Chapter 14: The Basal Ganglia

The basal ganglia are a collection of subcortical nuclei that have captured the fascination of clinicians and scientists for well over a century because of the remarkable range of behavioral dysfunction associated with basal ganglia disease. Movement control deficits are among the key signs, ranging from the paucity and slowing of movement in Parkinson disease and the writhing movements of Huntington disease to the bizarre tics of Tourette syndrome and distorted postures of dystonia. Unmistakingly, these clinical findings indicate that one important set of basal ganglia functions is regulating our motor actions. How do the basal ganglia fit into an overall view of the organization of the motor systems? Unlike the motor cortex and several brain stem nuclei, which have direct connections with the spinal cord and motor neurons, the basal ganglia influence movements by acting on the descending pathways; this is similar to the cerebellum.

In addition to producing movement control deficits, basal ganglia disease can also impair intellectual capacity and affect, pointing to important roles in cognition and emotion. Dementia is an early disabling consequence of Huntington disease and can be present in patients with advanced stages of Parkinson disease. The basal ganglia play important roles in aspects of drug addiction and psychiatric disease.

Although the basal ganglia continue to be among the least understood of all brain structures, their mysteries are now yielding to modern neurobiological techniques for elucidating neurochemistry and connections. For example, the basal ganglia contain virtually all of the major neuroactive agents that have been discovered in the central nervous system. Although the reason for this biochemical diversity remains elusive, such knowledge can be used to treat some forms of basal ganglia disease. Indeed, the discovery that the brains of patients with Parkinson disease are deficient in dopamine quickly led to the development of drug replacement therapy. Knowledge about connections of the basal ganglia with the rest of the brain has led to a major revision of the traditional views of basal ganglia organization and function. Discoveries about basal ganglia circuitry and pathways have even led to therapeutic neurosurgical and neurophysiological procedures.

This chapter first considers the constituents of the basal ganglia and their three-dimensional shapes, partly from a developmental context. Next, their functional organization is surveyed, emphasizing the distinctive roles of the basal ganglia in movement control, cognition, and emotions. (Chapter 16 revisits the basal ganglia in relation to emotions and psychiatric disease.) Finally, this chapter examines the regional anatomy of the basal ganglia using a series of myelin-stained sections and MRI slices through the cerebral hemispheres and brain stem.

Separate Components of the Basal Ganglia Process Incoming Information and Mediate the Output

The many components of the basal ganglia are best learned, in a general way, from the outset; then their functional and clinical anatomy can be mastered. As we will focus on later in the context of their connections, the components of the basal ganglia can be divided into three categories: input, output, and intrinsic nuclei (Table 14–1). The input nuclei receive afferent connections from brain regions other than the basal ganglia, in particular the cerebral cortex, and in turn project to the intrinsic and output nuclei. There are three input nuclei, merged into a single structure termed the striatum (Figure 14–2): (1) the caudate nucleus, (2) the putamen, and (3) the nucleus accumbens. The functions of the striatum do not correspond precisely to its component anatomical parts. Most of the caudate nucleus participates in eye movement control and cognition, whereas the putamen participates mostly in control of limb and trunk movements. Emotions are mediated by the nucleus accumbens, together with adjoining parts of the caudate nucleus and putamen; the emotional striatum is commonly termed the ventral striatum. Given that the striatum is really a composite of three nuclei, it is not surprising that it has a complex shape.

The output nuclei project to regions of the diencephalon and brain stem that are not part of the basal ganglia. There are three nuclei on the output side of the basal ganglia (Table 14–1; Figure 14–2B1, B2): the internal segment of the globus pallidus, associated mostly with the putamen and limb and trunk control; the substantia nigra pars reticulata, primarily involved in cognition and eye movements along with the caudate nucleus, and a portion of the ventral pallidum, important for emotions with the ventral striatum. These nuclei are located deep within the base of the brain; they are shown schematically in Figure 14–2 in relation to a transparent view of the striatum.

The intrinsic nuclei are also located deep within the base of the brain; their connections are largely restricted to the basal ganglia (Table 14–1; Figure 14–2). The basal ganglia have five intrinsic nuclei: the external segment of the globus pallidus, a portion of the ventral pallidum (separate from the output part), the subthalamic nucleus, the substantia nigra pars compacta, and the ventral tegmental area (Figure 14–2). Their connections are closely related to the input and output nuclei.

