphasia
R - left hemineglect (variable, mild)
D. MCA inferior devision –> region posterior to central sulcus:
- contralateral face and arm cortical-type sensory loss (agraphesthesia, astereognosis)
- contralateral homonymous hemianopsia [optic radiations]
L - Wernicke’s aphasia
R - left hemineglect (severe)
Describe branches, major structures supplied, and major deficits from occlusion:
A. Anterior choroidal artery
B. Posterior cerebral artery
A. Anterior choroidal artery - deep branch off of internal carotid –> supplies choroid plexus, ventricles, optic tract and internal capsule
Damage - contralateral homonymous hemianopsia [optic tract]; contralateral hemiplegia (pure motor hemiparesis) [posterior limb internal capsule]
B. Posterior cerebral artery branch of basilar artery –> supplies midbrain, thalamus, medial temporal and occipital lobe
Damage - homonymous hemianaopsia with macular sparing (macula also supplied by MCA) [primary visual area]
L - transcortical sensory aphasia; IF it affects posterior corpus callosum –> alexia (inability to read) without agraphia (inability to write) - cannot read what they wrote
Deep stroke - contralateral hemianesthesia (or central pain syndrome in 10%)
Describe watershed infarcts incl common locations and deficits
Watershed areas susceptible to decreased systemic blood pressure or stroke
- ACA-MCA watershed territory
- man in a barrel - sensory and motor loss to proximal upper limbs, but no effect on legs
- transcortical motor aphasia (comprehends but cannot respond) - MCA -PCA
- transcortical sensory aphasia (cannot comprehend but fluent response)
[Alzheimer’s disease]
- Describe main clinical and pathological characteristics
- Treatment
- Alzheimer’s disease - most common age-related degenerative dementia
- most cases sporadic
- onset before age 60 = familial AD
- pathology:
A. neuritic plaques - extracellular deposits of amyloid beta protein 42 –> induce inflammatory response
B. neurofibrillary tangles - intracellular deposits of tau protein
C. Atrophy/neuronal loss - first in medial temporal lobe (hippocampus –> memory, entorhinal cortex)
- esp atrophy of cholinergic neurons –> cognitive loss associated with depletion of acetylcholine - Treatment - physical and mental exercise!
- non-competitive, covalent, reversible acetylcholinesterase inhibitors (e.g. Aricept)
[Alzheimer’s]
- APP and its processing
- “Amyloid Hypothesis”
- Evidence for Amyloid hypothesis
- APP = Amyloid Precursor Protein, ubiquitously expressed, used for cell signaling, adhesion, and axonal transport
A. APP acted on by beta secretase –> then gamma secretase –> Abeta (40 and 42 aa), no clear function
B. APP acted on by alpha secretase –> then gamma secretase –> P3 (anti-amyloidogenic pathway) - Amyloid Hypothesis: the extracellular aggregates of insoluble Abeta42 are the causal factor of Alzheimer’s –> disrupts neuronal and synaptic function –> neurodegeneration –> cognitive deficits
- Evidence for Hypothesis:
A. transgenic mouse models - mice over-expressing APP and tau develop AD –> see Abeta-42 plaques (and not AB-40 –> 42 more likely to aggregate) –> familial AD
B. APP gene on Chromosome 21 - adults with Trisomy 21/Down Syndrome develop familial AD
C. mutations within APP gene –> abnormal processing –> increased production of AB-42
D. gain of function mutation of presenilin PS1/PS2 proteins (part of gamma secretase) –> mice have accelerated AB-42 deposition; associated with familial AD
E. ApoE4 allele –> impairs AB-42 clearance –> increases risk of sporadic AD (but not necessary/sufficient)
[Alzheimer’s]
- Evidence against Amyloid hypothesis
- Refined Amyloid Hypothesis
- Evidence Against:
A. some patients with AD do not have plaques on autopsy
B. some people with plaques did not have AD
C. reduction in plaque load did not improve memory
D. some mouse models of AD - memory deficits prior to plaques - Refined Amyloid Hypothesis
