Descending Control and the Basal Ganglia

A stroke deep in the left hemisphere weakens the right face, arm and leg. A cut through the right half of the spinal cord in the neck weakens the right arm and leg. Same tract, opposite sides.

The difference is where the lesion sits relative to one crossing. This lesson uses that crossing to place lesions, then turns to the basal ganglia, deep nuclei that never reach the spinal cord yet decide, in the classic model, whether a movement goes ahead. You will treat that circuit as a chain of plus and minus signs, use it on two diseases, and see where it breaks.

The upper motor neuron: its crossing and its signs

A lower motor neuron is a motor neuron in the brainstem or the spinal cord’s ventral horn whose axon leaves the central nervous system and ends on muscle; you met it in motor units and reflexes. An upper motor neuron is a neuron in the cortex or brainstem whose axon descends to control lower motor neurons, directly or through interneurons. A tract is a bundle of axons inside the central nervous system, and a decussation is a place where a tract crosses the midline. Ipsilateral means on the same side; contralateral means on the opposite side.

The corticospinal tract starts in layer V of primary motor cortex, with contributions from premotor, supplementary motor and parietal areas. Its axons pass through the corona radiata, the posterior limb of the internal capsule, the cerebral peduncle of the midbrain and the base of the pons, and form the medullary pyramids. In the caudal medulla most of them cross at the pyramidal decussation. Estimates vary between sources, from roughly 75 to 90%. The crossed fibres run in the lateral column of the cord as the lateral corticospinal tract and end mainly on interneurons of the intermediate grey matter and on ventral horn motor neurons. In macaques some cortical cells contact digit motor neurons directly (Rathelot and Strick, 2006). The uncrossed minority forms the anterior tract, most of whose fibres appear to cross segmentally. How they cross during development is in crossing the midline.

A lower motor neuron lesion causes weakness with low tone and reduced or absent reflexes, because the motor limb of the reflex arc is cut; later the muscle wastes and may show fasciculations, the visible twitches of single motor units firing on their own. An established upper motor neuron lesion causes weakness with raised tone, brisk stretch reflexes, clonus (rhythmic beats of contraction set off by a sudden stretch) and an extensor plantar response, in which stroking the sole makes the great toe extend. Independent finger movements are often lost. Two timing traps: right after a spinal cord injury the limbs below can be flaccid and areflexic (spinal shock), and spasticity appears later; and an upgoing toe is normal in infants, so it is a sign only after infancy.

The face adds one more clue. Corticobulbar fibres to the motor neurons for the lower face come mainly from the opposite cortex, while the forehead receives input from both sides. An upper motor neuron lesion above the brainstem therefore weakens the contralateral lower face and spares the forehead.

Worked problem: two cases. Assume one focal lesion, examined weeks after onset so the upper motor neuron signs have developed.

Case 1. Weakness of the right lower face, right arm and right leg, with raised tone, brisk reflexes and an extensor plantar response on the right.

• Step 1: upper motor neuron signs put the lesion in the descending pathway, not the motor neurons or nerves.
• Step 2: the lower face is involved. Fibres for voluntary face movement end on facial motor neurons in the pons, so the lesion is above the facial nucleus: in the hemisphere, or occasionally in the pons above that level.
• Step 3: above the decussation the deficit is contralateral, so right-sided weakness means a left-sided lesion.
• Answer: most likely the left hemisphere, for example the posterior limb of the left internal capsule, where descending fibres for the face, arm and leg are packed into a small space.

Case 2. The same right arm and leg signs, but the face is normal. Vibration sense is lost on the right, and pain and temperature are lost on the left below about the C6 dermatome.

• Step 1: the face is spared, which fits a lesion below the facial nucleus, probably in the cord; the sensory findings in step 3 test this.
• Step 2: in the cord the corticospinal fibres have already crossed, so the weakness is ipsilateral: a right-sided lesion.
• Step 3: check with sensation (touch and pain). Dorsal column fibres ascend on the same side and cross in the medulla, so right vibration loss points to the right cord. Spinothalamic fibres cross within a segment or two of entry, so right cord damage removes pain and temperature on the left, starting a little below the lesion.
• Answer: a right hemisection of the cord near C5, with lower motor neuron signs expected at the level itself, where ventral horn cells are destroyed.

The basal ganglia as a signed loop

A nucleus in the brain is a cluster of neuron cell bodies with shared connections. The basal ganglia include the striatum (caudate and putamen), the external and internal segments of the globus pallidus (GPe and GPi), the subthalamic nucleus (STN), and the substantia nigra, whose pars reticulata (SNr) works like GPi and whose pars compacta (SNc) holds dopamine neurons. The basal ganglia do not project to the spinal cord. Their output acts through the thalamus, which projects back to cortex, and through brainstem targets.