The Complex Shapes and Fractionation of Basal Ganglia Components Are Understood by How the Basal Ganglia Develop

Learning the numerous components and subdivisions of the basal ganglia is a challenge. Taking a developmental perspective helps to understand two key features of the anatomy of the basal ganglia: the complex three-dimensional shape and fractionation of the components of the basal ganglia into subdivisions. The caudate nucleus develops a C-shape, largely as a consequence of cerebral cortex development. As the cortex expands caudally and inferiorly, forming the occipital and temporal lobes (Figure 14–3A), underlying structures—including the caudate nucleus and lateral ventricle—follow. This expansion and change in shape are produced by the birth and migration of cells along predetermined axes. This imparts a distinctive shape of the caudate nucleus in relation to the shapes of the other two striatal components. The C-shape of the caudate nucleus results in three components: head, body, and tail (Figure 14–3C).

A second developmental process contributes to formation of some of the basal ganglia subdivisions. Development of axon projection to and from the cerebral cortex in the internal capsule divides many basal ganglia components into separate nuclei, thereby increasing the complexity of the nomenclature. Figure 14–3B, schematic coronal sections through the developing forebrain, shows a single developing striatum (Figure 14–3B1) and separation of the caudate nucleus (head and body) and the putamen by the internal capsule. Three developing axon projections within the internal capsule are key, those from (1) the thalamus to the cortex (ie, to layer 4); (2) the cortex (layer 6) back to the thalamus; and (3) the cortex (layer 5) to the striatum, brain stem, and spinal cord. For the striatum, these internal capsule axons incompletely divide the striatum into the three components, leaving behind cell bridges (Figure 14–3C). Throughout its entire course, the caudate nucleus is medial to the internal capsule, and the putamen, lateral. Figure 14–4A shows the course of the corticospinal tract in the internal capsule; its path can be followed between the head of the caudate and the putamen. The nucleus accumbens is largely that portion of the striatum rostral and inferior to the anterior limb of the internal capsule. The tail of the caudate nucleus is separated from the putamen by additional projection fibers.

The internal capsule also separates the internal segment of the globus pallidus and the substantia nigra pars reticulata, similar to the striatal cell bridges, shown in maturity in Figure 14–3. In humans, cells of the substantia nigra pars reticulata and internal segment of the globus pallidus are scattered between each other within the internal capsule (see Figure 14–15). In addition to being part of the same structure but separated by the internal capsule, the morphology, neurotransmitter content, and connections of neurons in the internal segment of the globus pallidus and the substantia nigra pars reticulata are similar.

Although not understood from a simple developmental perspective, the anterior commissure separates the external segment of the globus pallidus from the ventral pallidum. However, many neurons in the ventral pallidum have connections and a neurochemistry similar to the globus pallidus external segment—like that of an intrinsic nucleus—and others, especially in the more caudal ventral pallidum, have properties like the internal segment of the globus pallidus, an output nucleus.

Direct and Indirect Pathways Form Common Circuits Throughout All Functional Divisions of the Basal Ganglia

The general organization of the basal ganglia from input to output is shown in Figure 14–5. Like the cerebellum, a basic circuit describes the basal ganglia, irrespective of motor, cognitive, or emotional function. As described, the basal ganglia are divided into input, output, and intrinsic nuclei (Figure 14–5A). Beginning with all areas of the cerebral cortex, information passes through the input nuclei and then the output nuclei. Connections with the thalamus target several nuclei that, in turn, project to different areas of the frontal lobe. These differential projections confer the distinctive functions of the basal ganglia (discussed below). Connections with the brain stem motor control centers target the pedunculopontine nucleus, important in gait control, and the superior colliculus, for saccadic eye movements. As an example of the flow of information through the basal ganglia, follow the path in Figure 14–5B, from the frontal lobe, to the putamen, globus pallidus internal segment, thalamus, and back to the cerebral cortex (to primary motor cortex).

There are functionally and clinically important connections with the intrinsic nuclei. The external segment of the globus pallidus and the subthalamic nucleus are part of a basal ganglia circuit that receives input from other basal ganglia nuclei and in turn projects back (Figure 14–5A). The substantia nigra pars compacta and the ventral tegmental area contain dopaminergic neurons that project to the striatum, as well as to portions of the cortex (Figure 14–5A). Dopamine has a neuromodulatory action on striatal neurons. There are many different dopamine receptor subtypes and, depending on the particular subtype present on the postsynaptic neuron, dopamine either depolarizes or hyperpolarizes striatal neurons.

