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Chapter 4: Basal Ganglia

James Knierim, Ph.D., Department of Neuroscience, The Johns Hopkins University

Last Review 20 Oct 2020

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4.1 Introduction

The previous three chapters have described the anatomy and function of the four levels of the motor system hierarchy: the spinal cord, the brainstem, the motor cortex, and the association cortex. Two other brain structures can be considered as “side loops” in the motor hierarchy. They influence the processing of motor control and modulate the output of the descending pathways without directly causing motor output. Both of these structures—the basal ganglia and the cerebellum—are now known to have other functions in addition to modulating motor control. Because the most obvious clinical signs of damage to these areas are a wide variety of motor impairments, they are still generally considered to be motor structures. Basal ganglia dysfunction causes a set of symptoms that are quite different from damage to descending motor pathways, and thus the basal ganglia were at one time considered to form an “extrapyramidal motor system” that was distinct from the pyramidal tract pathways. It is now known that the basal ganglia do not originate a separate motor pathway. Instead, they influence and modulate the activity of motor cortex and the descending motor pathways in ways that cause distinct symptoms when different basal ganglia structures are damaged.

4.2 Gross Anatomy of the Basal Ganglia

The basal ganglia comprise a distributed set of brain structures in the telencephalon, diencephalon, and mesencephalon (Figure 4.1 and Table 1). The forebrain structures include the caudate nucleus, the putamen, the nucleus accumbens (or ventral striatum) and the globus pallidus. Together, these structures are named the corpus striatum. The caudate nucleus is a C-shaped structure that is closely associated with the lateral wall of the lateral ventricle. It is largest at its anterior pole (the head), and its size diminishes posteriorly as it follows the course of the lateral ventricle (the body) all the way to the temporal lobe (the tail), where it terminates at the amygdaloid nuclei. The putamen is also a large structure that is separated from the caudate nucleus by the anterior limb of the internal capsule. The putamen is connected to the caudate head by bridges of cells that cut across the internal capsule. Because of the striated appearance of these cell bridges (Figure 4.1B), the caudate and putamen are collectively referred to as the striatum or neostriatum, and the nucleus accumbens is often called the ventral striatum. Functionally, the caudate nucleus and the putamen are considered equivalent to each other; indeed, most mammals have only a single nucleus called the striatum. It is unclear whether there is any functional significance of the separation of the striatum into the caudate and putamen in primates. The putamen and the globus pallidus are collectively called the lenticular nucleus, or lentiform nucleus. The globus pallidus is divided into two segments: the internal (or medial) segment and the external (or lateral) segment.

Figure 4.1 Basal ganglia structures. (A) Location of basal ganglia components in idealized brain section. (B) Cell bridges between the caudate and putamen give a striated appearance.

 

Table I Basal Ganglia Nomenclature

The subthalamic nucleus is part of the diencephalon; as its name implies, it is located just below the thalamus. The substantia nigra is a midbrain structure, composed of two distinct parts: the pars compacta and the pars reticulata. The substantia nigra is located between the red nucleus and the crus cerebri (cerebral peduncle) on the ventral part of the midbrain. The pars compacta is the source of a clinically important dopaminergic pathway to the striatum; loss of neurons in this area is the cause of Parkinson’s disease (see below). An area that is functionally analogous to the substantia nigra pars compacta is the ventral tegmental area, which is located nearby and makes a dopaminergic projection to the nucleus accumbens.

Historically, the amygdaloid complex and the claustrum were considered parts of the basal ganglia. However, modern usage usually restricts the term to those structures that cause the motor impairments characteristic of the extrapyramidal syndrome (caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra).

4.3 Basal Ganglia Afferents

Figure 4.2 Figure 4.2 Basal ganglia afferents. For diagram simplicity, in this and subsequent figures, the caudate and putamen are represented by the putamen only, as the two regions have similar connections.

