Basal Ganglia Flashcards
1
Q
4 Major Structures
A
- Striatum = caudate + putamen (divided by internal capsule); input
- Substantia nigra = pars compacta + pars reticulata
- Subthalamiic nucleus = input nucleus
- Globus Pallidus (GP) = internal (similar to pars reticulata) + external
2
Q
Basic Loop Skeleton
A
- Cortex —> input stage of striatum —> output stage in GPi or SNr —> special region in VL thalamus —> back to specific area of cortex
- Also input from SNc to striatum
- Also input from sub thalamic nucleus —> GP
3
Q
Which neurotransmitters are secreted at each part of loop?
A
- Cortex —> striatum is excitatory (glutamate)
- Striatum —> GPi or SNr is inhibitory (GABA)
- GPi or SNr —> thalamus is inhibitory (GABA)
- SNc —> striatum is excitatory (dopamine)
- Subthalamic nucleus —> GPi/SNr is excitatory (glutamate)
4
Q
Rate Model of BG Dysfunction
A
- Parkinsons
- Removal of dopamine excitation from SNc —> dec stratal inhibition of GPi —> inc GPi inhibition of VL —> less motor output (hypokinesia)
- Hemibalism
- Removal of excitation from sub thalamic nucleus —> dec inhibition by GPi of VL thalamus —> inc motor output (hyperkinesia)
5
Q
3 Ways Rate Model Fails to Explain BG Dysfunction
A
- 1- does not explain rigidity and tremor in Parkinsons
- 2- Pallidotomy (surgical removal of globes pallidus) helps Parkinsons while you would expect that no GPi would cause hyperkinesia
- 3- Abnormal patterns of firing tends to correlate w/ severe disease not simple patterns
6
Q
4 Reasons the BG is so easily damaged
A
- High metabolic demand; needs oxygen
- Vulnerable to hypoxia
- CO
- High conc of certain neuroTs (GABA, dopamine, Ach, Serotonin) so any problem in production, storage, metabolism or release of these causes problems
- High conc of heavy metals (toxic accumulation)
- Copper -
- Iron - in GP and SNr (Hallervorden-Spatz disease - dystonia)
- Manganese - in GP and subthalamic nucleus - Parkinson-like
- Selective affinity for MPTP (contaminant in homemade heroin)
- Akinesia and rigidity (Parkinson-like)
7
Q
4 Hypothesis About Role of BG
A
- Selection of desired movements and suppression of those that compete w/ them
- Retention and recall of procedural knowledge
- Linking cost and benefits to how behaviors are performed
- Tutors or trains cortical circuits for certain skills or habits
8
Q
3 Categories of BG Movement Disorders
A
- Hypokinetic
- Akinesia - problem w/ initiating movement
- Bradykinesia - can initiate but then slow performance
- Hyperkinetic
- Involuntary movements
- Chorea
- Athetosis
- Torsion spasm (torsion dystonia) - tonic contraction of proximal body
- Resting tremor in Parkinsons
- Involuntary movements
- Change in muscle tone
- Inc - rigidity in Parkinsons
- Dec - Huntingtons
9
Q
Chorea v Athetosis
A
- Chorea - rapid, sporadic, fragmented dance-like movements (Huntingtons)
- Athetosis - slow spreading contractions of closely related muscle groups
10
Q
Rest v Action Tremors
A
- Rest Tremor - when limb is supported against gravity not activated (Parkinsons); 4-6 Hz
- Action Tremor - during voluntary movement
- Postural - when limb is in set posture but not at rest