- Ab-42 forms oligomers before reaching size of plaques –> interact with specific receptors (e.g. LilrB2) –> Ca2+ influx in cell –> actin cytoskeleton disruption and synaptic loss –> neurodegeneration
- plaques could be protective because the AB-42 is not interrupting cell processes in oligomer form
- transgenic mice lacking LilrB2 protected against neuronal damage + memory deficits
[Alzheimer’s]
- Pathology of neurofibrillary tangles
- Link to Alzheimers
- Neurofibrillary tangles - intracellular deposits of hyperphosphorylated tau protein
- tau associated with microtubules (and mutation linked to frontotemporal dementia)
- when hyperPed, becomes less soluble and more prone to forming aggregates –> disrupts axonal transport
- hyperphosphorylated due to:
i. tau mutation
ii. oxidative stress
iii. AB-induced immune response with increased cytokines - Formation of tau angles is downstream of AB-42 in neurodegenerative cascade
- increased production of AB-42 in brain –> synaptic loss –> oxidative injury + altered phosphatase activities –> hyperphosphorylated tau –> neurofibrillary tangles –> dementia
*more likely to develop AD with low serum AB-42 (less clearance from brain) and high tau
Define and differentiate between dementia and delirium and mild cognitive impairment
- Dementia and delirium both describe failure in brain function
A. Delirium - acute confusional state that represents change in baseline attention and awareness and fluctuates in severity; waxing + waning consciousness
B. Dementia - significant cognitive decline in 1+ domains (executive function, memory, language, etc)
i. sense of decline
ii. cognitive testing shows decline
iii. functional impairment (of everyday activities)
C. Mild cognitive impairment - decline in functioning from baseline not normal for age, affecting 1+ cognitive domains BUT not associated with functional impairment
-50% of people with MCI progress to dementia
Main differences:
Time course - delirium acute, dementia progressive
Primary symptom - delirium is global, dementia is isolated at first
Daily symptoms - delirium fluctuates, dementia continuous
Delirium Reversible and low mortality, dementia not reversible and 100% mortality
Delirium
- Etiology
- Assessment
- Treatment
Delirium - acute brain failure
1. Etiology - failure of cerebral metabolism due to availability of fuels (glucose, water, oxygen) OR their delivery or utilization
2. Assessment A. ABCs, vitals glucose B. History + physical exam C. Routine labs (CBC, BMP, LFTs, EKG) D. More labs - CT (Stroke), EEG (seizures), lumbar puncture (meningitis), etc.
- Treatment - medical emergency
ID and treat underlying cause
and symptomatic treatment if necessary (behavioral first, pharmacologic later)
Dementia
1. 4 Major types of neurodegenerative dementias
2. Etiology A. Reversible B. Arrestable C. Noncurable, nonprogressive D. Noncurable, progressive
- Assessment
- Treatment
Dementia - chronic brain failure
- Four major dementias: Alzheimer’s (Abeta42), frontotemporal dementia (Pick bodies - tau), dementia with Lewy bodies (alpha synuclein, also exists in PD), and Creutzfeld Jakob (prion)
- can be genetic or sporadic
- begin in pre-senescence
- involve abnormal protein aggregation in neural tissue –> disrupts neuronal function - Etiology - F»M, family history, cerebrovascular disease
A. Reversible - B12 deficiency, syphilis, sleep disorder, thyroid disease
B. Arrestable and non-reversible - structural lesions e.g. tumors, MS, head injuries
C. Non-curable, but slow progression - Alzheimer’s and Lewy body dementia [hallucinations + Parkinsonism + fluctuating attention]
D. Noncurable, and progressive - frontal temporal dementia, Cretuzfeld-Jacob, Huntington’s - Assessment - history, physical, cognitive assessment, testing
- Cognitive assessment - memory, orientation, calculation, arousal and attention + personality
- Testing - MRI or CT, TSH, B12, etc. - Treatment - behavioral therapy, cognitive enhancers, pharmaceuticals