The striatum is the main recipient of afferents to the basal ganglia (Figure 4.2). These excitatory afferents arise from the entire cerebral cortex and from the intralaminar nuclei of the thalamus (primarily the centromedian nucleus and parafascicularis nucleus). The projections from different cortical areas are segregated, such that the frontal lobe projects predominantly to the caudate head and the putamen; the parietal and occipital lobes project to the caudate body; and the temporal lobe projects to the caudate tail. The primary motor cortex and the primary somatosensory cortex project mainly to the putamen, whereas the premotor cortex and supplementary motor areas project to the caudate head. Other cortical areas project primarily to the caudate. Thus, along the C-shaped extent of the caudate nucleus, the caudate cells receive their input from the cortical regions that are close by. The enlarged head of the caudate reflects the large projection from the frontal cortex to the caudate. In addition, the nucleus accumbens (ventral striatum) receives a large input from limbic cortex.

In the motor regions of the basal ganglia, there is a motor homunculus similar to that seen in the primary motor cortex. Thus, the projections from the medial wall of the anterior paracentral lobule (the part of M1 that contains a representation of the legs and torso) innervate regions of the striatum that are next to the recipient zones from the dorsal surface of the precentral gyrus (the part of M1 that contains a representation of the arms and hands). Similarly, the projections from the lateral surface of the precentral gyrus (the part of M1 that contains a representation of the face) innervate regions that are next to the arm and hand representation. This topography of projections is maintained in the intrinsic circuitry of the basal ganglia.

4.4 Basal Ganglia Efferents

The major output structures of the basal ganglia are the globus pallidus internal segment (GPint) and the substantia nigra pars reticulata (SNr) (Figure 4.3). Both of these structures make GABAergic, inhibitory connections on their targets. The GPint projects to a number of thalamic structures by way of two fiber tracts: the ansa lenticularis and the lenticular fasciculus. The loop that processes sensorimotor information from the motor cortex and the somatosensory cortex projects to the ventral anterior (VA) and ventral lateral (VL) nuclei. The loop that processes other neocortical information projects to the dorsomedial nucleus (DM), intralaminar nuclei, and parts of the VA nucleus. The SNr projects to the superior colliculus, which is involved in eye movements, as well as to the VA/VL thalamic nuclei.

Figure 4.3 Basal ganglia efferents

4.5 Basal Ganglia Intrinsic Connections

A number of intrinsic pathways interconnect various basal ganglia structures (Figure 4.4).

Figure 4.4 Basal ganglia intrinsic connections

1. The striatopallidal pathway is a GABAergic, inhibitory connection between the striatum and both segments of the globus pallidus.
   
2. The striatonigral pathway is a GABAergic, inhibitory connection between the striatum and the SNr.
   
3. The globus pallidus external segment makes a GABAergic, inhibitory connection to the subthalamic nucleus.
   
4. The subthalamic nucleus makes glutamatergic, excitatory connections onto both segments of the globus pallidus and the SNr. This pathway is the only purely excitatory pathway among the intrinsic pathways of the basal ganglia.
   
5. The nigrostriatal pathway makes a dopaminergic synapse onto striatal neurons. As we will see below, this is a mixed pathway, with excitatory effects on some striatal neurons and inhibitory effects on others.
   

Two pathways process signals in the basal ganglia

There are two distinct pathways that process signals through the basal ganglia: the direct pathway and the indirect pathway. These two pathways have opposite net effects on thalamic target structures. Excitation of the direct pathway has the net effect of exciting thalamic neurons (which in turn make excitatory connections onto cortical neurons). Excitation of the indirect pathway has the net effect of inhibiting thalamic neurons (rendering them unable to excite motor cortex neurons). The normal functioning of the basal ganglia apparently involves a proper balance between the activity of these two pathways. One hypothesis is that the direct pathway selectively facilitates certain motor (or cognitive) programs in the cerebral cortex that are adaptive for the present task, whereas the indirect pathway simultaneously inhibits the execution of competing motor programs. An upset of the balance between the direct and indirect pathways results in the motor dysfunctions that characterize the extrapyramidal syndrome (see below).

Direct pathway. Although the connectivity patterns of the direct and indirect pathways are relatively straightforward, the predominance of inhibitory connections in the system can make an understanding of the functional circuitry complicated and non-intuitive (Figure 4.5).

Figure 4.5 Direct/indirect pathways. Solid lines represent direct pathway and dashed lines represent indirect pathway. (The output from GPi is common to both pathways.) Green lines represent excitatory connections and red lines represent inhibitory connections. Click on individual pathway names to view each pathway in isolation.

