Motor Control Circuits: Basal Ganglia & Cerebellum

Basal ganglia circuitry

The loop. The basal ganglia do not send fibers to the spinal cord; they gate movement through a cortex–striatum–pallidum–thalamus–cortex loop. The striatum (caudate + putamen) is the input nucleus, receiving glutamate from the cortex and dopamine from the substantia nigra pars compacta (SNc). The output nuclei, the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr), fire tonically and inhibit the ventral anterior and ventral lateral (VA/VL) thalamus with GABA; the thalamus in turn excites motor cortex. Movement proceeds when that brake is released. The lentiform nucleus is the putamen plus globus pallidus, and the corpus striatum is the caudate plus lentiform nucleus.

Pharmacologic consequences. Because acetylcholine opposes dopamine in the striatum, muscarinic antagonists such as benztropine and trihexyphenidyl ease parkinsonian tremor, whereas D2 blockers (antipsychotics, metoclopramide) produce drug-induced parkinsonism.

Hypokinetic and hyperkinetic disorders

Parkinson disease. Pigmented dopaminergic neurons of the SNc degenerate, leaving a pale substantia nigra, and surviving neurons contain Lewy bodies (eosinophilic intracytoplasmic α-synuclein inclusions). Without dopamine the direct pathway weakens and the indirect pathway (with an overactive STN) strengthens, so GPi over-inhibits the thalamus. The result is the TRAP tetrad: resting pill-rolling tremor at about 4–6 Hz, cogwheel rigidity, akinesia or bradykinesia, and postural instability, with masked facies, micrographia, hypophonia and a shuffling gait. MPTP, a contaminant of illicit synthetic opioids, is converted by MAO-B to the toxin MPP⁺, which destroys SNc neurons and causes abrupt parkinsonism.

The logic of hyperkinesia. Hypokinetic disorders reflect too much GPi output; hyperkinetic disorders reflect too little. Losing the indirect-pathway striatal neurons (early Huntington disease) or the subthalamic nucleus (hemiballismus) removes the brake, disinhibiting the thalamus and releasing involuntary movements.

Hemiballismus. Sudden, violent flinging of the proximal arm and leg on one side usually follows a lacunar infarct or small hemorrhage in the contralateral STN, typically in patients with hypertension or diabetes; losing the STN's glutamate drive lowers GPi output and disinhibits the thalamus. Nonketotic hyperglycemia can also produce hemichorea-hemiballismus.

Chorea. Brief, irregular, flowing movements migrate from one body part to another and point to the caudate. Huntington disease is an autosomal dominant CAG repeat expansion in HTT on chromosome 4, with anticipation (mostly on paternal transmission), loss of striatal GABAergic neurons and caudate atrophy that enlarges the frontal horns of the lateral ventricles (unlike the midbrain atrophy of progressive supranuclear palsy or the putaminal T2 signal of Wilson disease); chorea is joined by depression, irritability, dementia and a high suicide risk. Sydenham chorea follows group A streptococcal infection by months: antibodies against streptococcal antigens cross-react with basal ganglia neurons, and it is a major criterion for rheumatic fever. Pregnancy (chorea gravidarum) or estrogen, SLE and antiphospholipid syndrome, levodopa and tardive dyskinesia from chronic antipsychotics also cause chorea.

Athetosis and dystonia. Athetosis is slow, snake-like writhing of the fingers and hands from basal ganglia damage (cerebral palsy after kernicterus, Huntington disease), often mixed with chorea as choreoathetosis. Dystonia is sustained co-contraction of agonists and antagonists producing twisting postures: torticollis, blepharospasm, writer's cramp, or an acute dystonic reaction (torticollis, oculogyric crisis) after antipsychotics, treated with IV benztropine or diphenhydramine. Focal dystonias respond to botulinum toxin injections.

Myoclonus and tics. Myoclonus is a sudden shock-like jerk. It can be physiologic (hiccups, hypnic jerks) or pathologic in metabolic encephalopathy (uremia, liver failure; asterixis is negative myoclonus), after hypoxic brain injury, and in Creutzfeldt-Jakob disease, where rapidly progressive dementia, startle myoclonus and periodic sharp-wave complexes on EEG reflect misfolded prion protein. Tics are stereotyped movements or sounds preceded by an urge and briefly suppressible, as in Tourette syndrome.

Tremor and Wilson disease

Tremor localizes. A resting tremor that fades with movement means parkinsonism. An intention tremor that grows as the finger approaches the target means disease of the ipsilateral cerebellar hemisphere or its outflow. A postural or action tremor, seen with arms outstretched or when holding a cup, means essential tremor or enhanced physiologic tremor (hyperthyroidism, caffeine, β-agonists, anxiety, alcohol withdrawal, lithium).