The output of the basal ganglia depends on two complementary pathways

Whereas the basal ganglia have a daunting complexity, there is a logic to the connections that helps explain their overall actions. A pair of complementary circuits—termed the direct and indirect pathways—have opposing actions on their downstream structures. The connections from the striatum to the output nuclei and then to the thalamus and brain stem, described above, comprise the direct path (Figure 14–5A, B), which promotes the actions of the basal ganglia. By contrast, connections from the striatum to three intrinsic nuclei—the external segment of the globus pallidus, part of the ventral pallidum, and the subthalamic nucleus—comprise the indirect path (Figure 14–5A, B inset), which inhibits the actions of the basal ganglia. In Figure 14–5B (inset) follow the path from the striatum, globus pallidus external segment, subthalamic nucleus, and then globus pallidus internal segment. For the components of the basal ganglia that control limb and trunk movements, eye movements, and facial muscles, the direct path enables these actions and the indirect path puts the brakes on. Box 14–1 shows schematically how neuronal activity changes in the direct and indirect paths as information from the cortex is processed from one structure to the next. Aberrant direct path functions in many movement disorders appear to drive excessive muscle tone, tics, and habitual behaviors, and aberrant indirect path functions produce debilitating akinesia, bradykinesia, and rigidity in Parkinson disease. It is thought that similar facilitatory and suppressive actions influence the nonmotor functions of the basal ganglia as well. We consider below how the complementary actions of the direct and indirect paths occur, in the context of the diversity of neurotransmitter actions in the basal ganglia.

Knowledge of Basal Ganglia Connections and Neurotransmitters Provides Insight Into Their Function in Health and Disease

Many neurotransmitters and neuromodulatory substances are present in the various basal ganglia nuclei (Figure 14–6). The excitatory neurotransmitter glutamate is used by corticostriatal neurons (the major input to the basal ganglia), thalamic neurons that project to the striatum, and the projection neurons of the subthalamic nucleus. Surprisingly, the major neurotransmitter of the basal ganglia is γ-aminobutyric acid, or GABA, which is inhibitory. In the striatum, the projection neurons, termed medium spiny neurons because they have abundant dendritic spines (see Figure 1–2), use GABA as their neurotransmitter. The axons of these neurons project to the two segments of the globus pallidus, the ventral pallidum, and the substantia nigra pars reticulata. Medium spiny neurons also contain neuropeptides, with two distinct neuron classes containing either enkephalin or substance P (and dynorphin). Enkephalin thus marks indirect path striatal neurons and substance P, direct path. When one understands that direct and indirect path neurons have a different neurochemistry, it is easier to appreciate that they can be differentially vulnerable to pathological processes. Projection neurons of the internal and external segments of the globus pallidus and the substantia nigra pars reticulata also contain GABA. Thus, the output of the basal ganglia, similar to that of the cerebellar cortex, is inhibitory. The significance of this common synaptic organization is not yet apparent.

Neurons in the substantia nigra pars compacta and the ventral tegmental area contain dopamine. The activity and function of the postsynaptic targets of these nuclei, the striatum and portions of the frontal lobe, are under important regulation by dopamine. Dopamine can be excitatory or inhibitory depending on the balance of dopamine receptor subtypes present on the postsynaptic neuron's membrane. Acetylcholine is another common neurotransmitter in the basal ganglia; it is present in striatal interneurons. Striatal cholinergic interneurons play an important role in regulating diverse basal ganglia functions, including plasticity.

Parkinson disease is a hypokinetic movement disorder

In Parkinson disease, there is a major impairment in initiating movements, termed akinesia, and a reduction in the extent and speed of movements, called bradykinesia (see Figure 14–7C1). These are called hypokinetic signs because movements become impoverished. In addition, patients exhibit a resting tremor, and when an examiner moves their limbs, a characteristic stiffness or rigidity can be noted. The dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmental area degenerate in Parkinson disease, and striatal dopamine is profoundly reduced. The term substantia nigra means black substance. This name derives from the presence of the black pigment neuromelanin, a polymer of the catecholamine precursor dihydroxy-phenylalanine (or dopa), which is contained in the neurons of the pars compacta. Not surprisingly, neuromelanin is not present in the substantia nigra pars compacta of Parkinson patients. Dopaminergic neurons in other parts of the central nervous system are also destroyed in Parkinson disease. Dopamine loss in the basal ganglia, however, apparently produces the most debilitating neurological signs. Dopamine replacement therapy using a precursor to dopamine, L-dopa, leads to a dramatic improvement in the neurological signs of Parkinson disease.

Researchers have an important tool in the study of Parkinson disease. They discovered that a certain kind of synthetic heroin produces a permanent clinical syndrome in humans that is remarkably similar to Parkinson disease. This substance contains the neurotoxin MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which is a meperidine derivative that kills the dopaminergic neurons of the substantia nigra pars compacta (as well as other dopaminergic neurons in the central nervous system). When monkeys are given MPTP, they too develop parkinsonian signs, including akinesia, bradykinesia, rigidity, and tremor.

