Flashcards in Lectures 34-36, 38, Basal Ganglia and OCD Deck (108):
Basic basal ganglia connectivity
Cerebral cortex--> striatum --> globus pallidus / substantia nigra --> thalamus --> cortex
Inputs to BG and corresponding NTs
Cortex (glu), thalamus (glu), midbrain (DA), raphe nuclei (5-HT), locus coeruleus (NE)
Major cortical input to BG is from which lobe?
Thalamic inputs to BG (3)
Ventral, intralaminar, medial dorsal
Two parts of the SN and their NTs
SN pars compacta = DA; SN pars reticulata = GABA
LC and Raphe are located in which brainstem region?
Parts of the striatum. Basic function?
Dorsal (C + P); Ventra (NAS, olfactory tubercle); receives most extrinsic projections
Where is the nucleus accumbens located? What NT?
Leans on septum pellucidum in the ventral portion of the striatum; GABA
Where is the olfactory tubercle located? What NT?
Medially, below the anterior commissure; GABA
Where is the subthalamic nucleus located?
Medially to BG, caudal to thalamus
What cell type in the striatum receives inputs and projects outputs? What NT?
Medium spiny neurons; GABA
Two types of medium spiny neurons (organize via their respective NTs and receptors)
1. substance P, D1 (excitatory via adenylyl cyclase); 2. enkephalin, D2 (inhibitory via adenylyl cyclase)
Where does the dorsal striatum project to? (2)
Globus pallidus (internal and external segments); Substanti nigra (pars reticulata and compacta)
Where does the ventral striatum project to? (2)
Ventral pallidum and VTA
More likely to visualize which segment of GP in cross section?
Where is the ventral pallidum?
Ventral to the GP (beneath anterior commissure)
The major outputs from the BG are all ________ and arise from? (3)
GABAergic; GPi, SNpr, VP
Where do the major outputs from BG system project to? What do you notice about this?
Mostly thalamus: Ventral groups, MD, ILN; same areas as major inputs!
Fiber bundles from BG to thalamus...combine with what?
Thalamic fasciculus w/ cerebellar efferents
Then where does the thalamus project?
The same frontal lobe structures that input into BG (mostly motor)
Inputs to BG are mostly what? Outputs are mostly what?
What are the functions of the five loops of the BG
Motor, oculomotor, cognitive (2), limbic
Model of BG function states...Which family of medium spiny neurons?
Direct (striatonigral) Path facilitates movement through disinhibition of thalamocortical activity; substance P/D1
The end of the direct path stimulates where, which loops back to where? And who projects DA to where?
VA/VL --> cortex; SNpc to striatum
How is the indirect pathway different?
SNpc projects to D2 receptors in striatum, which is inhibitory --> GPe --> disinhibits STN --> excites GPi/SNpr --> inhibits thalamus and cortex
What does the indirect pathway result in?
Inhibits BG output by increasing inhibition of thalamocortical pathway
What is the hyperdirect pathway? Describe the path.
Fast way to repress undesired behaviors (because indirect would be slower); Ctx --> STN --> (+) output structures of thalamus (GPi/SNpr)
What happens to the direct pathway in PD, broadly and specifically.
DECREASED, SNpc is damaged, so striatum is less active, so it does NOT disinhibit output structures, leading to inhibited thalamus/cortex
What happens to the indirect pathway in PD?
INCREASED, SNpc is damaged, so striatum is MORE active, suppressing GPe, disinhibiting STN, more activity in output structures, suppressing activity of thalamus and cortex
Huntington's Disease is characterized by what change to the BG?
Atrophy of medium spiny neurons in dorsal striatum
HD is primarily thought to affect what pathway? How?
Indirect pathway; loss of striatum leads to overactive GPe, an inhibited STN, so no excitation to the output structures, so no inhibition of the thalamus/cortex
Hemiballismus is characterized by what symptom and what nucleus damage?