Essential tremor. The most common movement disorder produces a bilateral postural and action tremor of the hands, often with head or voice tremor. It frequently runs in families in an autosomal dominant pattern, worsens with stress and caffeine and improves transiently with alcohol. Propranolol or primidone is first-line; levodopa does not help.

Wilson disease. Autosomal recessive ATP7B mutations prevent copper from being loaded into ceruloplasmin and excreted in bile, so copper accumulates in the liver (hepatitis, cirrhosis, acute liver failure), the putamen and lenticular nucleus (wing-beating tremor, dysarthria, dystonia, parkinsonism, drooling), the cornea (Kayser-Fleischer rings) and red cells (Coombs-negative hemolysis), with psychiatric symptoms. Serum ceruloplasmin is low and 24-hour urinary copper high. Chelators (penicillamine, trientine) and zinc, which induces enterocyte metallothionein to block copper absorption, are the mainstays; liver transplant cures severe disease.

Cerebellar circuitry

Inputs. Mossy fibers from the pontine nuclei (cortical information), spinocerebellar tracts (including the dorsal nucleus of Clarke) and vestibular nuclei excite granule cells, whose parallel fibers make weak contacts with many Purkinje cells. Climbing fibers from the contralateral inferior olive each wrap a single Purkinje cell with a powerful excitatory signal that conveys motor error and drives motor learning.

Output. Purkinje cells are the only output of the cerebellar cortex, and they are GABAergic: they inhibit the deep cerebellar nuclei, which provide the excitatory output. From lateral to medial the nuclei are dentate, emboliform, globose and fastigial ("Don't Eat Greasy Foods"); the dentate serves the lateral hemispheres and the fastigial the vermis.

Why signs are ipsilateral. Output leaves through the superior cerebellar peduncle, which decussates to the contralateral red nucleus and VL thalamus; that side's motor cortex sends a corticospinal tract that crosses back. Each cerebellar hemisphere therefore coordinates the limbs on its own side. Inputs arrive through the middle peduncle (from the contralateral pons) and the inferior peduncle (spinal, olivary and vestibular).

Cerebellar lesions

Vermis. Midline lesions of the vermis and flocculonodular lobe disturb axial control: truncal ataxia, titubation and a wide-based, lurching gait with relatively normal limb coordination. Chronic alcohol use selectively degenerates the anterior superior vermis, and medulloblastoma, a childhood tumor, arises in the vermis.

Hemispheres. Lateral lesions from stroke, tumor or multiple sclerosis produce ipsilateral limb ataxia: dysmetria with past-pointing, intention tremor, dysdiadochokinesia (clumsy rapid alternating movements), rebound, hypotonia, gaze-evoked nystagmus and scanning dysarthria. Patients drift or fall toward the side of the lesion.

Romberg tests proprioception, not the cerebellum: a cerebellar patient is unsteady even with eyes open, whereas a patient with dorsal column disease becomes unsteady only when the eyes close.

Hereditary ataxias

Friedreich ataxia. The most common inherited ataxia is an autosomal recessive GAA repeat expansion in FXN that reduces frataxin, a mitochondrial protein needed for iron-sulfur cluster assembly. Mitochondrial iron builds up and oxidative damage destroys the dorsal columns, spinocerebellar and lateral corticospinal tracts and dorsal root ganglia. Childhood-onset gait ataxia, dysarthria, loss of vibration and position sense, areflexia with Babinski signs, pes cavus, kyphoscoliosis and diabetes follow, and hypertrophic cardiomyopathy is the leading cause of death.

Ataxia-telangiectasia. Autosomal recessive loss of ATM, a kinase that senses DNA double-strand breaks and activates repair and cell-cycle checkpoints, causes cerebellar ataxia from Purkinje cell loss beginning in toddlers, conjunctival and skin telangiectasias, IgA and IgG2 deficiency with recurrent sinopulmonary infections, elevated AFP, sensitivity to ionizing radiation, and a high risk of leukemia and lymphoma.

Spinocerebellar ataxias. Most SCAs (SCA1, 2, 3 or Machado-Joseph disease, 6, 7) are autosomal dominant polyglutamine CAG expansions that cause adult-onset progressive ataxia, dysarthria and eye movement abnormalities, often with anticipation; SCA7 adds retinal degeneration.

Vitamin E deficiency (fat malabsorption, abetalipoproteinemia, α-tocopherol transfer protein defects) mimics Friedreich ataxia and is treatable, so check a vitamin E level in any young patient with ataxia.