9/20 Basal Ganglia - Glendinning Flashcards
what are the basal ganglia?
tightly woven group of nuclei in cerebrum, diencephalon, midbrain
- caudate nucleus
- putamen
- globus pallidus
- external segment
- internal segment
- subthalamic nucleus
- substantia nigra
functions of basal ganglia
regulate frontal lobe, motor, limbic fx
*involved in several neurodegen, neuropsych disorders
- motor disorders: movement disorders or extrapyramidal disorders
- disorders of “habit”/neuropsych disorders: addiction, OCD, tics
basal ganglia loop fx
help facilitate motor cortical areas
- initiating movement
- sequencing movement
- automaticity
bc they play a role in gating proper initiation of movement, lesions to this area lead to incr/decr movement
overview: basal ganglia regulation of motor areas
basal ganglia…
- inputs: premotor cortex, primary motor cortex
- output: VA (ventral ant) and VL (ventral lat) thalamus → projects back up to cortical areas
DO NOT get sensory feedback
- BG are not sensory structures (as opposed to cerebellum, which gets a lot of sensory input)
basal ganglia anatomy
striatum
- caudate: head/body/tail, wraps around lateral wall of lateral ventricle
- putamen: lateral to caudate nucleus
- C/P are referred to as a unit bc they come from same embryological tissue, perform the same fx. would be same structure except that they are bisected by internal capsule
globus pallidus: medial to putamen
- comprised of internal and external segments
*together, putamen + globus pallidus = lentiform nucleus
basal ganglia structures outside cerebrum
- subthalamic nucleus (diencephalon)
- substantia nigra (mesencephalong)
- pars compacta neurons: deep, contain dopamine, which modulates BG fx
- pars reticulata neurons: more superficial
dopamine modulates basal ganglia
3 pathways
- associated fx
- associated diseases
1. mesostriatal (nigrostriatal) pathway
- fx: movement control
- Parkinson’s Disease
2. mesolimbic pathway
- fx: reward pathway
- schizophrenia
- depression
3. mesocortical pathway
- fx: working memory
- schizophrenia (negative signs)
2 “connected” units within basal ganglia
even though separated somewhat in space,
- caudate and putamen
- globus pallidus and substantia reticulata of substantia nigra
receive same inputs, perform same fx in response to those inputs
general flow of info through basal ganglia loops
normal excitation in basal ganglia loops
normal inhibition in basal ganglia loops
cortex → caudate/putamen → VA/VL complex of thalamus → cortex
- cortex then influences motor output
under normal circumstances,
- thalamus is providing excitatory (Glu) stim → cortex
- cortex is providing excitatory (Glu) stim → motor pathways
- globus pallidus (GPi & SN reticulata) is providing tonic inhibition (GABA) stim → VA/VL thalamus
excitation and disinhibition
GPi&SN_reticulata are inhibiting the thalamus, reducing level of excitatory signal to cortex/motor pathways
implication:
stimulate the GPi&SN_ret → increase inhibition → decrease movement
INHIBIT the GPi&SN_ret → decrease inhibition → increase movement
- state known as disinhibition
excitation/inhibition of GPi
players & roles
subthalamic nucleus: excites GPi → inhibition of cortex/movement
- lesions produce EXTRA movement (contralat hemiballismus)
striatum: inhibits GPi → excitation of cortex/movement (disinhibition)
basal ganglia “direct” pathway
facilitates movement via disinhibition
cortex sends excitatory signal to striatum → potentiates inhibitory signal to GPi → disinhibition of thalamus leads to increased movement
basal ganglia “indirect” pathway
inhibits movement
cortex sends excitatory signal to striatum →
striatum sends INHIBITORY signal to GPe →
GPe reduces its inhibitory signal to subthalamus →
- GPe is typically inhibiting subthalamic
- inhibition of GPe means LESS INHIBITION of subthalamic means MORE EXCITATION of GPi
subthalamic nucleus sends large excitatory signal to GPi →
GPi sends large inhibitory signal to thalamus
→ inhibits movement
graphic summary of direct and indirect pathways
striatal dopamine receptors
dopamine receptors are located on medium spiny neurons
- dendritic spines receive cortical inputs
- base of spines receive dopaminergic inputs
medium spiny neurons project to
- globus pallidus
- substantia nigra pars reticulata
dopamine receptors
families and characteristics
metabotropic receptors
D1 receptor family : EXCITATORY
- incr cAMP
- incr PIP2 hydrolysis
- Ca mobilization
- PKC activation
D2 receptor family : INHIBITORY
- decr cAMP
- incr K current
- decr voltage-gated Ca current
role of dopamine in pathways
nigrostriatal dopamine facilitates “direct” pathway via D1 receptors (excitatory)
SNpc releases dopamine → hits DA1 receptor on striatum, excitation occurs
- potentiates inhibitory signal to GPi → increases disinhibition → increases movement!
