Quiz #4 Flashcards
Basal Ganglia Pathways - Summary
- The “natural” tendency of the direct pathway is to facilitate movement.
- The “natural” tendency of the indirect pathway is to decrease movement.
- Dopamine facilitates movement:
• it activates the direct pathway via D1 receptors
• it inhibits the indirect pathway via D2 receptors - Acetylcholine goes with the “natural” tendency of the pathway: • it activates the direct pathway – facilitating movement • it activates the indirect pathway – decreasing movement
Neurotransmitters in the BG
In Striatum
1. Acetylcholine (ACh) is excitatory to the direct and indirect pathways
2. Dopamine is excitatory through D1 receptors to the direct pathway
3. Dopamine is inhibitory through D2 receptors to indirect pathway
*** Thus, the direct pathway is excited by both ACh and dopamine
and the indirect pathway is excited by ACh and opposed by dopamine
In Pathways (direct and indirect)
- Glutamate (GLU) is excitatory
- GABA is inhibitory
Key points about BG circuits
1. The connection between the substantial nigra pars compacta and the striatum is dopaminergic.
2. Both direct and indirect pathways go from the striatum to the globus pallidus pars interna (GPi) and the substantia nigra pars reticulata (SNr).
• Direct pathway goes there directly (GABAergic neuron)
• Indirect pathway has interposed: two GABAergic neurons [one to GPe and then to subthalamic nucleus (STN)], and one glutamatergic neuron
- The output from the GPi/SNr is inhibitory to the thalamus (GABA).
- The output from the thalamus is excitatory to the cortex (GLU).
Parkinson’s - mechanism of decreased movement
1. Direct Pathway Effects
• Without dopamine the direct pathway, which normally favors movement, becomes less active and thus produces less movement
• ACH acting in the direct pathway as an “activator” can try to compensate, but net effect is a decrease in the activity in the direct pathway
2. Indirect Pathway Effects
• Without dopamine the indirect pathway, which favors “no movement”, becomes less inhibited, i.e. more active and thus produces less movement
• ACH further excites the indirect pathway and the net effect is increased activity in the indirect pathway
levodopa (+/- carbidopa)
MOA: precursor of dopamine; carbidopa inhibits peripheral metabolism via dopa decarboxylase
Clinical: most efficacious drug used in Parkinson’s disease (PD)
Kinetics: oral COMT and MAO type B inhibitors can prolong effect; initial honeymoon phase, doses can last around 5 or more hours; afterwards typically 3-4 hours
SEs: GI upset dyskinesias behavioral effects
Notes: on-off phenomena
dopamine agonists:
Names:
pramipexole; ropinirole apomorphine–short acting injectable rotigotine (long acting transdermal form)
bromocriptine– NOT used in PD
MOA: D2 agonists (apomorphine bromocriptine, and ropinirole); D3 agonist (pramipexole)
clinical: pramipexole, ropinirole, rotigotine used as sole agents at various stages of PD but side effects may outweigh benefits in later stages s adjunct to L-dopa s apomorphine used as rescue therapy
kinetics: oral
pramipexole: short half-life (tid dosing), renal elimination ropinirole, CYP1A2 metabolism, drug interactions
possible long-acting formulations available
transdermal rotigotine provides 24hr dopamine agonist coverage
SEs: anorexia, nausea, vomiting constipation postural hypotension dyskinesias mental disturbances (psychosis); sudden sleepiness;compulsive behaviors (e.g., shopping & gambling) . . .
Notes: pramipexole and ropinerole being non-ergot agonists, do not have as significant cardiac and GI effects as ergot agonists; still need to monitor for hypotension; few cases of cardiac issues of pramipexole but not clearly defined so still used
bromocriptine is an ergot and not widely used because of ergotism, vasoconstriction, erythromelalgia
MAO inhibitors
Names: rasagiline, selegiline
Mech: inhibit MAO type B
clinical: rasagiline/selegiline for mild PD s both drugs adjunctive with L-dopa
kinetics: oral s selegiline has amphetamine metabolite–BID dosing w/ second dose given in early afternoon; rasagiline is given once daily