- Kinetic -when limb is in motion (intention or terminal)
- Task-specific
11
Q
Essential Tremor
A
- MOST COMMON (10% of those over 65 yo)
- Autosomal dominant
- Upper limbs > head > lower > voice & usually bilateral
- Usually manifests in 20s or 60s
- No visible pathology BUT think it is inferior olive —> cerebellum —> thalamus —> motor cortex pathway
- Tx (all dec amp not frequency)
- Beta blockers (esp propanolol b/c crosses BBB)
- Primidone (anti-convulsant; metabolized to phenobarbital); somnolence
- Deep Brain Stim - stimulate Vim thalamus so no permanent lesion
- Gamma knife —> irreversible lesion to thalamus
12
Q
Cerebellar Tremor
A
- SLOW (2-4 Hz) and intention so at end of movement
- Tx same as essential but less effective overall
13
Q
Psychogenic Tremor
A
VARIABLE (abrupt onset, distractable, spontaneous episodes)
14
Q
2 Genetic Variations of Dystonia
A
- DYT1 mutation - affects torsin A (chromosome 9); may be involved in protein folding/trafficking; high concentrations in SNc; usually childhood onset
- DYT5 (Dopa-responsive dystonia) - generalized dystonia in early childhood w/ diurnal variation; marked improvement w/ L-dopa; caused by mutation in GTP cyclohydrolase (makes co-factor) or tyrosine hydroxyls (both needed for dopamine production)
15
Q
Types of Primary Dystonia (5)
A
- Primary
- Only abnormal finding
- Usually generalized/hereditary in kids & focal/random in adults
1- Cervical dystonia - co-contraction of neck and shoulder muscles
2- Blepharospasm - forced eye closures
3- Oromandibular dystonia - contraction of jaws, mouth, lower face
4- Laryngeal dystonia - vocal cords affected to hyper adduction during speech
5- Task - specific - writer’s cramp or athletes or musicians
16
Q
What is the proposed pathology of dystonia?
A
Abnormal activation patterns from GP to thalamus —> inc in synchronous contraction of agonist/antagonist —> unwanted overflow movement
17
Q
Dystonia Tx
A
- First line = botulinum toxin (prevents release of Ach at NMJ); repeat every 3-6 mo
- May also try anticholinergics, benzodiazepines, dopamine-depleting drugs
- Last resort = DBS to GPi not thalamus (need higher levels of stimulation)
18
Q
How does Parkinson’s affect both direct and indirect pathways?
A
- Direct Path: Motor cortex –> putamen –> GPi/SNr –> thalamus –> motor cortex (GO)
- D1 excitation on putamen
- NO dopamine means … less inhibition of GPi by striatum so more GPi inhibition of thalamus/motor
- Indirect Path: Motor cortex –> putamen –> GPe –> STN –> GPi –> thalamus –> motor cortex (INHIBITS)
- D2 inhibition on putamen
- NO dopamine means … less inhibition of putamen by dopamine – > more inhibition of GPe by putamen –> less inhibition of STN –> excites GPi so more GPi inhibition of thalamus/motor
19
Q
5 Intracellular Mechanisms of Parkinson’s Pathology
A
- Mitochondria impairment
- Oxidative stress
- Protein misfolding and aggregation (Lewy bodies - cytoplasm inclusions - proteins aggregate)
- Alpha - synuclein
- Failure of ubiquitin-proteasome system to remove proteins
- Inflammation
20
Q
Parkinson’s Epidemiology
A
- Inc risk if male (2:1) and age; some monogenetic but very rare; usually combo of genetic and environmental factors