nigrostriatal dopamine inhibits “indirect” pathway via D2 receptors (inhibitory)
SNpc releases dopamine → hits DA2 receptor on striatum, inhibition occurs
- inhibits inhibitory signal to GPe → potentiates inhibitory signal to subthalamus → dampens excitatory signal to GPi → dampened inhibitory signal from GPi → increased movement!
SUMMARY: dopamine is excitatory to direct pathway, inhibitory to indirect pathway → FACILITATES MOVEMENT in both cases!
role of Ach interneurons in striatum
pharma link
20% of striatal neurons contain ACh
- preferentially excite INDIRECT PATHWAY → increase inhibition → decrease movement
implication: anticholinergics can have tx benefit in PD
general classification of movement disorders
3 types
hypokinesia
- too little movement
- “negative sx”
hyperkinesia
- too much movement
- “positive sx”
dyskinesia
- abnormal movement
- often drug induced by tx for psych/PD/etc
*all contralateral to lesion!
negative sx
akinesia: no movement (can’t initiate)
bradykinesia: slow movements
decreased postural adjustments
hypokinesia: decr amplitude of movement
rigidity: “waxy”, “lead pipe”, “cogwheeling”
all best characterized by PD
positive sx
occur at rest
hemiballismus: spontaneous, invol movements
- usually due to lacunar infarcts in subthalamic nucleus
chorea: almost cont rapid movements of face, tongue, limbs
- most common: Huntington’s disease
athetosis: slow, writing movements (hands, fingers)
- can’t maintain fixed position
- often kids with cerebral hypoxia affecting BG
dystonia
- slower, twisting postures triggered by voluntary movements
- role of BG is unclear: could be disorder of synaptic plasticity in BG
- botulinum tox, electrical stim of GP has shown some benefit
most common: writer’s cramp
most cases familial
hyperkinetic sx
tics: sudden, brief action preceded by an urge to perform it
- Tourette’s Syndrome is characterized by persistent motor and vocal tics
Restless Leg Syndrome (RLS): discomfort and urgent desire to move legs
- usually during sleep, usually relieved by movement
- familial pattern
- might be related to DA neurotrans!
- PET scans show decr D2 receptors
tardive dyskinesia
most commonlly in schizophrenia from antipsychotic or antiemetic drugs
- prolonged use of DA antagonists → receptor hypersensitivity
- can persist after discont of drugs
- less of an issue with new anti-psychs
can cause any dyskinesia or combo
tremor
why do tremors happen?
cerebellum, thalamus, BG all have regular, oscillating rhythms
- disruption in rhythm leads to tremor
- Parkinson’s (3-5 Hz at rest)*
- hands and arms common; can also include legs and mouth
- begins unilaterally
essential tremor (5-8 Hz)
- hands, arms, face, legs, trunk
- usually bilat (cerebellar origin)
4 parallel basal ganglia pathways
general loop: cortex → striatum → pallidum → thalamus → back to cortex
- motor → abnormal movement
- oculomotor → abnormal eye movements
- cognition (prefrontal) → poss relationship to psychosis and impaired exec fx
- emotions (limbic) → addictive/impulsive behaviors
Huntington’s Chorea
what is it
symptoms
psych manifestations
tx
autosomal dominant neuroderen disorder with cell loss in caudate and putamen, also frontal/temporal cortex
- progressive → leads to akinetic/rigid form of disease
major sx:
- chorea
- dementia
psych manifestations
- anxiety
- mood changes
- OCDs
- impulsiveness
- cognitive impairment
- memory loss
tx: drugs that decrease dopamine
which pathway is affected in Huntington’s?
cells in INDIRECT pathway affected
- caudate and putamen die, which means…
inhibitory signal to GPe is dampened
→ inhibitory signal from GPe to subthalamus is amplified
→ excitatory signal from subthal to GPi is dampened
→ inhibitory signal from GPi to thalamus is dampened
→ movement is increased!