There are several hyperkinetic movement disorders

Huntington disease is a hyperkinetic disorder (see Figure 14–7C2). One hyperkinetic sign of this disorder is chorea, which is characterized by involuntary rapid and random movements of the limbs and trunk. Involuntary distal limb movements, such as writhing of the hand, or athetosis, may also occur. Patients with Huntington disease also develop dementia. Huntington disease is inherited as an autosomal dominant disorder. In most patients, Huntington disease presents during midlife. The Huntington gene is located on the short arm of chromosome 4 and codes for a protein, huntingtin, whose function is not yet known. The gene mutation that causes Huntington disease is an expansion of the nucleotide sequence of CAG (>35 repeats) at the 5′ end. This is translated into huntingtin having an excessively long polyglutamine repeat that makes medium spiny neurons particularly vulnerable to cell death. This mutation, which is present in all cells of the body but apparently affecting primarily medium spiny neuron function, also leads to the dysfunction and death of neurons in other brain regions, including the cortex. Although neurodegeneration is widespread in Huntington disease, pathological changes occur earliest in striatal neurons that contain enkephalin, which are part of the indirect path (Figure 14–6). Interestingly, several neurodegenerative diseases are associated with a polyglutamine repeat mutation.

Another hyperkinetic disorder is hemiballism (see the clinical case in this chapter). This remarkable clinical disturbance occurs after damage to the subthalamic nucleus, an intrinsic basal ganglia nucleus. Hemiballism causes patients to make uncontrollable, rapid ballistic (or flinging) movements of the contralateral limbs. These movements are produced by motion at proximal limb joints, such as the shoulder and elbow.

Parallel Circuits Course Through the Basal Ganglia

One important aspect of basal ganglia circuitry is that they comprise parallel anatomical loops. Three important points relate to the general organization of these parallel circuits:

1. Each loop originates from multiple cortical regions that have similar general functions.

2. Each loop passes through different basal ganglia and thalamic nuclei, or separate portions of the same nucleus. These include the motor thalamic nuclei—the ventrolateral nucleus (a part distinct from the one receiving cerebellar input), and the ventral anterior nucleus—and the medial dorsal nucleus, which serves cognition, emotions, and eye movements.

3. Each loop targets separate portions of the frontal lobe.

Through their diverse connections, each loop mediates a different set of functions. Although many parallel loops originate from various cortical areas, anatomical and physiological studies have focused on four major loops (Figure 14–8): the skeletomotor, oculomotor, prefrental cortex (or cognitive), and limbic loops. Each of these loops comprises many subcircuits. The skeletomotor loop plays important roles in the control of facial, limb, and trunk musculature (Figure 14–8A1). Inputs originate from the primary somatic sensory and frontal motor areas and project back to the frontal motor areas (Figure 14–8B). Animal experiments show separate circuits within the skeletomotor loop, originating from the different motor, premotor, and somatic sensory areas, passing through different parts of the globus pallidus, and ultimately terminating in different premotor and motor areas. The oculomotor loop plays a role in the control of saccadic eye movements. Key inputs derive from the frontal eye field, which is important in the production of rapid conjugate eye movements through brain stem projections, and the posterior parietal association cortex, which processes visual information for controlling the speed and direction of eye movements (Figure 14–8A2). The output of this loop is to the frontal eye movement control centers (Figure 14–8; see Chapter 12). More is known about the organization of these two movement control loops than about the other two loops.

The associative loop plays a role in cognition and executive behavioral functions, such as strategic planning of behavior. Receiving inputs from diverse association areas, this loop projects primarily to the dorsolateral prefrontal cortex, and some premotor regions as well (Figure 14–8A3, B). Though principally involved in thought and reasoning and in the highest level of organizing goal-directed behaviors, the prefrontal cortex has relatively direct connections with premotor areas involved in movement planning.

The limbic loop participates in the motivational regulation of behavior and in emotions. The term limbic derives from the limbic system, the brain system that comprises the principal structures for emotions. The limbic association cortex and the hippocampal formation provide the major input to the limbic loop. The limbic loop engages the most distinct set of basal ganglia circuits: the ventral striatum—which includes the nucleus accumbens and ventromedial portions of the caudate nucleus and putamen—and the ventral pallidum (Figure 14–8A4). The limbic association cortex in the anterior cingulate gyrus is the major frontal lobe recipient of the output of the limbic loop (Figure 14–8B).

Integration of Information Between the Basal Ganglia Loops

Behaviors result from integration of complex sensory, cognitive, and motivational information. It is therefore not surprising that, in addition to the parallel loops (Figures 14–8 and 14–9A), the basal ganglia have also many different ways to integrate information between loops. Three kinds of basal ganglia integrative circuits are highlighted (Figure 14–9B). First, there is overlap in the input connections—those between the cortex and the striatum—as well as within intrinsic circuitry. Second, there appears to be integrative subregions, or "nodal points of convergence" within the basal ganglia loops. For example, while most connections of the dorsolateral prefrontal cortex are to the parts of the striatum in the associative loop, there are smaller focal projections to parts of the ventral striatum for integrating cognition with emotions and reward and to dorsal regions for linking basic eye and limb muscle control with more complex behaviors. Third, the descending corticothalamic projection, which we first examined in detail in the sensory systems (see Figure 4–11 and Figure 2–18), is more widespread than the ascending thalamocortical projection.