Concussion
- Define
- Pathophysiology
- Clinical presentation
Concussion
- Define - mild traumatic brain injury
- diffuse with no structural changes (no imaging abnormality)
- rapid onset of short-lived impairment that resolves spontaneously - Pathophysiology - change to hypermetabolic state (up to 10 days)
- increased glucose metabolism
- increased calcium influx –> swelling –> body adapts through decreased blood flow –> negative effect of this is that brain cells vulnerable to cell death - Clinical presentation
- symptoms (headache, emotional lability)
- physical signs (loss of consciousness, amnesia)
- cognitive impairment (slowed reaction times)
- confusion, headache, dizziness, blurry vision, nausea
- provocative tests to elicit symptoms if you’re not sure they have a concussion
Concussion
- When should someone be sent in for imaging
- Which imaging should be done when
- Treatment
- When player can be sent back into field
- Second Impact syndrome
Concussion 4. BEAN BASH B- behavior abnormal E- emesis A - >65 N- neurological deficit B - bleeding A - altered mental status S - skull fracture H - hematoma
- CT if worried about TBI (e.g. bleeding)
MRI if prolonged symptoms and no improvement - Treatment - cognitive and physical rest
- Need to pass neuropsych tests - balance/romberg testing, vestibulo-ocular examination
No return unless asymptomatic at rest and exertion (though some athletes still have headache) - Second impact syndrome - bad brain injury following minor one –> cerebral edema and herniation; in high schoolers and younger; 100% morbidity and can lead ot death
[Primary Headaches] - Migraines
- ID features of migraine headaches
- Pathophysiology
- Treatment
- Migraine features - F»M
- unilateral and long (4-24 hours)
- pounding
- photophobia
- nausea
- aura (classic migraines)
- family history; comorbid anxiety/depression - Pathophysiology - complex neurovascular process
- trigger in brainstem nuclei –> moves from back to front of brain –> activates pain receptors in trigeminal system –> CGRP vasodilator –> release of inflammatory factors incl substance P, bradykinin, serotonin –> headache - Treatment
A. Abortive therapy - help headache at the time
-NSAIDs, enti-emetics, triptans or ergotamine
B. Preventive - take to prevent headaches
- non-pharmacologic (acupuncture, headache log)
- pharmacologic (anti-convulsants, CGRP inhibitors)
[Primary Headaches] -Trigeminal autonomic cephalalgia 1. Cluster headaches A. Clinical features B. mechanism C. treatment
- Hemicrania
A. Paroxysmal
B. SUNCT
Trigeminal autonomic cephalalgia - include cluster headaches, hemicrania
- Cluster headaches - severe unilateral headache, multiple per day for weeks with remission periods
A. excruciating throbbing pain + ipsilateral autonomic features: lacrimation, nasal congestion, forehead sweating, Horner’s
- unable to lie down, incapacitated; >30 minutes
- M»F; periodicity (same time of day) - can be woken up in middle of the night
B. Mechanism: trigger in hypothalamus, pain mediated by CN V + parasympathetic CN VII
C. Treatment: abortive (02), preventive (verapamil) - Hemicrania - severe unilateral pain that responds to indomethacin
A. Paroxysmal - sharp, throbbing headache multiple times x day and < 30 minutes; (while continua type is nonstop > 3 mos)
B. SUNCT - v short (single burning stabs) but 100x day; red or tearing in ipsilateral EYE
[Primary Headaches]
- Tension Headaches
A. Clinical features
B. Pathophysiology
Clinical features for the following:
- New Daily persistent headache
- Ice Pick
- Thunderclap
- Tension headaches - most common type, M=F
A. Clinical features:
- bilateral
- pressing/tightening
- lasting min - days
- no throbbing, photophobia, nausea, not worse with routine physical activity
B. Pathophysiology - mechanism unknown