Parkinson Disease
basics
risks/decr risk
neurodegen disease
progressive and chronic
risk factors
- family history
- older age
- exposure to pesticides
- migraine
risk diminishers
- coffee
- cig smoking
PD cardinal symptoms
begin unilaterally
1. bradykinesia: slowed movement
2. resting tremor: “pill rolling”
3. rigidity: lead pipe (through range of motion) OR cogwheeling (w reg jerking)
4. postural instability
other PD motor symptoms
MOTOR
- masked facies (hypomimia)
- Parkinson’s gait: festinating
- loss of automaticity (can’t do two things at once, ex. stand, shake hands)
- stooped posture
- difficulty moving
NON-MOTOR
lots of signs incl personality changes, psych sx
dx for Parkinson’s disease
1. look at symptoms and history
- bradykinesia + one other sx
- resting tremor (pill rolling)
- rigidity: lead pipe
- postural instability is a later syndrome
2. rule out other causes
- repeated stroke, multiple head injury, encephalitis, neuroleptic tx, exposure to toxins (Mn, CO, MPTP), cerebral tumor, hydroceph
3. look for supportive evidence
- responsiveness to Levodopa
- unilateral onset
- other typical motor/non-motor signs
neuropatho of PD
death of cells in substantia nigra
- degree of cell death correlated to severity of sx
neurons that do exist in substantia nigra have abnormal aggregations of proteins: Lewy bodies
Lewy bodies
spherical masses within cell body of PD substantia nigra cells containing abnormal aggregations of proteins
- primarily alpha-synuclein: cytosol protein in many regions of brain, normal involved in vesicular transport
treatments for PD
what are they? problems?
pharmaceutical
- dopamine agonists: L-DOPA (dopamine precursor, crosses bbb)
- MAO inhibitors
- anti-cholinergics
*problem with dopamine: “honeymoon period” at first, then on/off phenomena (dyskinesia, patho gambling - risk taking)
surgical lesions
- thalamus: for young pt with unilat tremor, no rigidity/bradykinesia
- globus pallidus (GPi): for tremor, rigidity
deep-brain stim
- globus pallidus internus
- subthalamic nucleus
- thalamus
deep brain stimulation
sites
theoretical goals
risks
GPi or subthalamic nucleus
theoretically,
- normalizes outputs
- blocks APs
serious risks/adv effects as well: headache/pain, infection (10%), death
neuroprotective tx
lots of compounds for various reasons (pramipexole, CoQ10, creatine, green tea polyphenol, inosine, isradipine, cogane)
exercise is both neuroprotective and neurorestorative (after lesions)
*
“Parkinsonism Plus” syndromes
diseases that share characteristics of PD
characterized by:
- lack of resting tremor
- symmetrical sx
- early postural instability
- lack of response to dopamine
PD clinical diagnosis accuracy is approx 80%
progressive supranuclear palso
most common form of atypical Parkinsonism
pathophysiology
- neurodegenerative, affects multiple regions of rostral midbrain
- red nucleus
- superior colliculus
- subthalamic nucleus
- globus palliduson
onset/progression:
sx begin after 50, progress more rapidly than PD
symptoms
- imbalance/falling/trunk rigidity
- compare to PD: limb rigidity
- swallowing changes
- decr range of vertical eye movement (often first sign)
- dementia
tx: SOME relief from dopaminergic tx
secondary Parkinsonism
caused by: stroke, tumor, infection, exposure to toxins (CO, Mn), drug exposure
ex. MPTP → frozen addicts