The direct pathway starts with cells in the striatum that make inhibitory connections with cells in the GPint. The GPint cells in turn make inhibitory connections on cells in the thalamus. Thus, the firing of GPint neurons inhibits the thalamus, making the thalamus less likely to excite the neocortex. When the direct pathway striatal neurons fire, however, they inhibit the activity of the GPint neurons. This inhibition releases the thalamic neurons from inhibition (i.e., it disinhibits the thalamic neurons), allowing them to fire to excite the cortex. Thus, because of the “double negative” in the pathway between the striatum and GPint and the GPint and thalamus, the net result of exciting the direct pathway striatal neurons is to excite motor cortex.

Think of it as a multiplication equation, with an excitatory connection (E) equal to +1 and an inhibitory connection (I) equal to –1:

Because the two negative numbers cancel each other out.

Indirect pathway. The indirect pathway starts with a different set of cells in the striatum. These neurons make inhibitory connections to the external segment of the globus pallidus (GPext). The GPext neurons make inhibitory connections to cells in the subthalamic nucleus, which in turn make excitatory connections to cells in the GPint. (Remember that the subthalamic-GPint pathway is the only purely excitatory pathway within the intrinsic basal ganglia circuitry.) As we saw before, the GPint neurons make inhibitory connections on the thalamic neurons. To see the net effects of activation of the indirect pathway, let us work backwards from the GPint. When the GPint cells are active, they inhibit thalamic neurons, thus making cortex less active. When the subthalamic neurons are firing, they increase the firing rate of GPint neurons, thus increasing the net inhibition on cortex. Firing of the GPext neurons inhibits the subthalamic neurons, thus making the GPint neurons less active and disinhibiting the thalamus. However, when the indirect pathway striatal neurons are active, they inhibit the GPext neurons, thus disinhibiting the subthalamic neurons. With the subthalamic neurons free to fire, the GPint neurons inhibit the thalamus, thereby producing a net inhibition on the motor cortex.

Again, think of a multiplication analogy:

Because there are 3 negative numbers in the equation, the net effect is negative.

Thus, as a result of the complex sequences of excitation, inhibition, and disinhibition, the net effect of the cortex exciting the direct pathway is to further excite the cortex (positive feedback loop), whereas the net effect of cortex exciting the indirect pathway is to inhibit the cortex (negative feedback loop). Presumably, the function of the basal ganglia is related to a proper balance between these two pathways. Motor cortex neurons have to excite the proper direct pathway neurons to further increase their own firing, and they have to excite the proper indirect pathways neurons that will inhibit other motor cortex neurons that are not adaptive for the task at hand (see below).

The nigrostriatal projection

An important pathway in the modulation of the direct and indirect pathways is the dopaminergic, nigrostriatal projection from the substantia nigra pars compacta to the striatum (Figure 4.5). Direct pathway striatal neurons have D1 dopamine receptors, which depolarize the cell in response to dopamine. In contrast, indirect pathway striatal neurons have D2 dopamine receptors, which hyperpolarize the cell in response to dopamine. The nigrostriatal pathway thus has the dual effect of exciting the direct pathway while simultaneously inhibiting the indirect pathway. Because of this dual effect, excitation of the nigrostriatal pathway has the net effect of exciting cortex by two routes, by exciting the direct pathway (which itself has a net excitatory effect on cortex) and inhibiting the indirect pathway (thereby disinhibiting the net inhibitory effect of the indirect pathway on cortex). The loss of these dopamine neurons in Parkinson’s disease causes the poverty of movement that characterizes this disease, as the balance between direct pathway excitation of cortex and indirect pathway inhibition of cortex is tipped in favor of the indirect pathway, with a subsequent pathological global inhibition of motor cortex areas.

4.6 Functions of the Basal Ganglia

Motor functions

The function of the basal ganglia in motor control is not understood in detail. It appears that the basal ganglia is involved in the enabling of practiced motor acts and in gating the initiation of voluntary movements by modulating motor programs stored in the motor cortex and elsewhere in the motor hierarchy (Figure 4.6). Thus, voluntary movements are not initiated in the basal ganglia (they are initiated in the cortex); however, proper functioning of the basal ganglia appears to be necessary in order for the motor cortex to relay the appropriate motor commands to the lower levels of the hierarchy.