Wild, flailing muscles; STN
Describe the pathway in Hemiballismus
No STN in indirect pathway means no excitation of the output structures, so overactive thalamus and and cortex
Parkinson symptom constellation (4)
Bradykinesia, rigidity, postural instability, tremor
Parkinson ancillary features (3)
Freezing, hypophonia, bradyphrenia (slow thinking)
Asymmetrical onset, pill rolling, 3-5 Hz, postural re-emergent tremor, resting, chin/tongue, disappears in sleep
What other disease has a postural re-emergent tremor?
Poor dexterity with decrementing (worsening) rapid alternating movements, micrographia, hypomimia, infrequent blinking
Increased resistance to passive movement (ratcheting)
Short strides, multipivot turn, loss of postural reflexes (>2 steps to recover from push = impaired)
Cardinal feature of PD? (and 4 related symptoms)
Asymmetric: rigidity, tremor, slowness, postural instability
Supportive features for PD diagnosis
Proressive and marked improvement with levadopa
Name and describe the major pathological finding of PD
Lewy body! Eosinophilic inclusion in neuron containing ubiquinated protein, alpha synuclein and neurofilament; forms due to misfolded alpha synuclein that cannot be cleared
What do misfolded alpha synuclein proteins form into?
Is the Lewy Body itself pathogenic?
No! Attempt to deal with oxidative stress, etc caused by amyloid fibrils
T/F: Lewy Bodies can be transferred between neurons?
Genes related to PD are in which organelles? Early or late onset?
Mitochondria and degradation system; early
T/F: All PD patients have Lew Bodies
False! Those w/ mitochondrial-related genetic factors do not
What medications are first given? And SEs...
Levodopa (motor fluctuations, dyskinesia), dopamine agonists (sedation, impulse control issues, hallucinations), MAOB inhibitors
Why don't we give young patients levodopa right away?
Can cause motor issues with increased use. Also cycle through periods where it works, periods of ON (dyskinesia) and periods of OFF time.
Older patients will get what drug "up-front"
What regions are targeted with deep brain stimulation for PD? How much can tremor be decreased? What is NOT improved by DBS?
GPi or STN; 75-90%; freezing/postural issues/cognitive issues
Prodromal (non-motor) symptoms (4)
Constipation, anosmia, REM behavioral disorder, psych
Lewy Body/PD Dementia symptomology (4); Lewy Bodies are where?
1. Visual hallucinations; 2. Dementia; 3. Fluctuations of attention/arousal; 4. Parkinsonism that begin ~1 year of dementia; cortical regions
Define Multiple System Atrophy
Autonomic Dysfunction (orthostatic hypotension, incontinence, impotence) w/ PD or Cerebellar symptoms
Age of onset of MSA
Parkinson's signs of MSA
Asymmetric w/ major gait disorder
Cerebellar signs of MSA
Gait disorder, limb ataxia, nystagmus
Pathology of MSA
Alpha synuclein inclusions in oligodendrocytes
Define Progressive Supranuclear Palsy and onset (one big difference from PD). What are the other PD-like symptoms? What's missing?
SYMMETRICAL bradykinesia; 70s; early balance problems (falls w/in a year); no tremor
Eye movement signs of PSP
Supranuclear vertical palsy (cannot look up)
Cognitive signs of PSP
Frontal lobe dementia
Pathology of PSP
Accumulation of tau
Define Corticobasal Degeneration, PD-ike symptoms, and onset
Asymmetric bradykinesia and rigidity in one limb (useless, alien limb); gait/postural instability; 60s-70s
Is CBD responsive to levodopa?
Cortical signs of CBD
Apraxia (cannot perform purposeful actions), cortical sensory loss (cannot identify objects by touch), dementia
"Humming-Bird Sign" (atrophy of midbrain, flat tectum)
"Hot cross bun" in pons and "hyperintense putaminal rim"
Asymmetric cortical atrophy (opposite to symptomatic side)
Secondary etiologies in PD and some examples
Meds (neuroleptics, anti-seizure), toxins (MO, CO, CN, pesticides), structural (tumor), infection (HIV, syphilis)
T/F: Removing exposure to secondary etiologies always removes symptoms?