- peripheral sensitization (muscle tension in pericranial region) in episodic TH driving central pain sensitization in chronic TH - New Daily persistent headache - daily, unremitting headache that doesn’t go away (>3 mos)
- not aggravated by normal activity, chronic from outset - Ice Pick - series of stabs in V1 region
- responsive to indomethacin - Thunderclap - sudden onset, severe; need to rule out hemorrhage
[Secondary Headaches] - Clinical features of the following
- Sinus headache
- Medication overuse headache
- Idiopathic Intracranial hypertension
- Low CSF pressure
- Sinus headache - feel pressure on sinuses –> dull, deep throbbing in center of head
- misnomer bc no pain receptors on sinuses
- worse in cold/damp weather, worse with bending down/leaning over and sudden movements
- allergies and asthmas are big risk factors - Medication overuse headache - >2x week
- regular overuse for >3 mos of drugs incl caffeine, excedrin, triptans, opioids, NSAIDs - Idiopathic Intracranial hypertension i.e. pseudotumor cerebri
- increase in CSF with no structural CNS abnormality or outflow obstruction
- looking at optic discs and see blurry edge, papilledema
- do spinal tap for immediate relief - Low CSF pressure - due to spinal taps
- positional - get worse on sitting/standing
- epidural blood patch - their blood will clot up spinal tap hole
[Secondary Headaches] - Clinical features of the following
- Chiari malformation
- Cranial neuralgias
- Temporal arteritis
- Chiari malformation - downward displacement of cerebellar tonsils into cervical canal - syringomyelia (Cavity in cervical region) common
- cape and shawl sensory distribution
- remove back part of bone for cerebellum to expand
- headache with valsalva (bending head forward, coughing) - Cranial neuralgias e.g. trigeminal neuralgia
- inject nerve to quiet it down
- older adults
- sharp, brief, lancinating pain - Temporal arteritis - systemic inflammation of temporal artery
- pain on chewing + headache –> can lead to irreversible monocular vision loss
- treat with steroids
Seizures 1. Define 2. Mechanism 3. Types: A. General B. Focal i. simple partial ii. complex partial iii. secondary generalized
- Seizure - transient episode with signs/symptoms of excessive synchronous neuronal activity (abnormal - brain should be doing different things!)
- physical patterns based on region of brain involvement - Mechanism - increased neuronal excitability (too much glutamate, aspartate; too little GABA) and reduced seizure threshold
- also excess synchronization and inability to self-terminate
- synapse channel remodeling makes it permanent - Seizure types
A. General - bilateral and symmetric
-GTC general tonic-clonic convulsion (tonic stiffening and clonic jerking) with sympathetic systems, tongue biting
- can also be atonic (drop), absence (brief staring, triggered by hyperventilation), myoclonic (brief jerks)
B. Focal seizures - abnormal electrical conductance in limited part of brain
i. simple partial - no alteration of consciousness
ii. complex partial - alteration of consciousness; gaze or head deviations; no recall of event
iii. secondary generalized - focal that quickly moves into general
Epilepsy
1. Define
- Categories
A. Idiopathic
B. Symptomatic
C. Cryptogenic
3. Localization symptoms A. Temporal B. Frontal C. Parietal D. Occipital
- Status epilepticus
- Epilepsy - seizures that are recurrent, unprovoked, stereotyped (coming from same area in the brain)
- Seizure categories
A. Idiopathic/Genetic -without particular cause, but probably polygenetic inheritance
e.g. childhood absence epilepsy
B. Symptomatic/Structural and Metabolic - attributed to known brain insult
e.g. tumor, injury, fever, metabolic
C. Cryptogenic/Unknown - v severe type of epilepsy but do not know why
e.g. infantile spasms
3. Localization symptoms A. Temporal i. medial - staring, automatisms, fear ii. lateral - staring, vertigo, hearing B. Frontal - brief, bizarre, nocturnal C. Parietal - sensory D. Occipital - visual phenomena