SEs: typically well tolerated with mild nausea, GI upset or dizziness reported; metabolized in liver; renally excreted
Notes: typically avoid meperdine, tramadol, and dextromethorphan–risk of serotonin syndrome s extremely rare risk of serotonin syndrome with TCA’s and SSRI’S
COMT inhibitors
names: entacapone and tolcapone
MOA: block L-dopa metabolism by COMT in periphery (both) and dopamine metabolism by COMT in CNS (tolcapone only)
clinical use: prolong L-dopa actions
kinetics: oral, multiple daily dosing
SEs: relates to increased levels of L-dopa (see above) acute hepatic failure (tolcapone)
Notes: urine can be discolored orange
antimuscarinic agents
names: trihexyphenidyl; benztropine
MOA: decrease excitatory actions of cholinergic neurons in striatum by blocking muscarinic receptors
clinical use: improve tremor, rigidity, dystonia
kinetics: multiple daily dosing
tox: typical “atropine-like” side effects: dry mouth, blurry vision, urinary retention, avoid in those with glaucoma
notes: trihexyphenidyl used for PD; benztropine more for druginduced parkinsonism
Amantadine
“dirty drug”;
MOA: NMDA receptor antagonist; anticholinergic properties, releases dopamine from nerve terminals
clinical use: good for mild symptoms, dystonia and for dyskinesias s adjunct to L-dopa
kinetics: TID standard dosing; can be used QID
tox: constipation, livedo reticularis, dry mouth, dry eyes, urinary retention, psychosis, fatigue, myoclonus
notes: only drug to treat L-dopa induced dyskinesias but efficacy is not long lasting s originally developed as antiflu medication
Brainstem development & columns
Basal Plate: efferent
- general somatic efferent (GSE) - striated muscles of trunk and limbs, also tongue and eye movements
- general visceral efferent (GVE) - pregnaglionic parasympathetic neurons (autonomic control),
- —inneravtes smooth muscles of glands, gut, lungs and cardiac muscles
- special visceral efferent (branchial arches)
Lateral Plate: afferent
- general visceral afferent (GVA) - sensory info from thoracic and admonial viscera
- general somatic afferent (GSA) - sensory info from body wall
Functional Classes of Cranial Nerves
Alar - sensory: (lateral)
- SSA (special somatic afferent): 8
- GSA (general somatic afferent): 5, 7, 9, 10
- SVA (special visceral afferent): 7, 9, 10 [taste- to NTS]
- GVA (general visceral afferent): 9, 10
Basal - motor: (medial)
- GVE (general visceral efferent): 3, 7, 9, 10
- SVE ( special visceral efferent): 5, 7, 9, 10, 11
- GSE (general somatic efferent): 3, 4, 6, 12
Branchial Arches
first:
- Nerve: mandibular of trigeminal (V3)
- muscles: mastication, temporaliz, tongue stuff, mylohupid, tensor typani, tensor palatini, ptetygoids
second:
- nerve: facial nerve (CN7)
- muscles: facial expression, stylohyoid, platysma
third:
- nerve: glossopharyngeal (CN 9)
- muscle: stylopharyngeuous
fourth & sixth:
- nerve: vagus (CN 10)
- muscles: larynx and pharynx
fifth dissapeared
Facial Nerve (CN 7)
nerve of second cranchial arch
sensory and motor
Functional Components:
- GSA: sensations from skin of the concha of the auricle, small patch of skin behind ear
- SVA: taste from anterior 2/3s of tongue
- SVE: muscles of facial expression, styolohyoid, stapedius
- GVE: lacrimal, submandibular and sublingual glands - mucus membranes of nose, hard/soft palate
cranial nerve motor/sensory
purely motor:
3, 4, 6, 11, 12
purely sensory:
1, 2, 8
both:
5, 7, 9, 10
primary intracranial tumors
38%: meningioma 30%: neuroepithelial 16%: pituitry craniopharygioma 8%: cranial nrve sheath 2%: lymphomas 6% other
glial cell development
types of macroglia: - astrocytes - oligodendrocytes -ependymal cells (microglia are resident cells of innate immune system -- not neuroepithelial derived)
tumors from these cells all resemble each other (glial tumors)
Glial tumors
Astro:
- PCA: Grade 1, pilocytic astrocytoma (generally cured with srugery), do not progress
- SEGA: Grade 1, subependymal giant cell tumor
- Diffuse astrocytoma: Grade 2
- PXA: Grade 2, pleomorphic xanthatrocytoma
- PMA: Grade 2, ?
