The projections from the medium spiny neurons of the caudate and putamen to the internal segment of the globus pallidus and substantia nigra pars reticulata are part of a “direct pathway” and, as just described, serve to release the upper motor neurons from tonic inhibition. This pathway is summarized in Figure 18.8A. A second pathway serves to increase the level of tonic inhibition and is called the “indirect pathway” (Figure 18.8B). This pathway provides a second route linking the corpus striatum with the internal globus pallidus and substantia nigra pars reticulata. In the indirect pathway, another population of medium spiny neurons projects to the lateral or external segment of the globus pallidus. This external division sends projections to both the internal segment of the globus pallidus and the subthalamic nucleus of the ventral thalamus (see Figure 18.1). But, instead of projecting to structures outside of the basal ganglia, the subthalamic nucleus projects back to the internal segment of the globus pallidus and to the substantia nigra pars reticulata. As already described, these latter two nuclei project out of the basal ganglia, which thus allows the indirect pathway to influence the activity of the upper motor neurons.

Figure 18.8

Disinhibition in the direct and indirect pathways through the basal ganglia. (A) In the direct pathway, transiently inhibitory projections from the caudate and putamen project to tonically active inhibitory neurons in the internal segment of the globus (more...)

The indirect pathway through the basal ganglia apparently serves to modulate the disinhibitory actions of the direct pathway. The subthalamic nucleus neurons that project to the internal globus pallidus and substantia nigra pars reticulata are excitatory. Normally, when the indirect pathway is activated by signals from the cortex, the medium spiny neurons discharge and inhibit the tonically active GABAergic neurons of the external globus pallidus. As a result, the subthalamic cells become more active and, by virtue of their excitatory synapses with cells of the internal globus pallidus and reticulata, they increase the inhibitory outflow of the basal ganglia. Thus, in contrast to the direct pathway, which when activated releases tonic inhibition, the net effect of activity in the indirect pathway is to increase inhibitory influences on the upper motor neurons. The indirect pathway can thus be regarded as a “brake” on the normal function of the direct pathway. Indeed, many neural systems achieve fine control of their output by a similar interplay between excitation and inhibition.

The consequences of imbalances in this fine control mechanism are apparent in diseases that affect the subthalamic nucleus. These disorders remove a source of excitatory input to the internal globus pallidus and reticulata, and thus abnormally reduce the inhibitory outflow of the basal ganglia. A basal ganglia syndrome called hemiballismus, which is characterized by violent, involuntary movements of the limbs, is the result of damage to the subthalamic nucleus. The involuntary movements are initiated by abnormal discharges of upper motor neurons that are receiving less tonic inhibition from the basal ganglia.

Another circuit within the basal ganglia system entails the dopaminergic cells in the pars compacta subdivision of substantia nigra and modulates the output of the corpus striatum. The medium spiny neurons of the corpus striatum project directly to substantia nigra pars compacta, which in turn sends widespread dopaminergic projections back to the spiny neurons. These dopaminergic influences on the spiny neurons are complex: The same nigral neurons can provide excitatory inputs mediated by D1 type dopaminergic receptors on the spiny cells that project to the internal globus pallidus (the direct pathway), and inhibitory inputs mediated by D2 type receptors on the spiny cells that project to the external globus pallidus (the indirect pathway). Since the actions of the direct and indirect pathways on the output of the basal ganglia are antagonistic, these different influences of the nigrostriatal axons produce the same effect, namely a decrease in the inhibitory outflow of the basal ganglia.

The modulatory influences of this second internal circuit help explain many of the manifestations of basal ganglia disorders. For example, Parkinson's Disease is caused by the loss of the nigrostriatal dopaminergic neurons (Figure 18.9A and Box B). As mentioned earlier, the normal effects of the compacta input to the striatum are excitation of the medium spiny neurons that project directly to the internal globus pallidus and inhibition of the spiny neurons that project to the external globus pallidus cells in the indirect pathway. Normally, both of these dopaminergic effects serve to decrease the inhibitory outflow of the basal ganglia and thus to increase the excitability of the upper motor neurons (Figure 18.10A). In contrast, when the compacta cells are destroyed, as occurs in Parkinson's disease, the inhibitory outflow of the basal ganglia is abnormally high, and thalamic activation of upper motor neurons in the motor cortex is therefore less likely to occur.