In organizing behavior, the various parallel circuits of the basal ganglia appear to have distinct functions. This is how we think the loops function for initiating and controlling when you reach for a glass of water. The limbic loop participates in the initial decision to move, motivated by thirst. The prefrontal cortex loop participates in formulating the goal plan, for example, how, where, and when to reach for the water. The oculomotor and skeletomotor loops assist in the programming and execution of the particular behaviors to achieve the goal. For example, these loops are important in coordinating eye and limb movements to accurately direct your hand to the glass. When we are very thirsty, our movements are faster and more reactive. We think that the integrative connection from the limbic loop to the motor loop is one way for this to happen.

The rest of this chapter examines the regional anatomy of the parts of the brain that contain the components and associated nuclei of the basal ganglia. This examination begins with a horizontal slice through the cerebral hemispheres and diencephalon because it permits visualization of the various components of the internal capsule, which form major subcortical landmarks. From there, the chapter moves on to coronal slices through the basal ganglia and thalamus. Finally, we consider the brain stem targets of the basal ganglia. In addition to explaining the regional anatomy of the basal ganglia, this discussion also provides an overall view of the deep structures of the cerebral hemispheres.

The Anterior Limb of the Internal Capsule Separates the Head of the Caudate Nucleus From the Putamen

In horizontal section, the internal capsule is shaped like an arrowhead pointed toward the midline (Figure 14–4A). The internal capsule contains ascending thalamocortical fibers and descending cortical fibers. The three main segments of the internal capsule are the anterior limb, the posterior limb, and the genu, which connects the two limbs (Figure 14–4). Complementing the three main segments of the internal capsule are the retrolenticular and sublenticular portions. They are named for their locations with respect to the lenticular nucleus, which comprises the putamen and globus pallidus.

The anterior limb separates the head of the caudate nucleus from the putamen. This limb contains axons projecting to and from the prefrontal association cortex and the various premotor cortical areas. The posterior limb separates the putamen and the globus pallidus (lenticular nucleus) laterally, from the thalamus and caudate nucleus, medially. The posterior limb contains the corticospinal tract, probably most of the corticobulbar tract, as well as the projections to and from the somatic sensory areas in the parietal lobe. Only coronal sections through the posterior limb cut through the thalamus. The key structures can be seen in the MRI (Figure 14–10B), which is the same plane as the myelin-stained section (see inset in Figure 14–10).

An important feature of the complex three-dimensional structure of the caudate nucleus can be identified in Figure 14–10A. Because the caudate nucleus has a C-shape, it can be seen in two locations in this section. The head of the caudate nucleus is located rostromedially, and the tail of the caudate nucleus is located caudolaterally. (The body of the caudate nucleus is dorsal to the plane of section.) In certain coronal sections, the caudate nucleus is also seen in two locations (dorsomedially and ventrolaterally) (see below). Whereas it is too small to identify, the approximate location of the tail of the caudate is shown in the MRI (Figure 14-10B).

The Three Components of the Striatum Are Located at the Level of the Anterior Horn of the Lateral Ventricle

A coronal slice through the anterior limb of the internal capsule reveals the three components of the striatum (Figure 14–11): the caudate nucleus (at this level, the head of the caudate nucleus), the putamen, and the nucleus accumbens. Although the internal capsule courses between the caudate nucleus and the putamen, striatal cell bridges link the two structures. As a further reminder that the three striatal components are not separate structures, the nucleus accumbens together with the ventromedial portions of the caudate nucleus and putamen (Figure 14–11A) comprise the ventral striatum, the striatal component of the limbic loop (Figure 14–8A4). (The olfactory tubercle is sometimes included within the ventral striatum; it is located on the basal surface of the forebrain. A portion of the tubercle receives olfactory inputs.) The septum pellucidum is a pair of thin connective tissue membranes that form the medial walls of the anterior horn and body of the lateral ventricles on the two sides (Figure 14–11A). Between the two septa is a cavity in which fluid may accumulate.

The head of the caudate nucleus bulges into the anterior horn of the lateral ventricle (Figure 14–11A, B). Gross changes in the structure of the caudate nucleus in a patient with Huntington disease also can be seen (Figure 14–11C). Patients with Huntington disease exhibit a loss of medium spiny neurons. This cell loss is most noticeable in the progression of the disease as a reduction in the size of the head of the caudate nucleus. Note the loss of the characteristic bulge of the head of the caudate nucleus into the lateral ventricle in the Huntington disease patient (Figure 14–11C).