Figure 4.6 The basal ganglia and motor cortex form a processing loop whereby the basal ganglia enables the proper motor program stored in motor cortex circuits via the direct pathway and inhibits competing motor programs via the indirect pathway. The proper motor programs are selected based on the desired motor output relayed from cortex. Note that the complex circuits of the direct and indirect pathways are schematically diagramed as single neurons for clarity of illustration.

Recall that the major output from the basal ganglia is an inhibitory connection from the GPint (or SNr) to the thalamus (or superior colliculus). Studies of eye movements in monkeys have shed light on the function of the basal ganglia loop. Normally, the SNr neurons are tonically active, suppressing the output of the collicular neurons that control saccadic eye movements. When the direct pathway striatal neurons are excited by the cortical frontal eye fields, the SNr neurons are momentarily inhibited, releasing the collicular neurons from inhibition. This allows the appropriate collicular neurons to signal the target of the eye movement, allowing the monkey to change its gaze to a new location. The movement was initiated in the frontal eye fields; however, the proper activation of the eye movement required that collicular neurons be released from the inhibition of the basal ganglia.

What is the function of the tonic inhibitory output of the basal ganglia? Recall from the Motor Cortex chapter that stimulating the motor cortex of monkeys at various locations results in stereotyped sequences of movements, such as bringing the hand to the mouth or adopting a defensive posture. It appears that a number of “primitive” motor programs are stored in the cortex, and motor control may require the activation of these elemental motor programs in the precise temporal order to accomplish a sophisticated motor plan. It is important that only one motor program be active at a given time, however, such that one motor act (e.g., use hand to bring food to the mouth) is not competing with a conflicting motor act (e.g., use hand to shield face from dangerous object). It is thought that the basal ganglia is normally active in suppressing inappropriate motor programs, and that activation of the direct pathway temporarily releases one motor program from inhibition, enabling it to be executed by the organism. Thus, the basal ganglia act as a gate that enables the execution of automatic programs in the hierarchy.

Figure 4.7 Dopaminergic neurons signal unexpected reward or unexpected absence of reward (Hollerman and Schultz, 1998). (A) If a reward occurs unexpectedly, the dopaminergic neuron fires briskly. This may strengthen the cortical motor programs that led up to the reward. (B) If a reward occurs that the monkey previously learned was predicted by a stimulus, the neuronal firing is not altered, thus signaling that all is proceeding normally. (C) If the reward-predicting stimulus does not produce a reward, the neuronal firing is inhibited. This inhibition may weaken the cortical motor programs that did not produce the expected reward.

Which motor programs should be released from inhibition at a given moment? The basal ganglia may have a major role in learning what motor acts result in rewards for the organism. This information is provided by the dopaminergic neurons of the SNc and ventral tegmental nucleus. Recordings from these neurons in monkeys have shown that they tend to respond when the monkey receives an unexpected reward, and they tend to be inhibited when the monkey fails to receive an expected reward (Figure 4.7). Because the net effect of activation of the nigrostriatal pathway is to excite the direct pathway and inhibit the indirect pathway, this pattern of dopaminergic firing may be involved in tuning the relative balance of direct/indirect pathway activity to enhance the firing of cortical motor programs that produce rewarding outcomes and to suppress the activity of motor programs that do not result in reward. In this way, motor habits can be constructed that tend to reward the animal.

Cognitive functions

As mentioned earlier, there are a number of cortical loops through the basal ganglia that involve prefrontal association cortex and limbic cortex. Through these loops, the basal ganglia are thought to play a role in cognitive function that is similar to their role in motor control. That is, the basal ganglia are involved in selecting and enabling various cognitive, executive, or emotional programs that are stored in these other cortical areas. Moreover, the basal ganglia appear to be involved in certain types of learning. For example, in rodents the striatum is necessary for the animal to learn certain stimulus-response tasks (e.g., make a right turn if stimulus A is present and make a left turn if stimulus B is present). Recordings from rat striatal neurons show that early in training, striatal neurons fire at many locations while a rat learns such a task on a T-shaped maze (Figure 4.8). This suggests that initially the striatum is involved throughout the execution of the task. As the animal learns the task and becomes exceedingly good at its performance, the striatal neurons change their activity patterns, firing only at the beginning of the trial and at the end. It appears that the learned programs to solve this task are now stored elsewhere; the firing of the striatal neurons at the beginning of the maze presumably reflects the enabling of the appropriate motor/cognitive plan in the cortex, and the firing at the end of the maze is presumably involved in evaluating the reward outcome of the trial.

