Basal ganglia

What it normally does

• The substantia nigra pars compacta sends dopamine to the striatum (the nigrostriatal pathway). Dopamine excites the go pathway through D1 receptors and inhibits the stop pathway through D2 receptors. Both actions point the same way: dopamine turns movement on.

  Losing that dopamine gives Parkinson disease, and any drug that blocks D2 reproduces it.

• Two pathways run through the loop. The direct pathway releases the thalamus from inhibition and lets a movement out (go). The indirect pathway runs through the subthalamic nucleus, which drives the globus pallidus interna to clamp the thalamus shut (stop). This loop tunes movement; it does not carry the command, which stays in the corticospinal tract.

  Destroy the brake and unwanted movement escapes — chorea and hemiballismus — and it explains why these patients are slow or wriggly but never weak.

• Cholinergic interneurons inside the striatum release acetylcholine, which opposes dopamine. What matters is not the dopamine level alone but the dopamine-to-acetylcholine ratio (a balance, not a number).

  Blocking D2 receptors tips the balance and causes drug-induced parkinsonism and acute dystonia, and an antimuscarinic corrects it by dropping the other side.

• Striatal dopamine receptors adapt to how much dopamine arrives. Starve them for months and D2 receptors are upregulated and become supersensitive; flood them in pulses and the response becomes unstable.

  Long-term antipsychotic use produces tardive dyskinesia, and long-term levodopa produces peak-dose dyskinesia.

What goes wrong

• Parkinson disease← from “The substantia nigra pars compacta sends dopam…”

  Dopamine neurons in the substantia nigra pars compacta die, with clumps of alpha-synuclein (Lewy bodies) inside those that remain. Less dopamine reaches the striatum, so the go pathway is under-driven and the stop pathway is under-braked at the same time — the patient gets less movement from both directions. The nigra has substantial spare capacity, so motor signs do not appear until roughly half the nigral neurons and around 60-80% of striatal dopamine have been lost. Degeneration is not symmetric, so it starts on one side.

  Asymmetric rest tremor plus bradykinesia plus rigidity. Australian prevalence estimates vary widely with method, on the order of 100,000 people living with it (published figures range from about 70,000 to 150,000), mostly presenting after 60, and it is the second commonest neurodegenerative disease after Alzheimer disease. Diagnosis is clinical; a good sustained response to levodopa supports it.

  You would find: Movements that are slow, small and get smaller as they repeat (bradykinesia) — watch finger tapping fade out over ten taps. A 4-6 Hz tremor in one hand at rest that damps when they reach for a cup. Cogwheel catching at the wrist, brought out by distracting them with the other hand. Reduced arm swing on one side, a shuffling gait that festinates and cannot stop, a quiet monotonous voice, shrinking handwriting (micrographia), a face that has stopped moving (hypomimia). Power is normal — this is not a stroke.

• Drug-induced parkinsonism (and acute dystonic reaction)← from “Cholinergic interneurons inside the striatum r…”

  Any drug that blocks striatal D2 receptors stops dopamine from lifting the brake, tipping the dopamine-acetylcholine balance toward acetylcholine. Antipsychotics do it (haloperidol and risperidone most, quetiapine and clozapine least), and so do the antiemetics metoclopramide and prochlorperazine, which nobody thinks of as brain drugs. Blockade reaches both sides, so signs usually appear on both sides together. Block D2 abruptly and hard and instead of slowness you get an acute dystonic reaction — a sustained pull of neck, jaw or eyes.

  Second commonest cause of parkinsonism after Parkinson disease, and the commonest reversible one — usually settles over weeks to months once the drug stops, occasionally taking up to a year. Ask what was started in the last three to six months and include the antiemetics. Aboriginal and Torres Strait Islander Australians are hospitalised for psychotic illness at substantially higher rates than other Australians, so exposure to D2 blockers, and therefore this complication, falls more heavily on those communities.