The striatum has a compartmental organization

Whereas in myelin-stained sections the three striatal components appear identical and homogeneous, staining for neurotransmitters and neuromodulators or specific afferent connections reveals heterogeneity. Cholinergic markers, for example, stain a matrix of tissue that contains a higher concentration surrounding patches, also called striosomes, of low marker concentration (Figure 14–12A). The axon terminations of cortical and dopaminergic neurons also have a nonuniform distribution of their striatal terminations. For example, projections from the prefrontal association cortex to the head of the caudate nucleus, comprising part of the associative loop, form patches of dense terminations (Figure 14–12B; inset shows corticostriatal neurons, red). Complementary projections from the posterior parietal cortex also form termination patches, but they interdigitate with those from the prefrontal cortex (Figure 14–12B inset; blue). Callosal neurons are also shown in the schematic (green) because they are labeled by the technique shown in Figure 14–12B. Importantly, compartments related to particular connections and neurochemical distributions appear to be independent, overlapping in some areas and separate in others. The functional significance of fractionating the striatum into compartments related to the different markers and inputs has remained elusive and is among the most important of the many unresolved questions concerning basal ganglia organization.

The External Segment of the Globus Pallidus and the Ventral Pallidum Are Separated by the Anterior Commissure

The external segment of the globus pallidus and part of the ventral pallidum, as discussed earlier, are intrinsic basal ganglia nuclei that send their axons to the subthalamic nucleus. These two structures are likely one and the same, but separated by the anterior commissure (Figure 14–13A). This commissure interconnects specific structures of the temporal lobe. Another portion of the ventral pallidum contains the output neurons that project to the thalamus. Circuits routing through the external segment of the globus pallidus are part of the skeletomotor, cognitive, and oculomotor loops; the circuits through the ventral pallidum are part of the limbic loop.

The Ansa Lenticularis and the Lenticular Fasciculus Are Output Tracts of the Internal Segment of the Globus Pallidus

The putamen, external segment of the globus pallidus, and internal segment of the globus pallidus are separated from one another by thin white matter laminae (Figure 14–14; see All–20 for their nomenclature). The internal segment of the globus pallidus is a major output of the basal ganglia (Figure 14–14A). Neurons of this nucleus project their axons to the thalamus (and brain stem, see below), through two anatomically separate pathways: the lenticular fasciculus and the ansa lenticularis. The axons of the lenticular fasciculus course directly through the internal capsule, but these axons are not clearly visualized until they collect medial to the internal capsule (Figure 14–14B). The internal capsule appears to be a barrier for fibers of the ansa lenticularis; these fibers course around it to reach the thalamus (Figure 14–14A, B). The ansa lenticularis and lenticular fasciculus converge beneath the thalamus and join fibers of the cerebellothalamic tract to form the thalamic fasciculus (Figure 14–14B). Deep brain stimulation (DBS) of the internal segment of the globus pallidus is a common treatment of Parkinson disease and dystonia, a rare genetic movement disorder (see later section on basal ganglia circuitry and DBS).

The three major thalamic targets of the output nuclei of the basal ganglia (Figure 14–8A) can be identified in Figures 14–14 and 14–15: the medial dorsal nucleus, the ventral lateral nucleus, and the ventral anterior nucleus. Most of the fibers of the deep cerebellar nuclei also terminate in the ventral lateral nucleus but in a separate portion than axons from the basal ganglia. Two intralaminar thalamic nuclei (see Chapter 2), the centromedian and parafascicular nuclei, are anatomically closely related to the basal ganglia because they provide a major direct input to the striatum (like that of cortex). These thalamic nuclei also project to the frontal lobe, which is the cortical target of the basal ganglia. Because the intralaminar nuclei have widespread cortical projections, they are considered diffuse-projecting thalamic nuclei and not relay nuclei (see Chapter 2).

Lesion of the Subthalamic Nucleus Produces Hemiballism

Ventral to the thalamus is the subthalamic region, which consists of a disparate collection of nuclei. The major nucleus in this brain region is the subthalamic nucleus (Figure 14–15A). A lesion of the subthalamic nucleus produces hemiballism, a hyperkinetic disorder, characterized by ballistic movements of the contralateral limbs (see clinical case and Box 14–1; Figure 14–7C2). The connections of the subthalamic nucleus are complex. Receiving input from the external segment of the globus pallidus as well as from the motor cortex, the subthalamic nucleus projects back to both the external and internal segments of the globus pallidus (Figure 14–15). The subthalamic nucleus is also reciprocally connected with the ventral pallidum (Figure 14–13). The subthalamic nucleus, along with the internal segment of the globus pallidus, is a key target of DBS for treatment of Parkinson disease (see later section on DBS).