Figure 4.8 Habit learning in striatum (Jog et al., 1999). (A) A rat is trained to run down a T-shaped maze and make a left turn for food reward if it hears a high-pitch tone or make a right turn for food reward if it hears a low-pitch tone. (B) Early in training, as the rat is beginning to learn the task, striatal neurons fire at locations all over the maze, especially at the choice point. (C) Late in training, when the rat has mastered the task and performs very quickly and accurately, the striatal neurons now fire only at the start and ends of the maze.

In humans, the basal ganglia appear to be necessary for certain forms of implicit memory tasks. Like motor habit learning discussed above, many types of cognitive learning require repeated trials and are often unconscious. An example is probabilistic classification (Figure 4.9). In this type of task, people have to learn to classify objects based on the probability of belonging to a class, rather than on any explicit rule. In one experiment, subjects were shown a deck of cards with different symbols. Each symbol was associated with a certain probability of predicting rain or sunshine, and the subjects had to say on each trial whether the symbol was a predictor of rain or sunshine. Because the same symbol sometimes predicted sunshine and other times predicted rain, the subjects could not devise a simple rule, and they made many errors at first. Over time, however, they began to get better at classifying the symbols appropriately, although they still often claimed to be guessing. Patients with basal ganglia disorders were impaired at this task, suggesting that the processing of the cognitive loops of the basal ganglia are somehow involved in our ability to subconsciously learn the probabilities of predicted outcomes associated with particular stimuli.

Figure 4.9 Patients with basal ganglia disorders are impaired in learning this implicit probabilistic classification task in which they have to predict the weather based on a set of 4 cue cards (Packard and Knowlton, 2002).

4.7 Disorders of the Basal Ganglia

A number of neurological disorders result from damage to the basal ganglia. Two of these disorders (Parkinson’s disease and Huntington’s disease) will be briefly discussed here to relate the concepts learned in this chapter to the symptoms of the disorders. More thorough treatment of these disorders will be given in the chapter on Disorders of the Nervous System.

Nigrostriatal pathway and Parkinson’s disease

Figure 4.10 Parkinson’s disease and Huntington’s disease. Click on disease names to see neural damage that produces the disorders.

Parkinson’s disease is characterized by slowness or absence of movement (bradykinesia or akinesia), rigidity, and a resting tremor (especially in the hands and fingers). Patients have difficulty initiating movements, and once initiated the movements are abnormally slow. The cause of Parkinson’s disease is the loss of the dopaminergic neurons in the substantia nigra pars compacta (Figure 4.10). From one’s knowledge of the effects of the nigrostriatal pathway on the direct and indirect pathways, it becomes straightforward to see why the loss of this pathway results in the poverty of movement symptomatic of Parkinson’s disease. Because the nigrostriatal pathway excites the direct pathway and inhibits the indirect pathway, the loss of this input tips the balance in favor of activity in the indirect pathway. Thus, the GPint neurons are abnormally active, keeping the thalamic neurons inhibited. Without the thalamic input, the motor cortex neurons are not as excited, and therefore the motor system is less able to execute the motor plans in response to the patient’s volition.

Indirect pathway and Huntington’s disease

The symptoms of Huntington’s disease are in many respects the opposite of the symptoms of Parkinson’s disease. Huntington’s disease is characterized by choreiform movements: involuntary, continuous movement of the body, especially of the extremities and face. Often these movements resemble pieces of adaptive movements, but they occur involuntarily and without behavioral significance. Huntington’s disease results from the selective loss of striatal neurons in the indirect pathway (Figure 4.10). Thus, the balance between the direct and indirect pathways becomes tipped in favor of the direct pathway. Without the normal inhibitory influence on the thalamus that is provided by the indirect pathway, thalamic neurons can fire randomly and inappropriately, causing the motor cortex to execute motor programs with no control by the patient.

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