Basal Ganglia

Question 1

What are the basal ganglia?

Answer 1

• these are bundles of grey matter (nuclei) found deep within the white matter of the cerebral hemispheres
• they communicate with the cortex to help with the generation of movement

Question 2

Explain the layout/organization of the structures involved in the basal ganglia.

Answer 2

• lateral to the thalamus lies the lentiform nucleus (made up of the globus pallidus and putamen) with the internal capsule in between the two
• lateral to the lentiform nucleus lies the external capsule, and then the claustrum, and then the extreme capsule, and then the insula cortex
• lying on top of the thalamus and putamen is the large C-shaped caudate nucleus
• underneath the thalamus is the subthalamus, followed by the substantia nigra (between the two is the superior colliculus, below the substantia nigra is the crus cerebri/cerebral peduncles) of the midbrain

Question 3

What are the parts of the lentiform nucleus? The parts of the substantia nigra?

Answer 3

• lentiform nucleus: (medial to lateral) globus pallidus internus, globus pallidus externus, putamen
• substantia nigra: (superior to inferior) pars compacta (dark) and pars reticulata

Question 4

What is the traditional grouping of the basal ganglia? What about the more modern grouping based on function?

Answer 4

• traditional: lentiform nucleus, claustrum, caudate nucleus, amygdala
• modern: lentiform nucleus, caudate nucleus, subthalamus, substantia nigra

Question 5

What is the corpus striatum? Neostriatum? Paleostriatum?

Answer 5

• corpus striatum: putamen + globus pallidus + caudate
• neostriatum (AKA striatum): putamen + caudate
• paleostriatum: just the globus pallidus

Question 6

Explain the basic pathway of movement generation, and where the basal ganglia fit in.

Answer 6

• pre-motor cortex generates the idea of movement, sends it to the basal ganglia for review and to get proper motor plan
• from basal ganglia, signals are sent back to the cortex (via the thalamus), which then give off the corticospinal tracts

Question 7

Direct Pathway

Answer 7

• this results in the disinhibition of the thalamus, resulting in cortical stimulation and generation of movement
• cortex projects to striatum, which projects to GPi, which projects to thalamus, which projects back to cortex
• corticostriatal fibers (glutamate) stimulate striatum, increasing activity of striatopallidal internal fibers (GABA and substance P) that inhibit the activity of pallidothalamic fibers (GABA), resulting in thalamic disinhibition (thalamocortical fibers are glutaminergic and stimulate the cortex)
• normally, when we are not moving, there is no cortical input to the striatum, and so the GPi fibers are active and inhibiting the thalamus
• when we do move, cortical input stimulates the striatum to inhibit the GPi, allowing the thalamus to stimulate the cortex

Question 8

Indirect Pathway

Answer 8

• this results in the disinhibition of the subthalamus, resulting in the stimulation of the globus pallidus internus, which will inhibit the thalamus, thus inhibiting the cortex from making unwanted movements
• cortex projects to striatum, which projects to GPe, which projects to subthalamus, which projects to GPi, which projects to thalamus, which projects back to cortex
• corticostriatal fibers (glutamate) stimulate striatum, increasing activity of striatopallidal external fibers (GABA and met-enkephalin) that inhibit the activity of pallidosubthalamic fibers (GABA), resulting in the disinhibition of the subthalamus, which will stimulate the GPi to inhibit the thalamus
• when we move, cortical input stimulates the striatum to inhibit the GPe, allowing the subthalamus to stimulate the GPi, which will inhibit the thalamus (this inhibits the generation of unwanted movements)

Question 9

How do the direct and indirect pathways work together to generate proper movement?

Answer 9

• direct pathway stimulates agonistic movements, while the indirect pathway inhibits antagonistic movements

Question 10

What role does the substantia nigra play in the basal ganglia pathways?

Answer 10

• the substantia nigra (pars compacta) modulates/fine-tunes these pathways by projecting to the striatum via dopaminergic nigrostriatal fibers
• the dopaminergic input will result in the further stimulation of the direct pathway and in the inhibition of the indirect pathway; note that both of these actions result in increased thalamic activity, thus promoting movements
• the SNpc facilitates/enhances/kick-starts the movement

Question 11

How can the substania nigra both stimulate and inhibit the basal ganglia pathways with just one neurotransmitter?