  You would find: Bradykinesia and rigidity, usually symmetrical, coming on over weeks after a drug is started or the dose raised, often with a symmetric postural tremor. Symmetry is a strong pointer but not a rule — a sizeable minority are asymmetric, so asymmetry does not exclude it. The acute version arrives within hours to days of the first dose: torticollis, trismus, or eyes forced upward (oculogyric crisis) in a frightened young person who looks like they are having a seizure and is not.

• Tardive dyskinesia← from “Striatal dopamine receptors adapt to how much …”

  Months to years of D2 blockade leaves striatal receptors chronically starved, so on the classical account the neuron upregulates them and they become supersensitive. Whatever dopamine does arrive now over-suppresses the indirect pathway, and unwanted movement escapes. It is the mirror image of drug-induced parkinsonism caused by the same drug. (The supersensitivity model is the standard teaching but is not the whole story — it does not explain why the movements persist after the drug is long gone.)

  Risk climbs with duration of exposure and with age, and it is often permanent even after the drug is withdrawn. Anticholinergics make it worse, not better. Review the need for the causative drug and consider switching to a lower-risk agent such as clozapine or quetiapine; a VMAT2 inhibitor is the drug treatment for persistent, disabling dyskinesia.

  You would find: Repetitive chewing, lip smacking, tongue pushing against the cheek, grimacing, sometimes writhing fingers or rocking. Usually noticed by family, not the patient. The giveaway trap: it gets worse when you reduce the dose (the blockade that was masking it lifts) and better when you raise it — which is why raising the dose is the wrong instinct.

• Huntington disease← from “Two pathways run through the loop. The direct …”

  An expanded CAG repeat in the HTT gene on chromosome 4, autosomal dominant and fully penetrant at 40 or more repeats (36-39 is reduced penetrance). The abnormal huntingtin protein kills GABAergic medium spiny neurons in the striatum, and the indirect (stop) pathway goes first. Lose the brake and unwanted movement escapes through the thalamus to the cortex. Repeats expand more readily during spermatogenesis, so paternal transmission carries a higher risk of earlier, more severe disease in the child (anticipation).

  Onset usually 30-50, prevalence of the order of 10 per 100,000 in populations of European ancestry, with a high suicide risk that shapes every conversation — predictive testing goes through a clinical genetics service with counselling, never opportunistically. Different picture in an Aboriginal family from Arnhem Land or Groote Eylandt: think Machado-Joseph disease (SCA3), which reaches the highest reported prevalence in the world in those communities.

  You would find: Restless, dance-like movements that the patient disguises by folding them into a purposeful gesture — smoothing the hair, crossing the legs. Motor impersistence is the bedside test: they cannot hold the tongue out for ten seconds or keep a steady grip on your fingers (milkmaid grip). Before the movements, irritability, apathy and loss of planning, and a family history sometimes described only as nerves or drinking. MRI shows caudate atrophy and squared-off lateral ventricles.

• Hemiballismus← from “Two pathways run through the loop. The direct …”

  Classically a lacunar infarct in one subthalamic nucleus, supplied by small deep perforating arteries. The subthalamic nucleus is the engine of the stop pathway. Take it out and the brake on one side is gone, so the opposite limbs fling. In practice imaging often shows the lesion elsewhere in the contralateral basal ganglia rather than in the subthalamic nucleus itself — the principle (loss of the indirect pathway's drive) still holds.

  Sudden unilateral chorea is vascular until proven otherwise — image the head. It usually settles over weeks to months. The other cause to know is hyperosmolar hyperglycaemia (non-ketotic), which produces the same picture with a bright striatum on T1 MRI, so check the glucose; this matters more in Aboriginal and Torres Strait Islander communities, where type 2 diabetes is several times more common and occurs at younger ages.

  You would find: Sudden onset of violent, large-amplitude flinging of one arm, sometimes with the leg, on the side opposite the lesion. Worse with action, absent in sleep, and exhausting — patients bruise themselves on the bed rails. Typically an older person with hypertension or diabetes.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.