Sometimes, depending on the cause; often NOT with toxins
Rhythmic, oscillatory mov't of a body part
Define essential tremor; what happens when they drink?
Kinetic tremor condition = tremor during tasks, various frequencies; tremor attenuates w/ ETOH
Name 3 other tremor conditions
Enhanced physiological tremor (postural); Cerebellar Tremor (slow, kinetic tremor); PD tremor (pill rolling, primarily at rest)
Involuntary, sustained muscle contractions causing twisting/repetitive movements
What are some variations in dystonia?
Age of onset, focal (tend to be adult), generalized (tend to be child), hemidystonia (pallidal injury), etiology (genetic, degenerative, secondary)
Is dystonia associated with rigidity of muscles?
Involuntary, irregular flitting movements flowing across body movements
Huntington's Disease is...(cause and threshold)
Autosomal dominant repeat in HTT gene on chromosome 4, threshold number of repeats is 40
What's the association b/t repeat number and age of onset?
More repeats, younger onset
Treatment for HD
Tetrabenazine, neuroleptics, benzodiazepines
What's an important co-morbidity for HD?
Neuropsychiatric problems, including irritability, psychosis, suicide
Besides chorea, what kind of movement disorders do you see with HD?
Parkinsonism (early onset), dystonia
How does someone with HD die?
Atrophy of spiny neurons in striatum (atrophy of caudate)
Define tic disorder. What is special about tic disorder?
Quick, stereotype movements/vocalizations that can be temporarily suppressed; only mov't disorder that persists through sleep
Define myoclonus and how is it different from tic disorder
Involuntary, very brief muscle jerks that interrupts voluntary movements generated anywhere in CNS but NOT suppressible
Two sources of physiological myoclonus
Hiccups, hypnic jerks
What's an important pathological etiology of myoclonus?
Define Wilson's Disease. Age of onset?
Copper accumulation disorder related to AR disorder on chromosome 13; 20s - 30s
Describe the common neurological feature of Wilson's
Tremor (80%): if child presents w/ essential tremor, screen for Wilson's
How do you test for Wilson's?
Low serum cerulosplasmin, very high 24hr urine copper, low normal total serum copper and genetic testing
OCD is filed where in the DSM-5?
Obsessive-compulsive & related disorders
What is the time consuming threshold for OCD?
When does OCD typically onset?
Childhood (50% before age 14)
Obsessions; contrast to hallucinations
Recurrent, intrusive, disturbing thoughts; recognized as own thoughts
Compulsions; what can a compulsion NOT be in the book of OCD?
Repetitive, obsessive acts often driven by obsessions; pleasurable
What proportion of patients with Tourette's develop OCD symptoms? What about the converse (OCD patients w/ tics)
Two predominant theories of OCD
NT-based (5-HT/Glutamate) and Cortico-striato-thalamo-cortical loops
Some role for 5-HT in OCD, based on the fact that SSRIs are helpful for OCD
Role of glutamatergic involvement in OCD
Genetic, animal models of OCD, elevated glutamate, but no data for glutamate treatment efficacy
Abnormal OCD circuits
Increased activity in OFC, striatum, ACC
OCD animal model
SAPAP3 scaffolding protein at excitatory synapse in striatum deleted --> OCD that responds to SSRIs
Main treatments for OCD
SSRIs (other classes ineffective) or CBT (exposure and response prevention)
For OCD non-responders
Different SSRI, add an antipsychotic, neurosurgery
Describe ablation surgical OCD treatment
For severely impaired patients, ablated anterior capsulotomy/anterior cingulotomy
Where do the leads go in DBS for OCD?
Stimulate anterior limb of internal capsule (ventral capsule), deepest point on NA/ventral striatum