Answer 11

• the striatum has two types of dopamine receptors
• D1 receptors result in the stimulation of the direct pathway; they increase striatopallidal internal fiber activity, thus increasing the inhibition of the GPi
• D2 receptors result in the inhibition of the indirect pathway; they decrease striatopallidal external fiber activity, thus keeping the subthalamus inhibited (this results in decreased stimulation of GPi)

Question 12

When does the substantia nigra fire?

Answer 12

• when stimulated by the cortex via corticonigral fibers

- this occurs at the beginning of each movement

Question 13

What is the function of the substantia nigra pars reticulata?

Answer 13

• the substantia nigra pars reticulata is functionally similar to the globus pallidus internus (inhibits the thalamus) and has the same connections

Question 14

The striatum also has cholinergic neurons - what is the role of these?

Answer 14

• cholinergic neurons in the striatum are antagonistic to the dopaminergic nigrostriatal tracts
• thus, they inhibit the direct pathway and stimulate the indirect pathway (these actions result in the inhibition of movement)

Question 15

In terms of pathologic processes, generally speaking, what does a loss of the direct pathway result in? What about a loss of the indirect pathway?

Answer 15

• loss of direct results in bradykinesia/akinesia

- loss of indirect results in hyperkinesia/dyskinesia

Question 16

Parkinsonism

Answer 16

• degeneration of the substantia nigra pars compacta results in lack of dopaminergic input to basal ganglia –> decreased direct pathway and increased indirect pathway (indirect pathway dominates)
• this results in increased inhibition of the thalamus, leading to decreased cortical stimulation (bradykinesia)
• end-stage disease involves dementia

Question 17

What are the four major signs of Parkinsonism? What’s the pathology behind each?

Answer 17

• T.R.A.P.S.
• (resting) Tremor: lack of DA results in relative increase of cholinergic fibers, which stimulate reverberating circuit pathways, causing tremor
• Rigidity: lack of cortical stimulation results in decreased corticoreticular output, leading to increased (!) reticular activity, which causes increased tone
• Akinesia/bradykinesia: inhibited thalamus results in slowness of/inability to generate movement
• Postural instability w/ Shuffling gate

Question 18

Huntington’s Disease

Answer 18

• inherited degeneration of the caudate nucleus results in the loss of striatopallidal external fibers, leading to the loss of the indirect pathway (direct pathway dominates)
• this results in the over-inhibition of the subthalamus, keeping the GPi inhibited, and resulting in excess stimulation of the thalamus (dyskinesia, chorea)
• end-stage disease involves dementia

Question 19

DDx of Huntington’s Chorea

Answer 19

• if transient and short-term: Sydenham’s chorea (when rheumatic fever targets the caudate nucleus); mainly affects children
• if in young adult: Wilson’s disease (copper deposits in the lentiform and caudate nuclei)

Question 20

Compare the dyskinesias of chorea, athetosis, dystonia, myoclonus, and ballismus

Answer 20

• chorea: sudden, lightning-like, bursts of movement, usually of distal limbs (Michael Jackson dance)
• athetosis: a less-jerky, smoother version of chorea, usually of the upper distal limbs (Indian dance)
• dystonia: targeted muscles remain contracted, usually of the axial muscles ex) torticullis
• myoclonus: sudden, brief, explosive contraction; due to drugs, epilepsy, metabolic disease, hypoxia (asterixis!)
• ballismus: drastic, violent movements, more extreme than chorea, usually of the hips and shoulders (proximal limbs); usually due to lacunar stroke or other CVAs involving the subthalamus

Question 21

The nucleus accumbens is sometimes considered part of the basal ganglia - what does it do?

Answer 21

• the nucleus accumbens links the basal ganglia and the limbic system, and is associated with reward, gratification, and addiction

Question 22

What lies beneath the corpus striatum?

Answer 22

• the substantia innominata, which contains the nucleus basalis (this projects to the cortex and degenerates in Alzheimer’s)

Question 23

Striatal efferents going to the globus pallidus internus and the substantia nigra pars reticulata release which neurotransmitters? What about those going to the globus pallidus externus?