Very little is known of the function of the zona incerta (Figure 14–15), a nuclear region interposed between the subthalamic nucleus and the thalamus. The zona incerta receives projections from a variety of sources, including the spinal cord and cerebellum. Many of the neurons in the zona incerta contain GABA and have diffuse cortical projections.

The Substantia Nigra Contains Two Anatomical Divisions

The posterior limb of the internal capsule separates the internal segment of the globus pallidus from the substantia nigra, a separation that can be seen in coronal section (Figure 14–15). Like separation of the components of the striatum, cell bridges can be seen within the internal capsule, between the substantia nigra pars reticulata and internal segment of the globus pallidus. The substantia nigra pars reticulata and internal segment of the globus pallidus appear to be part of the same basal ganglia output nucleus that becomes largely separated by axons of the internal capsule. They are not identical, however. The substantia nigra pars reticulata is part of the oculomotor and cognitive/associative loops; it also projects to the superior colliculus (Figure 14–16A), which is important in controlling saccadic eye movements (see Chapter 12). The substantia nigra pars reticulata, which is adjacent to the basis pedunculi (Figures 14–15 and 14–16), contains GABA (Figure 14–6) and, like the internal segment of the globus pallidus, projects to the thalamus and pedunculopontine nucleus (see below).

The other division of the substantia nigra is the substantia nigra pars compacta; it consists of neurons containing dopamine. The projection of these neurons to the striatum forms the nigrostriatal tract. Dopaminergic neurons that project to the different striatal regions are topographically organized. The activity of many of the substantia nigra pars compacta neurons, shown in animal studies, is related to salient stimuli, such as a tone that predicts receiving a food reward, rather than particular features of the movement the animals perform. This salience reflects key inputs from the amygdala, which is involved in motivation and emotions, the reticular formation, which is involved in arousal, and serotonergic connections from the raphe nuclei.

The substantia nigra pars compacta is not the only midbrain region that contains dopamine. The ventral tegmental area is dorsomedial to the substantia nigra, beneath the floor of the interpeduncular fossa (Figure 14–16A). Dopaminergic neurons in the ventral tegmental area send their axons to the striatum via the medial forebrain bundle (see Chapters 15 and 16) as well as to the frontal lobe (see Figure 2–3B1).

The Pedunculopontine Nucleus Is Part of a Parallel Path From the Basal Ganglia to Brain Stem Locomotor Control Centers

Whereas much of the output of the basal ganglia is directed to the thalamus, and then back to the cerebral cortex, a second output circuit involves the pedunculopontine nucleus (Figure 14–16B). This is the descending projection of the basal ganglia, and it is thought to play an important role in locomotor function. The pedunculopontine nucleus has diverse functions, including regulating arousal, through diffuse ascending projections to the thalamus and cortex, and movement control, through descending projections. In animals, activation of the pedunculopontine nucleus promotes locomotor behaviors, whereas inhibition retards locomotor behaviors. It projects to brain stem locomotor centers and also has a small direct spinal projection. As discussed below, the pedunculopontine nucleus is a target of deep brain stimulation to alleviate the locomotor disturbances in Parkinson disease. Many of the neurons in this nucleus are cholinergic, including those projecting to the thalamus. The dorsal raphe nucleus, also located in the caudal midbrain-rostral pons (Figure 14–16B), gives rise to an ascending serotonergic projection to the striatum. In addition to projecting to the striatum, the dorsal raphe nucleus has extensive projections to most of the cerebral cortex and to other forebrain nuclei.

Stimulation-based Treatments for Movement and Nonmovement Disorders Rely on Knowledge of the Regional Anatomy and Circuitry of the Basal Ganglia

There is a long history of neurosurgical procedures to alleviate motor signs of severe basal ganglia disease, with the most effective being lesion of the internal segment of the globus pallidus produced by a technique termed electrocoagulation. This surgical procedure, termed pallidotomy, eliminated the abnormal output of the basal ganglia, thereby helping the remaining portions of the motor systems to function better. More recently, pallidotomy is a procedure of last resort in patients, only when L-dopa becomes less effective.

Deep brain stimulation, or DBS, has largely superseded pallidotomy, especially in developed countries. DBS is a neurophysiological approach to treating basal ganglia and other diseases, often with remarkably positive outcomes. The DBS electrode is implanted within the internal segment of the globus pallidus or the subthalamic nucleus, often bilaterally. By selection of the proper stimulation frequency and amplitude, neural activity of the aberrant output circuitry is altered and many of the parkinsonian signs are ameliorated. DBS of the internal segment of the globus pallidus is now routinely used for treatment of dystonia.