- Status epilepticus - seizures > 30 min
less important info
1. What are the steps to diagnosing epilepsy?
2. Specific types:
A. Lenox-Gastaut
B. West syndrome
C. Benign rolandic
3. Treatment
1. Diagnosis A. History B. Physical C. EEG - measures electrical activity generated by the cortex during wake and sleep (Esp stage 2 when most vulnerable to seizures) - look for spike and wave patterns
- Specific types:
A. Lenox-Gastaut - childhood-onset epilepsy more common in boys, tonic and atonic seizures; EEG shows slow spike and wave OR generalized paroxysmal fast activity (GPFA) seizure
B. West syndrome - infantile spasms with flexor/extensor events; EEG is chaotic with multifocal spikes; treat with ACTH
C. Benign rolandic - genetic and focal with gurgling, facial twitching; typically grow out of it - Treatment
- do not treat 1 seizure, at 2nd you diagnose epilepsy
and treat with anti-epileptic drug AEDs (max 2)
- then resective surgery
- if resective surgery not possible: ketogenic diet, vagal nerve or thalamic stimulation, corpus callosotomy for drop events (separate halves of the brain)
Treatment for dementia 1. Cholinesterase inhibitor A. Donezepil B. Rivastigmine C. Galantamine
- Memantine
- Drugs for BPSD (behavioral psychiatric symptoms in dementia)
- Drugs to avoid
Treatment for dementia - no curative treatment available, only slowing of decline in cognitive function
- Cholinesterase inhibitor - acetylcholine low due to loss of cholinergic neurons
- side effects - nausea/vomiting/diarrhea, bradycardia
A. Donezepil (Aricept) - noncompetitive, 1x daily, metabolized by CYPs
B. Rivastigmine (Exelon) - noncompetitive, oral 2x daily, for AD and PD
C. Galantamine (Razadyne) - competitive, 2x day, metabolized by CYPs - Memantine (Namenda) - noncompetitive NMDA-receptor antagonist
- used for more severe AD
- no interactions with CYPs - Drugs for BPSD (behavioral psychiatric symptoms) incl anxiety, depression, paranoia, agitation
- antidepressants, atypical antipsychotics (increased risk of stroke) - Drugs to avoid - drugs that aggravate cognitive impairment
- anticholinergics
- benzodiazepines
- other sedatives or hypnotics
List the representative drugs of choice for
- partial seizures
- generalized tonic‐clonic seizures
- absence
- myoclonic seizures
- status epilepticus
- partial seizures (simple and complex) - carbamazepine, phenytoin, valproate [conventional narrow spectrum drugs]; lamotrigine, topiramate, lacosamide [new broad spectrum]
- generalized tonic‐clonic seizures (grand mal)- carbamazepine, phenytoin, valproate [conventional]; levetiracetam [new]
- absence (petit mal)- ethosuximide (inhibits Ca2+ currents), valproate [conventional]
- myoclonic seizures - valproate, phenobarbital [conventional]; levetiracetam [new]
- status epilepticus - phenobarbital [conventional]; lorazepam [new]
Identify the 3 major mechanisms of antiseizure drug action
- Inhibit glutamate excitatory transmission (bc seizures due to increased neuronal excitability and hypersynchronization)
- drugs don’t have specific MOA, can affect multiple ion channels or receptors - Enhance GABA inhibition (either presynaptic or postsynaptic)
- GAPA transporters, transaminase, or GABA receptors
- GABAa - ion channel; activate to increase Cl- inflow –> hyperpolarization
- GABAb - Gprotein coupled receptor - Modify ion conductance
A. inhibit / inactivate Na+ channels –> reduce frequency of neuron firing [barbiturates, benzodiazepines]
B. Inhibit T-type Ca2+ channels; esp for absence seizures
Phenytoin
- MOA
- Use
- Pharmacokinetics
- Interactions
- Adverse effects
Phenytoin - oldest nonsedative anti-seizure drug
1. MOA: binds to and inactivates Na+ channels –> blocks repetitive firing of action potentials; decreases synaptic release of glutamate and increases GABA release
- Use: partial/focal seizure, generalized tonic-clonic seizures
- fosphenytoin (prodrug form) for IV, IM administration - Pharmacokinetics: highly hydrophobic, highly bound to plasma proteins –> 1/2 life 12-36 days (long)
- dose dependent absorption and elimination
- metabolized by CYP450s - Interactions: 99% bound to albumin; valproic acid competes for protein binding site –> increased free phenytoin; enhances enzymes responsible for OCP metabolism
- Toxicity: diplopia, ataxia, also hirsutism and gingival hyperplasia
- long-term: peripheral neuropathy, osteomalacia, low folate levels (megaloblastic anemia)
Carbamazepine
- MOA
- Use
- Pharmacokinetics
- Interactions