- 2nd most common neurodegenerative disorder behind Alzheimer’s
- 1-2% of those 65 yo +
21
Q
3 Categories of Parkinson’s Symptoms + Which are Cardinal?
A
1- Pre-motor (dec sense of smell, constipation, acting out dreams b/n no paralysis in REM)
2- 4 cardinal motor symptoms
3- non-motor (depression, anxiety, cognitive problems later in disease)
- Bradykinesia (necessary for dx) + 1 other cardinal motor sign (rest tremor, rigidity, postural instability/gait imbalance/freezing/festination)
- Festination = cannot stop once walking
- Freezing = walking in place - cannot move forward
22
Q
Parkinson’s Differential Dx
A
- Atypical parkinsonian syndromes - parkinson’s + extra signs (multiple system atrophy, supranuclear palsy w/ vertical gaze palsy, corticobasal degeneration, dementia w/ Lewy bodies)
- If acute or step-wise probably vascular (mini-stroke or microvascular disease in brain)
- Medication- induced (neuroleptics that block dopamine receptors, lithium)
- CO, manganese, post-encephalitis
23
Q
Parkinson’s Tx
A
- Pharm
- L dopa + Carbidopa (sinemet) - L dopa crosses BBB while carbidopa does not so just prevents peripheral breakdown
- D2 receptor agonists
- MAO B inhibitors
- COMT inhibitors (inchalf life of L dopa)
- DBS
- Used later when dyskinesia b/n L-dopa doses; persistent stimulation of the subthalamic nucleus –> normalize STN output to GPi
24
Q
Myoclonus + Classification + Tx
A
- Myoclonus - brief, shock-like, rapid movements
- Arise in CNS and cannot be suppressed by pt
- Pos - sudden contraction (jerk)
- Neg - sudden dec in tonic contraction; can no longer hold self up against gravity (“asterixis”)
- Classification
- Clinical/Descriptive - when (spontaneous, action, reflex) & where (generalized, segmental, focal, multi-focal)
- Physiological - cortical, subcortical or spinal localization (may predict which drugs will work and know what imaging to order)
- Etiology - cause
- Physiological - NO BRAIN DISEASE (hiccups or hypnic jerks when falling asleep)
- Essential - rare hereditary syndrome; myoclonus is only feature; resolves w/ alcohol
- Symptomatic - secondary to underlying brin disease
- Ex) Paraneoplastic, epilepsy, degenerative disease like Alzheimer’s or Lew bodies or prions, post hypoxia, drugs (SSRIs, narcotics, cocaine), metabolic - Tx - treat underlying cause; cortical myoclonus may respond to anticonvulsants (valproate, clonazepam, levetiracetam)
25
Q
Tics + Common Causes
A
- recurrent, non-rhythmic, stereotyped movements or sounds
- Can be simple or complex
- “Unvoluntary” - b/c can be suppressed (but then rebound after) BUT preceded by pressure/unpleasant feeling that is only resolved by tic
- Primary
- Hereditary and childhood onset
- Transient childhood tics, chronic motor tics, Tourettes - Secondary
- Manifestation of other brain disease; adult onset
- Drugs, post strep infection in kids (PANDAS), neurodegenerative disease
26
Q
Tourette’s
A
- Hereditary
- Dx - multiple motor tics + at least 1 vocal tic + distress/impairment + younger than 18 + not due to other brain problem
- Tx - neuroleptics, dopamine depletor, benzo (clonazepam), alpha agonist (clonidine), atypical anti-psychotic
27
Q
What is Wilson’s disease?
A
- Hereditary, autosomal recessive
- Prob w/ copper metabolism; mutation —> loss of function of trans-golgi ATPase that normally transports copper so it can be excreted in bile
- SO… copper accumulates in tissues (including basal ganglia)
28
Q
How does Wilson’s disease present?
A
- Mixture of motor problems b/c basal ganglia is so widespread (cerebellar ataxia, tremor, dystonia, psych probs, bulbar/facial involvement)
- Facial dystonia —> retracted upper lip (silly smile)
- Brown rings in cornea b/c copper deposits
- Liver disease, hepatitis, cirrhosis, hemolytic anemia, amino aciduria
- Labs… LOW serum caeruloplasmin (normally binds copper but now misfolds instead), LOW serum copper, HIGH urine copper
29
Q
How do you treat Wilson’s Disease?
A
- important b/c curable if early but fatal if not
- Inc urinary copper excretion - penicillamine or trientene (bind copper in blood then excrete in urine)
- Zinc salts - induce gut genes that encode proteins that bind dietary copper so not absorbed to begin with
- Liver transplant may be needed
**Should test siblings + genetic counseling