Knowledge that different portions of the internal globus pallidus and subthalamic nucleus are parts of the different functional basal ganglia loops has allowed neurosurgeons to position DBS electrodes for treatment of nonmotor disorders, as well, such as obsessive-compulsive disorders and Tourette syndrome. Because of their important interconnections with the cerebral cortex, DBS is also being explored for affective disorders (see Chapter 16).

Surprisingly, despite extensive use of DBS, we do not yet know the mechanism of its therapeutic action, for either movement or nonmovement disorders. DBS probably does not simply activate neurons. Rather, it modulates the activity of local neurons in the neighborhood of the electrode—both facilitation and suppression depending on a neuron's location—and these local effects are passed on to wider brain regions via monosynaptic and polysynaptic circuits. DBS may even function like a pacemaker, to change an abnormally slow and highly synchronized level of neuronal activity in the diseased brain—signatures of a resting functional state—to faster levels of activity, characteristic of a more active state.

The Vascular Supply of the Basal Ganglia Is Provided by the Middle Cerebral Artery

As described in Chapter 3, the vascular supply to the deep structures of the cerebral hemispheres—the thalamus, basal ganglia, and internal capsule—is provided by branches of the internal carotid artery and the three cerebral arteries. Most of the striatum is supplied by perforating branches of the middle cerebral artery; however, rostromedial regions are supplied by deep branches of the anterior cerebral artery (see Figure 3–7). Collectively, these branches of the anterior and middle cerebral arteries are termed the lenticulostriate arteries. Most of the globus pallidus is supplied by the anterior choroidal artery, which is a branch of the internal carotid artery.

Basal Ganglia Nuclei

The basal ganglia contain numerous component nuclei that can be divided into three groups based on their connections (Table 14–1; Figure 14–5): input nuclei, output nuclei, and intrinsic nuclei. The input nuclei consist of the caudate nucleus, the putamen, and the nucleus accumbens (Figures 14–2 and 14–11) and collectively are termed the striatum. The ventromedial portions of the caudate nucleus and putamen, together with the nucleus accumbens, comprise the ventral striatum. The output nuclei include the internal segment of the globus pallidus (Table 14–1; Figures 14–5, 14–13, and 14–14), a portion of the ventral pallidum (Figure 14–13), and the substantia nigra pars reticulata (Figures 14–15 and 14–16). The intrinsic nuclei comprise the external segment of the globus pallidus (Figure 14–13), a portion of the ventral pallidum, the subthalamic nucleus (Figure 14–15), the substantia nigra pars compacta (Figures 14–15 and 14–16), and the ventral tegmental area (Figure 14–16A).

Basal Ganglia Functional Loops

The basic input-output pathway through the basal ganglia links wide regions of the cerebral cortex with, in sequence, the input nuclei of the basal ganglia (striatum), the output nuclei, the thalamus, and a portion of the frontal lobe (Figure 14–5B). There are four key functional loops through the basal ganglia (Figure 14–8): the skeletomotor, oculomotor, associative, and limbic loops. The skeletomotor and oculomotor loops play important roles in the control of facial, limb, and trunk musculature and extraocular muscles; the associative loop may subserve tasks such as cognition and executive behavioral functions; and the limbic loop may function in the regulation of behavior and in emotions. The skeletomotor, oculomotor, and prefrontal cortex loops begin in the somatic sensory, motor, and association areas of the cerebral cortex and pass through the caudate nucleus and putamen (Figure 14–8). The output nuclei of these loops are the internal segment of the globus pallidus (Figure 14–14) and the substantia nigra pars reticulata (Figures 14–15 and 14–16). They, in turn, synapse in the ventrolateral, ventral anterior, and medial dorsal nuclei of the thalamus (Figures 14–15 and 14–16). The internal segment of the globus pallidus projects to the thalamus via two pathways: the ansa lenticularis and the lenticular fasciculus (Figure 14–15B). However, components of the various loops synapse on neurons located in different nuclei or in different portions of the same nuclei. The internal segment of the globus pallidus also projects to the pedunculopontine nucleus, which plays a role in arousal and movement control.

The limbic loop (Figure 14–8) begins in the limbic association cortex. The ventral striatum, which comprises the nucleus accumbens and the ventromedial parts of the caudate nucleus and putamen (Figure 14–11), is the principal input nucleus of the limbic loop; the output and thalamic nuclei of the limbic loop are the ventral pallidum (Figure 14–13) and the medial dorsal nucleus (Figure 14–15).

The cortical targets of the four loops are (Figure 14–8B) supplementary motor areas, premotor cortex, and primary motor cortex for the skeletomotor loop; frontal and supplementary eye fields for the oculomotor loop; prefrontal association cortex for the association loop; and anterior cingulate gyrus (and orbitofrontal gyri) for the limbic loop.