Subcortical Regions Receiving Pyramidal Input and Their Influence on the Pyramidal System

The largest subcortical extrapyramidal region receiving pyramidal input from both supragranular and infragranular regions of the motor cortices is the putamen (Figs. 31-1 and 31-2).⁴ Together with the caudate nucleus, this striatal area receives an information from all cortical regions. The putamen passes on processed information through both a direct activating and an indirect inactivating pathway to the basal ganglia output nuclei, the internal globus pallidus, and the substantia nigra pars reticulata.⁴ These basal ganglia regions are small in comparison with the striatum (100-fold fewer neurons) and contain large nonspiny γ-amino butyric acid–ergic (GABAergic) inhibitory projection neurons.

Figure 31-1 Basal ganglia internal feedback circuits (left) and throughput circuits (right). Projections from pyramidal neurons in the motor cortex innervate the putamen (red), the subthalamic nucleus (green), and the ventrolateral (gray) and caudal intralaminar (brown) thalamic nuclei. The basal ganglia output nuclei, the substantia nigra pars reticulata, and the internal globus pallidus (yellow), project to the motor thalamus (gray/brown) with information passing through a hyperdirect pathway from the subthalamus (green) or a direct pathway from the putamen (red) or an indirect pathway from the putamen (red) through the external globus pallidus (orange). Several feedback systems exist with information regulated within the putamen by γ-amino butyric acid–ergic (GABAergic) and cholinergic interneurons, by dopamine from the substantia nigra pars compacta (gray), and by glutamate from the caudal intralaminar thalamus (mauve). The subthalamic nucleus (green) and external globus pallidus (yellow) are strongly coupled.

Figure 31-2 Pyramidal input to the thalamus (left) and thalamocortical pathways (right). Some corticocortical pathways are also indicated. Information from the presupplementary motor cortex (or area) is relayed to the supplementary and premotor cortices through the ventrolateral anterior (purple) and caudal intralaminar (brown) nuclei, as well by direct corticocortical connections. Feedback from the premotor cortices to the pre-SMC occurs via the mediodorsal thalamus (blue), whereas reciprocal feedback between the primary (1°) motor cortex and the ventrolateral posterior thalamus (purple).

Striatal neurons also receive excitatory thalamic input from the ventral anterior, ventrolateral nuclei, and caudal intralaminar nuclei; receive inhibitory input from the external globus pallidus; and are modulated by dopamine from the substantia nigra pars compacta and mesencephalic tegmentum.^4,7 Overall dopamine enhances activity in the direct pathway and decreases activity in the indirect pathway.⁸ The striatum con tains mainly GABAergic spiny projection neurons and a small population of GABAergic and cholinergic interneurons (≈3% of striatal neurons). Striatal spiny neurons project to the globus pallidus and substantia nigra, as well as giving rise to dense local arbors that contact other spiny neurons.⁴ They are usually silent and discharge only when cortical information is received. The GABAergic interneurons establish contacts with the dendritic shafts of neighboring spiny neurons and form the structural basis for feedforward striatal surround inhibition. Striatal cholinergic interneurons, in contrast, are tonically active and play a major role in the learning of reward behavior.

The smallest subcortical extrapyramidal region receiving pyramidal input from layer V neurons of the motor cortices is the subthalamic nucleus.⁹ This is the only cortical input to this nucleus, and this hyperdirect pathway conveys powerful excitatory effects from the motor cortices to the globus pallidus and substantia nigra pars reticulata, bypassing the striatum, with shorter conduction times than in the direct striatal pathway.⁹ It also receives significant inhibitory input from the globus pallidus and striatum.¹⁰ The subthalamic nucleus contains nonspiny excitatory glutamatergic neurons that conduct short-latency excitatory responses to the globus pallidus and substantia nigra after cortical excitation.

Specific regions of the thalamus also receive pyramidal input from motor cortices.⁵ There is a reciprocal excitatory component from small layer VI neurons to the ventrolateral thalamus and a fast-conducting nonreciprocal excitatory component from layer V neurons that allows the synchronization of thalamocortical oscillations and information flow across functionally related cortical fields. Cortical regions associated with executive function (such as dorsolateral prefrontal cortex) have nonreciprocal connections to thalamic regions that project to premotor cortices (ventral anterior thalamus), whereas premotor cortices have nonreciprocal connections with thalamic regions that project to the primary motor cortex (ventrolateral thalamus).¹¹ The thalamus contains nonspiny excitatory glutamatergic neurons that conduct short-latency excitatory responses after appropriate cortical excitation. These interconnections between the cortex and thalamus largely determine cortical activity, facilitating information transfer from one cortical region to another through a feedforward mechanism. The output nuclei of the basal ganglia inhibit thalamocortical activity in the ventral anterior, anterior ventrolateral, and caudal intralaminar nuclei.¹¹

Subcortical Regions Participating in the Internal Regulation of Extrapyramidal Systems

There is significant internal modulation of the hyperdirect, direct, and indirect basal ganglia pathways (see Fig. 31-1). One of the basal ganglia regions that most influence striatal processing is the dopaminergic substantia nigra pars compacta, as discussed previously, although pallidal and thalamic projections also significantly modify striatal output. The large, tonically active, nonspiny dopaminergic neurons of the substantia nigra pars compacta receive input directly from striatal spiny projection neurons, which modifies their firing rate and patterns.⁸ This reinforces wanted behaviors and suppresses unwanted behaviors. These dopaminergic neurons also receive significant innervation from cortical, limbic, and brainstem regions and play a role in shifting attentional sets.

The basal ganglia region with the most internal connections is the external segment of the globus pallidus.⁴ These pallidal neurons receive most input from the striatum and the subthalamic nucleus, as well as a small dopaminergic projection from the substantia nigra. Individual neurons in the external globus pallidus innervate the output nuclei, the subthalamic nucleus, and the substantia nigra pars compacta.⁴ About 25% of them also innervate the striatal GABAergic spiny neurons. These neurons provide the anatomical substrate for the synaptic integration of functionally diverse cortical information within the basal ganglia and appear to work in parallel with the subthalamic nucleus and striatum to set up appropriate oscillatory activity within the basal ganglia.¹⁰ They are therefore in a position to provide level-setting control of the activity through virtually the whole of the extrapyramidal basal ganglia system.