- Adverse effects
Carbamazepine -
- MOA: many MOAs incl. prolonging recovery of Na+ channels from inactivation –> limits repetitive firing of action potentials
- decreases synaptic release of glutamate - Uses: primary drug for partial/focal and generalized tonic-clonic seizures (others used are phenytoin and valproic acid)
- Pharmacokinetics: complex; hydrophobic, absorbed slowly and erratically; metabolite is active, induces CYPs; no protein binding
- Interactions: its metabolism by CYP3A4 is induced by phenytoin, valproic acid, phenobarbitol; administering with valproic acid reduces latter’s concentration
- Adverse effects: diplopia, ataxia, agranulocytosis (leukopenia i.e. decreased WBCs), headache, dizziness; cognitive effects
- Asians at increased risk of inducing Stevens-Johnson syndrome
Valproic acid
- MOA
- Use
- Pharmacokinetics
- Interactions
- Adverse effects
Valproic acid
- MOA: prolongs recovery of Na+ channels from inactivation –> blocks high-frequency firing of action potentials
- increases amount of GABA in CNS - Uses: myoclonic seizures e.g. juvenile myoclonic epilepsy
- absence (also ethosuximide- blocks T-type Ca2+ channels)
- generalized tonic-clonic + partial/focal (also phenytoin and carbamazepine) - Pharmacokinetics: well absorbed rapidly and completely; 90% binding to plasma proteins, 95% hepatic metabolism; 1/2 life <15 hrs
- Interactions: Inhibits metabolism of phenytoin, phenobarbital, lamotrigine, lorazepam
- can displace phenytoin from albumin - Adverse effects: GI distress, sedation
- long-term: weight gain, hepatotoxicity, pancreatitis, teratogenic
Phenobarbital
- MOA
- Use
- Pharmacokinetics
- Interactions
- Adverse effects
Phenobarbital - oldest available, barbiturate
1. MOA - many, don’t really know - blocks Na+ reactivation and Ca2+ channels, decreases glutamate release, increases GABA
- Use - status epilepticus, virtually every seizure type
- Pharmacokinetics - complete but slow absorption; 50% bound to plasma proteins; inactivated by CYPs
- Interactions - induces UGT enzymes
- Adverse effects - low toxicity; sedation, nystagmus, ataxia, rash
less important material
- Describe the important pharmacokinetic and pharmacodynamic considerations
relevant to the long‐term use of antiseizure drugs - Toxicities of new antiseizure drugs:
lamotrigine
gabapentin
topiramate
- Anti-seizure drug use continues for 2+ years; taper slowly off them
- drug resistance
- poor absorption or rapid metabolism
- inhibit drug metabolism
- long-term use of phenytoin -> coarsening of facial features, hirsutism, peripheral neuropathy, osteomalacia, teratogenicity - Toxicities of new antiseizure drugs
- skin rash, risk of Stevens-Johnsons in Asians (lamotrigine)
- sedation and dizziness + poor efficacy (gabapentin)
- somnolence, fatigue, myopia, acute angle close glaucoma (topiramate)
For each subdivision of the hypothalamus [rostral-caudal], describe the nuclei, functions, and lesions:
- Preoptic area
- Anterior (supraoptic) region
- Middle (tuberal) region
- Posterior (mammillary region)
* all lesion symptoms together = hypothalamic syndrome
ANALOGY - CAR: anterior (hood) - cooling posterior (exhaust) - heating lateral (gas cap) - hunger ventromedial (gas tank) - satiety suprachiasmatic (sun roof) - sleepy
- Preoptic area:
A. Medial preoptic nucleus
B. Lateral preoptic nucleus - heat loss center, parasympathetic –> hyperthermia - Anterior (supraoptic) region - “Rest, Rhythms, Ruminate, Reproduce”
A. Periventricular
B. Suprachiasmatic [retinal input]- circadian rhythms/sleep
C. Anterior nucleus - sleep –> insomnia
D. Paraventricular and supraoptic nuclei - magnocellular cells synthesize ADH and oxytocin –> sent to posterior pituitary; lesions result in diabetes insipidus (polydipsia + polyuria) - Middle (tuberal) region
A. Dorsomedial nucleus –> lesion leads to passivity
B. Ventromedial nucleus - satiety center –> bilateral lesions lead to hyperphagia and obesity + rage/aggressive behavior
B. Lateral hypothalamic nucleus- hunger center –> bilateral lesions lead to anorexia
C. Arcuate nucleus - parvocellular cells secrete releasing hormones that control release of anterior pituitary hormones (ACTH, TSH, LH/FSH, GH, prolactin) –> lesion causes decreased secretion
*dopamine regulates secretion of prolactin - Posterior (mammillary region)
A. Posterior nucleus - heat conservation center, awakeness –> poikilothermy (temp varies with environment), sleepiness
B. Mammillary bodies - memory consolidation
