9/20 Basal Ganglia - Glendinning

Question 1

what are the basal ganglia?

Answer 1

tightly woven group of nuclei in cerebrum, diencephalon, midbrain

1. caudate nucleus
2. putamen
3. globus pallidus
   
   • external segment
   • internal segment
4. subthalamic nucleus
5. substantia nigra

Question 2

functions of basal ganglia

Answer 2

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

Question 3

basal ganglia loop fx

Answer 3

help facilitate motor cortical areas

1. initiating movement
2. sequencing movement
3. automaticity

bc they play a role in gating proper initiation of movement, lesions to this area lead to incr/decr movement

Question 4

overview: basal ganglia regulation of motor areas

Answer 4

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)

Question 5

basal ganglia anatomy

Answer 5

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

Question 6

basal ganglia structures outside cerebrum

Answer 6

1. subthalamic nucleus (diencephalon)
2. substantia nigra (mesencephalong)

• pars compacta neurons: deep, contain dopamine, which modulates BG fx
• pars reticulata neurons: more superficial

Question 7

dopamine modulates basal ganglia

3 pathways

• associated fx
• associated diseases

Answer 7

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)

Question 8

2 “connected” units within basal ganglia

Answer 8

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

Question 9

general flow of info through basal ganglia loops

normal excitation in basal ganglia loops

normal inhibition in basal ganglia loops

Answer 9

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

Question 10

excitation and disinhibition

Answer 10

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

Question 11

excitation/inhibition of GPi

players & roles

Answer 11

subthalamic nucleus: excites GPi → inhibition of cortex/movement

• lesions produce EXTRA movement (contralat hemiballismus)

striatum: inhibits GPi → excitation of cortex/movement (disinhibition)

Question 12

basal ganglia “direct” pathway

Answer 12

facilitates movement via disinhibition

cortex sends excitatory signal to striatum → potentiates inhibitory signal to GPi → disinhibition of thalamus leads to increased movement

Question 13

basal ganglia “indirect” pathway

Answer 13

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

Question 14

graphic summary of direct and indirect pathways

Answer 14

Question 15

striatal dopamine receptors

Answer 15

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

Question 16

dopamine receptors

families and characteristics

Answer 16

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

Question 17

role of dopamine in pathways

Answer 17

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!

Question 18

role of Ach interneurons in striatum

pharma link

Answer 18

20% of striatal neurons contain ACh

• preferentially excite INDIRECT PATHWAY → increase inhibition → decrease movement

implication: anticholinergics can have tx benefit in PD

Question 19

general classification of movement disorders

3 types

Answer 19

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!

Question 20

negative sx

Answer 20

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

Question 21

positive sx

Answer 21

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

Question 22

dystonia

Answer 22

• 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

Question 23

hyperkinetic sx

Answer 23

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

Question 24

tardive dyskinesia

Answer 24

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

Question 25

tremor why do tremors happen?

Answer 25

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)

Question 26

4 parallel basal ganglia pathways

Answer 26

_general loop_: cortex → striatum → pallidum → thalamus → back to cortex 1. _motor_ → abnormal movement 2. _oculomotor_ → abnormal eye movements 3. _cognition_ (prefrontal) → poss relationship to psychosis and impaired exec fx 4. _emotions_ (limbic) → addictive/impulsive behaviors

Question 27

Huntington's Chorea what is it symptoms psych manifestations tx

Answer 27

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

Question 28

which pathway is affected in Huntington's?

Answer 28

**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!

Question 29

Parkinson Disease basics risks/decr risk

Answer 29

neurodegen disease progressive and chronic _risk factors_ * family history * older age * exposure to pesticides * migraine _risk diminishers_ * coffee * cig smoking

Question 30

PD cardinal symptoms

Answer 30

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_

Question 31

other PD motor symptoms

Answer 31

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

Question 32

dx for Parkinson's disease

Answer 32

_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

Question 33

neuropatho of PD

Answer 33

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**

Question 34

Lewy bodies

Answer 34

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

Question 35

treatments for PD what are they? problems?

Answer 35

_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

Question 36

deep brain stimulation sites theoretical goals risks

Answer 36

GPi or subthalamic nucleus theoretically, 1. normalizes outputs 2. blocks APs _serious risks/adv effects as well_: headache/pain, infection (10%), death

Question 37

neuroprotective tx

Answer 37

lots of compounds for various reasons (pramipexole, CoQ10, creatine, green tea polyphenol, inosine, isradipine, cogane) **exercise is both neuroprotective and neurorestorative** (after lesions) *

Question 38

"Parkinsonism Plus" syndromes

Answer 38

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%

Question 39

progressive supranuclear palso

Answer 39

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

Question 40

secondary Parkinsonism

Answer 40

_caused by_: stroke, tumor, infection, exposure to toxins (CO, Mn), drug exposure ex. MPTP → frozen addicts