The output neurons of GPi and SNr are GABAergic and fire tonically, holding the motor thalamus under steady inhibition, like a foot resting on a brake. Movement needs the brake lifted.

Striatal projection neurons are themselves GABAergic, and two routes from them reach the brake. In the direct pathway, striatal neurons that express D1 dopamine receptors inhibit GPi and SNr directly. In the indirect pathway, striatal neurons that express D2 receptors inhibit GPe; GPe inhibits STN; and STN, which is glutamatergic, excites GPi.

Worked problem: count the signs. Give each excitatory link +1 and each inhibitory link −1, and multiply along the route. A positive product means activity entering the loop ends up increasing cortical drive; a negative product means it ends up decreasing it.

Direct: cortex→striatum (+1) × striatum→GPi (−1) × GPi→thalamus (−1) × thalamus→cortex (+1) = +1

Indirect: cortex→striatum (+1) × striatum→GPe (−1) × GPe→STN (−1) × STN→GPi (+1) × GPi→thalamus (−1) × thalamus→cortex (+1) = −1

The direct route has two inhibitions in series, which give disinhibition. The indirect route has three negatives, so its product is −1.

Now add dopamine. In the classic model, SNc dopamine excites D1 direct neurons and inhibits D2 indirect neurons. Exciting a +1 route raises cortical drive. Inhibiting a −1 route also raises it. So both actions push toward movement, and losing dopamine pushes both routes toward less movement: the prediction of akinesia. How D1 and D2 receptors couple to cAMP belongs to G proteins and cAMP and PKA; where dopamine is released and cleared is in transmitter systems.

This arithmetic is the logic of the rate model set out by Albin, Young and Penney in 1989 and by DeLong in 1990: a way to reason about the direction of a change, not a measured law of how firing rates add.

Parkinson’s and Huntington’s through the circuit

Parkinson’s disease. The motor signs (slowness, small movements, rigidity, rest tremor) appear after substantial loss of SNc dopamine neurons; published threshold figures vary. Ehringer and Hornykiewicz found striatal dopamine greatly reduced in post-mortem brains from patients (1960). Run the signs: without dopamine the direct route weakens and the indirect route strengthens, so GPe is more inhibited, STN is released, and GPi fires more. The thalamus is held down harder and movement is hard to start.

A dopamine precursor such as L-DOPA raises the dopamine available in the striatum, and the predicted overactive STN became a surgical target. In mice with dopamine depleted by 6-hydroxydopamine, driving direct-pathway neurons with light rescued the motor deficits Kravitz and colleagues measured (2010). Why the dopamine neurons die is taken up in neurodegeneration.

Huntington’s disease has a different cause: an expanded CAG repeat in the huntingtin gene (the mutation type is in mutation), not a primary loss of dopamine. In post-mortem tissue from 17 patients, Reiner and colleagues (1988) found the enkephalin-containing projection to GPe more affected in early and middle stages than the substance P projection to GPi, and broad loss in the most advanced cases. Run the signs for losing indirect striatal neurons: GPe is released, STN is more inhibited, GPi gets less excitation and fires less, and the thalamus is released. That is thought to contribute to chorea, the brief, irregular involuntary movements of early disease. Later loss of direct-pathway output is associated with the akinesia of late disease.

Where the box model breaks

The rate model predicts the sign of several clinical effects. Four sets of results show its limits.

First, the pathways do not alternate on and off. Cui and colleagues (2013) found calcium signals from both D1-expressing (direct-pathway) and A2A-expressing (indirect-pathway) striatal populations in mice rising around the start of an action. Freeze and colleagues (2013) found that stimulating either pathway produced both excitatory and inhibitory responses among SNr neurons in mice.

Second, there are more routes. In awake monkeys, Nambu and colleagues (2000) found that cortical stimulation evoked an early pallidal excitation that depended on STN and arrived faster than effects through the striatum: a hyperdirect pathway. And in mice, direct-pathway neurons branch. Labouesse and colleagues (2023) found that 147 of 148 SNr-labelled direct-pathway neurons in their sample also carried a GPe label. That is 147/148 = 99.3% of the SNr-labelled cells counted, not of all striatal neurons.

Third, rate may not be the main variable. Parker and colleagues (2018) found that dopamine depletion in mice disrupted the clustered activity of movement-related indirect-pathway neurons, a change in pattern rather than only in mean rate. Studies of parkinsonian animals and patients also report more bursting and synchronized oscillation in STN and GPi.

Fourth, some symptoms do not fit. The model gives no account of rest tremor, and deep brain stimulation of the STN relieves parkinsonian signs by a mechanism that is still unresolved. What the basal ganglia contribute to choosing actions by their value continues in motivation and reward.

Design problem

The rate model predicts that the STN is overactive in parkinsonism and that silencing it should help. Design a primate experiment to test this, and say what result would count against the model.