Answer 23

• those going to GPi and SNpr: GABA, substance P, and dynorphin
• those going to GPe: GABA and met-enkephalin

Question 24

Lesions in the basal ganglia will affect the ipsilateral or contralateral side?

Answer 24

• contralateral side!

- basal ganglia output ascends to the ipsilateral cortex (via the thalamus), affecting the contralateral side

Question 25

When does idiopathic Parkinsonism (Parkinson’s Disease) usually develop? What are some other causes of Parkinsonism? When does Huntington’s Disease usually develop?

Answer 25

• usually begins between 45-65 and then progresses from there
• drugs (MPTP), toxicities, Wilson’s disease, iatrogenic (most anti-psychotics, such as Stemetil for vertigo, are DA-receptor antagonists)
• (Huntington’s usually begins between 35-45)

Question 26

What gross morphological features do we see in Parkinsonism? What microscopic characteristics?

Answer 26

• gross: depigmentation of the substantia nigra

- microscopic: Lewy bodies containing alpha-synuclein protein

Question 27

What causes Huntington’s Disease? How do we treat it? What’s the prognosis?

Answer 27

• this is an A.D. inherited disorder characterized by CAG trinucleotide repeats (more than 40) in the HTT (AKA IT15) gene encoding the huntingtin protein found on chromosome 4p; as with all inherited trinucleotide repeat diseases, HD exhibits anticipation of subsequent generations
• there is no treatment; 70% die within 15 years of the disease onset

Question 28

What gross morphological features do we see in Huntington’s Disease? What microscopic characteristics?

Answer 28

• gross: smaller brain with striking atrophy of the caudate nuclei (with resulting enlargement of the lateral ventricles; hydrocephalus ex vacuo)
• microscopic: aggregates of huntingtin protein

Question 29

What type of heterogeneity is involved in Huntington’s disease?

Answer 29

• allelic heterogeneity (this is a single gene disease)

- as opposed to locus heterogeneity (where several genes can cause the disease) as seen in Alzheimer’s

Question 30

Explain what happens to L-dopa once it enters the periphery and once it enters the brain.

Answer 30

• in periphery, L-dopa gets rapidly degraded into O-methyldopa by the COMT enzyme and into dopamine by the AADC enzyme (a decarboxylase)
• L-dopa enters the brain via the BBB through aromatic amino acid transporter systems
• the amount that does make it to the brain gets converted into dopamine via AADC, which can then get converted into 3,4 dihydroxyphenylacetic acid (via the MAO enzyme) and into 3 methoxytyramine (via the COMT enzyme)
• (COMT: catechol-O-methyl transferase)
• (AADC: amino acid decarboxylase)
• (MAO: monoamine oxidase)

Question 31

What drug therapies are there for Parkinsonism?

Answer 31

• aim to increase dopaminergic action
• exogenous dopamine prodrug (Levodopa)
• DA receptor agonists (Pramipexole, Ropinirole)
• DA reuptake inhibitors (Amantadine)
• peripheral decarboxylase inhibitors (Carbidopa, Benserazide)
• COMT inhibitors (Entacapone)
• MAOb inhibitors (Selegiline)
• can also aim to decrease cholinergic actions w/ muscarinic receptor antagonists (Benzotropine)

Question 32

Levodopa

Answer 32

• “L-dopa” is the mainstay and most effective drug used to treat the Parkinsonism symptoms (mainly bradykinesia and rigidity)
• it requires to be taken up in the duodenum, and then gets actively transported through the BBB into the brain
• side effects: nausea, hallucinations, postural hypotension
• long-term use results in “on-off” fluctuations (the medication has sporadic periods of inactivity), and the development of dyskinesia

Question 33

(Peripheral) Decarboxylase Inhibitors

Answer 33

• (Carbidopa, Benserazide)
• these inhibit the AADC (amino acid decarboxylase) in the periphery, preventing the premature conversion of L-dopa into dopamine; results in more L-dopa being able to cross the BBB into the brain
• these are used in conjunction with L-dopa:
• Sinemet (L-dopa + Carbidopa)
• Madopar (L-dopa + Benserazide)

Question 34

COMT Inhibitors

Answer 34

• (Entacapone)
• these inhibit the catechol-O-methyl transferase (breaks down catecholamines) present in both the periphery and the brain, resulting in an increase the amount of dopamine generated from L-dopa; these drugs increase the “on” time of L-dopa by 1-2 hours
• often used as an adjunct to Sinemet or Madopar (the L-dopa + decarboxylase inhibitor combo drugs)
• can be given as a combined drug: Stalevo (L-dopa + Carbidopa + Entacapone)
• make sure to decrease the amount of L-dopa if you are adding this drug

Question 35

Which patients should you avoid giving COMT inhibitors to?