- anaplastoc astrocytoma: Grade 3
- glioblastoma (multiforme): Grade 4
Oligo:
- oligodendroglioma: Grade 2
- anaplastic oligo-dendroglioma: Grade 3
Epend:
- SE: grade 1, subependymoma
- MPE: grade 1, myxopapillaru ependymoma
- Ependymoma: grade 2
- anaplastic ependymoma: grade 3
Grade 1: non-infiltrating
Grades 2-4: infiltrating
low grade = grades 1 and 2
identifying infiltrative astrocytoma
slow growing, relatively little mass effect
subtle infiltration, best stained with IDH1
high grade feature: hypercelluarity and mitotic figure
frontal, temporal common, rarely seen in cerebellum
IDH1
mutated in many lower grade infiltrating astrocytomas and oligodendrogliomas
- can be helpful distinguishing between a neoplastic ocondition and a reative one
- produces and oncometabllite that impacts cellular orcessing
oligodendroglioma
purple clumps of calcifications
chicken wire - branching capillary vasculature
uniform cells with bland round nuclei and “fried-egg” appearance to cytoplasm (arrtifact)
common 1p/19q co-deletion
- if increased cell density and mitotic figures - anaplastic
mostly in adults frontal lobe white matter is common (60%) often present with seizures - median survival ~10 years - need IDH mutation AND p1/q19 deletions
glioblastoma
butterfly shape (impacts corpus callosum)
- hemorrahage and necrosis
- palisading necrosis
- microvascular proliferation
- IDH mutated is actually good for survival
- molecular subclass is a better way to segregate groups by urvival than histological criteria alone
ependymoma
perivacular pseduorosette
true ependymal rosettes
common in kids - posterior fossa (4th ventricle)
- adults: spinal or surpatentorioal (rare in kids)
pilocytic astrocytoma
cystic mass with mural nodule
biphasic architexture with dense and microcystic areas
- often occurs in children as a cerebellar mass but can occur in adults in other places
- oftne have BRAF alternaions
- pilocytic means hair-like - cells may have hair-like processes, often in bipolar arrangement
medulloblastoma
small blue cells,
homer wright rosete formation
molecular subtypes: WNT, SHH, C and D
– subgroup prognostics are age dependent (ex: SHH bad in adults but good in infants)
grade 4 most common in kids in the posterior fossa
meningioma
extra-axial mass dural tail usually grade 1 unless seen to be invading WHOLRS psammoma bodies (bright pink) more common in females than males, esp spinal (9:1) - most common intracranil tumor - usually benign
mets to brain
most common: lung, breast, colorectal, kidney (RCC), melanoma
prostate rare
dorsal spinocerebellar tract
peri[heral neurons enter below L3 and ascends in fasciculus gracilis then terminates in CLark’es nucleus
(T1-L2), lamina 6
enters via inferior cerebellar peduncle
terminates in intermediate zone of cerebellum (ipsilateral)
(cuneocerebellar – similar but for cervical area)
ventral spinocerebellar pathway
originates from border cells
crosses midline in anterior white commisure to form the ventro spino tract
enters cerebellum via superior cerebellar peduncle
and then corsses the midline AGAIN within the cerebellar white matter
terminates in vermis and intermediate zone
rostral – similar start in border cells. doesnt do the weird double criossing thing - enters via interfior cerebellar peduncle
cell types in cerebellum
inputs:
- mossy fibers –> granular cells
- climbing fibers –> Purkinje cells
outputs:
- Purkinje cells –> deep cerebellar nuclei
mossy fibers excite granular cells–> these excite purkinje cells
climbing fibers excite Purkinje cells (one to one)
Purkinje cells inhibit deep cerebellar nuceli
stellate, basket and goli cells are all inhibitory
Headache disorders
primary: - migraine - tension - cluster secondary: - brain tumors - anuerysms - infection - hangover - nose/sinus - head trauma
red flags for headache –imaging
systemic signs - rash, stiff neck neuro symtpmtoms onset - new or changed older patient onset - thunderclap or worst in life tinnitus, positional provocations, precipitated by exercise side locked
migraine
5 or more episodes 2 of 4 key characterstics: 1. one-sided 2. moderate to severe 3. throbbing 4. worse with activity associated with at least 2 of these symptoms: - light and sound sensitivyt - nasuea/ vomitting
lasts 4-72 hours
30% have aura (cortical spreading)
regualted by brainstem, vascular control centers
pain centers, trigeminal nerve, anterior cingulate gyrus
migraine generator: raphe nucleus, locus ceruleus, periaquductal grey matter
5 phases of migraine attack
- premonitory: yawn, mood, cravings, fatigue, thirst, stiff neck
- aura – visual, dizziness,
- headache - pain, light and sound sens, nausea, autonomic
- reoslution, pain fades, sleep
- postdrome: mood, hungover, hunger, urination
migraine treatment
abortive treatment:
triptans - serotonin receotpr agonists –vascualr contraindications
NSAIDs and antiemetics
prevention:
- antiepileptics, tricucly depressanrs, SSRIs, botox
supplemtns, gadgets
manic episode
for at least one week - mood: elevated and expansive, irritable - affect: happy, labile Cognitive: - distracted - inflated and grandiose - hyper religious and hyper sexual - racing thoughts, flight of ideas psychomotor/behavior: - hypertalkative - decreased sleep reackless, impulsive can be psychotic
treat with mood stablizer - valproate, lithium and maybe also add antidepressant (but never without mood stsbilzer)
medications for Tourette’s
alpha 2 agonists: guanfacine anti-epileptics: topiramte dopamine depletors: tetrabenzine atypical antipsychoticsL risperidone, aripiprazole typical antipsychotics - fluhenazine benzodiazepines: clonazepam botox
corticobulbar pathway
supranuclear lesions cause contralateral paralysis of lower face (upper motor neurn type)
lower motor neuron – whole face (still contralteral)
more crossed than uncrossed
contralteral paralysis in genioglossuss - tongue will deviate to contrlateral side of the lesion
if UMN: away from lesion
if LMN: towards lesion
auditory pathway
- cohclear division of CN 8–>
- ventral cochlear nuclei –>
- dorsal cochlear nuclei –>
- superior olivary complex –>
- trapezoid body –>
- lateral lemniscus –>
- inferior colliculus –>
- brachium of inferior colliculus —>
- medial geniculate nuclei –>
- primary auditory cortex