Figure 18.9

The pathological changes in certain neurological diseases provide insights about the function of the basal ganglia. (A) Left: The midbrain from a patient with Parkinson's disease. The substantia nigra (pigmented area) is largely absent in the region above (more...)

Box B

Parkinson's Disease: An Opportunity for Novel Therapeutic Approaches.

Figure 18.10

Summary explanation of hypokinetic disorders such as Parkinson's disease and hyperkinetic disorders like Huntington's disease. In both cases, the balance of inhibitory signals in the direct and indirect pathways is altered, leading to a diminished ability (more...)

In fact, many of the symptoms seen in Parkinson's disease (and in other hypokinetic movement disorders) reflect a failure of the disinhibition normally mediated by the basal ganglia. Thus, Parkinsonian patients tend to have diminished facial expressions and lack “associated movements” such as arm swinging during walking. Indeed, any movement is difficult to initiate and, once initiated, is often difficult to terminate. Disruption of the same circuits also increases the discharge rate of the inhibitory cells in substantia nigra pars reticulata. The resulting increase in tonic inhibition reduces the excitability of the upper motor neurons in the superior colliculus and causes saccades to be reduced in both frequency and amplitude.

Support for this explanation of hypokinetic movement disorders like Parkinson's disease comes from studies of monkeys in which degeneration of the dopaminergic cells of substantia nigra has been induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys (or humans) exposed to MPTP develop symptoms that are very similar to those of patients with Parkinson's disease. Furthermore, a second lesion placed in the subthalamic nucleus results in significant improvement in the ability of these animals to initiate movements, as would be expected based on the circuitry of the indirect pathway (see Figure 18.8B).

Similarly, knowledge about the indirect pathway within the basal ganglia helps explain the motor abnormalities seen in Huntington's disease (see Box A). In patients with Huntington's disease, medium spiny neurons that project to the external segment of the globus pallidus degenerate (see Figure 18.9B). In the absence of their normal inhibitory input from the spiny neurons, the external globus pallidus cells become abnormally active; this activity reduces in turn the excitatory output of the subthalamic nucleus to the internal globus pallidus (Figure 18.10B). In consequence, the inhibitory outflow of the basal ganglia is reduced. Without the restraining influence of the basal ganglia, upper motor neurons can be activated by inappropriate signals, resulting in the undesired ballistic and choreic (dancelike) movements that characterize Huntington's disease. Importantly, the basal ganglia may exert a similar influence on other non-motor systems with equally significant clinical implications (Box C).

Box C

Basal Ganglia Loops and Non-Motor Brain Functions.

As predicted by this account, GABA agonists and antagonists applied to substantia nigra pars reticulata of monkeys produce symptoms similar to those seen in human basal ganglia disease. For example, intranigral injection of bicuculline, which blocks the GABAergic inputs from the striatal medium spiny neurons to the reticulata cells, increases the amount of tonic inhibition on the upper motor neurons in the deep collicular layers. These animals exhibit fewer, slower saccades, reminiscent of patients with Parkinson's disease. In contrast, injections of the GABA agonist muscimol into substantia nigra pars reticulata decrease the tonic GABAergic inhibition of the upper motor neurons in the superior colliculus, with the result that the injected monkeys generate spontaneous, irrepressible saccades that resemble the involuntary movements characteristic of basal ganglia diseases such as hemiballismus and Huntington's disease (Figure 18.11).

Figure 18.11

After the tonically active cells of substantia nigra pars reticulata are inactivated by an intranigral injection of muscimol (A), the upper motor neurons in the deep layers of the superior colliculus are disinhibited and the monkey generates spontaneous (more...)