Answer 35

• COMT inhibitors CAN be combined with MAOb inhibitors, but they do not mix well with general MAO inhibitors (which are used to treat depression)
• thus, switch the anti-depressant from general MAO inhibitors to SSRIs or tricyclics in these patients

Question 36

MAO Inhibitors

Answer 36

• (MAOb inhibitor = Selegiline)
• these inhibit monoamine oxidase in the brain, preventing the oxidation of dopamine; these drugs increase the “on” time of L-dopa
• both MAOa and MAOb isoforms oxidize dopamine, but MAOa inhibitors also prevent the oxidation of other NTs (serotonin, adrenaline, and noradrenaline) and therefore have more side-effects than MAOb inhibitors
• make sure to decrease the amount of L-dopa if you are adding this drug
• (these can be used alone to treat some very mild cases of Parkinsonism)

Question 37

Dopamine Receptor Agonists

Answer 37

• (Pramipexole, Ropinirole, Rotigatine, Apomorphine)
• these don’t require dopamine
• can be used as an alternative to L-dopa to treat very mild cases of Parkinsonism
• side effects: sleepiness, psychosis, nausea, vomiting, dyskinesia, impulse control disorders (pathologic gambling, hypersexuality, etc.)
• (Apomorphine injections are a good rescue medication in patients experiencing a severe “off” period of L-dopa)

Question 38

Discuss drug therapy for Parkinsonism.

Answer 38

• no current drug therapy slows or stops the progression of the disease; they all provide symptomatic relief
• L-dopa is by far the best and least expensive; however its efficacy severely drops off after about 5 years (the “on-off” development progressively worsens), and there is the issue of dyskinesias developing with long-term use
• other drugs (MAOb inhibitors, DA receptor agonists) are fare less effective, but some recommend starting with these and saving L-dopa for when you really need it

Question 39

Anticholinergics in Parkinsonism Treatment

Answer 39

• (Benztropine)
• ACh antagonists help deal with the relative cholinergic overactivity seen in Parkinsonism; these help alleviate the resting tremor and rigidity seen in this disease
• side effects: dementia, urinary retention, constipation, dry mouth

Question 40

Explain the progression of Parkinson’s Disease.

Answer 40

• 50-70% of dopamine producing cells in the SNpc must be lost before deficits begin to appear
• often, there is a very long prodrome before the onset of the classic symptoms; anxiety, sleep disorders, hyposmia, constipation, orthostatic hypotension
• when the disease begins, it always starts asymmetrically and then progresses to become bilateral

Question 41

How do we treat nausea in patients with Parkinsonism?

Answer 41

• give them the anti-emetic Motilium, as it does NOT cross the BBB
• (most other anti-emetics do cross the BBB; remember that these are dopamine-antagonists and will interfere with drug therapy and make the disease worse!)

Question 42

In a patient presenting with parkinsonism, what should you suspect if you find Lewy bodies throughout the cortex and not just in the substantia nigra pars compacta?

Answer 42

• dementia with Lewy bodies (DLB)
• Lewy bodies throughout the cortex results in DLB (parkinsonism and dementia develop at same time)
• Lewy bodies only in the SNpc results in PD (parkinsonism and eventual dementia)

Question 43

Compare postural tremors, resting tremors, and intention tremors.

Answer 43

• postural (AKA essential): an action tremor, exacerbated by holding a posture/limb position
• resting: uncontrolled movement of distal limbs that is alleviated by intentional movement (pill rolling tremor of PD)
• intention tremor: slow zig-zag motion when pointing/extending towards a target (cerebellar dysfunction)