Review of Medical Physiology - William F. Ganong 2002

Functions of the Nervous System
Regulation of Posture and Movement
Basal Ganglia

Anatomical Overview

The term basal ganglia generally refers to five structures in each cerebral hemisphere: the caudate Nucleus, putamen, and globus pallidus—three large nuclear masses located beneath the Cerebral Cortex (Fig. 12-9)—along with the functionally associated subthalamic nucleus (body of Luys) and substantia nigra. The globus pallidus is divided into lateral and medial segments, whereas the substantia nigra consists of pars compacta and pars reticulata. Thalamic nuclei are also intimately connected with the basal ganglia. The caudate nucleus and putamen are collectively known as the striatum, while the putamen and globus pallidus together form the lentiform nucleus (Table 12-3).

The principal afferent projections to the basal ganglia terminate in the striatum (Fig. 12-10). These include corticostriatal fibers originating from all areas of the cerebral cortex, as well as projections from the centromedian Nucleus of the thalamus to the striatum.

Interconnections among the basal ganglia structures include the dopaminergic nigrostriatal pathway (extending from the substantia nigra to the striatum) and the reciprocal GABAergic pathway from the striatum to the pars reticulata of the substantia nigra. Both the caudate nucleus and putamen project to both segments of the globus pallidus. Nerve fibers from the lateral segment of the globus pallidus run to the subthalamic nucleus, which, in turn, sends fibers back to both segments of the globus pallidus and the substantia nigra.

The primary output pathway of the basal ganglia originates in the medial segment of the globus pallidus and projects via the thalamic fasciculus to the ventral lateral, ventral anterior, and centromedian nuclei of the thalamus. From these thalamic nuclei, fibers project to the prefrontal and premotor cortices. Additional projections run from the substantia nigra to the thalamus. These connections, along with their putative synaptic Transmitters, are illustrated in Fig. 12-10. Several secondary pathways also exist, targeting structures such as the habenula and superior colliculi. Nevertheless, the most critical basal ganglia circuitry involves the pathway from the cerebral cortex to the striatum, from the striatum to the medial segment of the globus pallidus, from the medial segment of the globus pallidus to the thalamus, and finally from the thalamus back to the cortex, thereby completing a reverberating circuit. The pathway from the medial segment of the globus pallidus to the thalamus is inhibitory, whereas the pathway from the thalamus to the cerebral cortex is excitatory.

The striatum contains a unique mosaic of striosomes interspersed within a surrounding matrix, each receiving distinct sets of terminals. Corticostriatal Neurons originating in deep layer V of the cortex terminate primarily within the striosomes, whereas those originating in layers II and III, as well as superficial layer V, terminate mainly in the matrix. Neurons whose Cell bodies lie within the striosomes project predominantly to dopaminergic neurons in the pars compacta of the substantia nigra, whereas a significant proportion of matrix-based neurons project to GABAergic neurons in the pars reticulata of the substantia nigra. The physiological significance of these segregated pathways, however, remains unclear.

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Fig. 12-9. The basal ganglia.

Metabolic Profile

The METABOLISM of the basal ganglia is notable for its diverse pathways and elevated rate of O₂ consumption. Copper concentrations are particularly high in the substantia nigra and the adjacent locus coeruleus. In Wilson's disease—an inherited autosomal recessive disorder of copper metabolism characterized by reduced plasma levels of the copper-binding protein ceruloplasmin—chronic copper toxicity occurs, leading to profound degenerative Changes in the lentiform nucleus.

Function

Our understanding of basal ganglia function remains incomplete. Lesions of the basal ganglia in experimental animals produce relatively subtle effects. However, recordings show that neurons in the basal ganglia, much like those in the lateral Regions of the cerebellar hemispheres, discharge prior to the initiation of movement. These observations, combined with detailed clinical analyses of human basal ganglia disorders and experimental studies using neurotoxins that selectively destroy dopaminergic neurons (see below), suggest that these nuclei play a vital role in movement planning and programming—or, more broadly, in the cognitive processes by which Abstract thought is translated into voluntary motor action (see Fig. 12-1). Impulses from the basal ganglia are relayed via the thalamus to motor cortical areas, and the corticospinal tract subsequently transmits these signals to motor neurons. Furthermore, excitatory potentials within the basal ganglia exhibit rhythmic oscillations, which are believed to serve a functional role analogous to the oscillations observed in thalamocortical loops (see Chapter 11).

Table 12-3. The basal ganglia

Fig. 12-10. Schematic diagram of the principal connections of the basal ganglia. Solid lines represent excitatory pathways, and dashed lines represent inhibitory pathways. Neurotransmitters are indicated where known. Glu = glutamate; DA = dopamine. The neurotransmitter acetylcholine is synthesized by striatal interneurons. PRSN = pars reticulata of the substantia nigra; PCSN = pars compacta of the substantia nigra. The subthalamic nucleus also has connections with the pars compacta of the substantia nigra, which are omitted from this diagram for simplicity.

The basal ganglia also contribute to specific cognitive processes, a function largely mediated by the caudate nucleus. This nucleus maintains extensive reciprocal connections with the frontal neocortex; consequently, damage to the caudate can impair The ability to evaluate and adapt to changing behavioral contingencies or delayed-response tasks. Moreover, lesions restricted to the HEAD of the left caudate nucleus and adjacent White matter in humans can result in a dysarthric form of aphasia that shares some similarities with Wernicke's aphasia while remaining distinct from it (see Chapter 16).

Human Basal Ganglia Disorders

Interestingly, while lesions of the basal ganglia in experimental animals often produce minimal deficits, pathological processes affecting these structures in humans result in striking and characteristic motor disorders. These clinical disturbances are broadly categorized into two types: hypokinetic and hyperkinetic. Hyperkinetic disorders are characterized by excessive, abnormal involuntary movements, such as chorea, athetosis, and ballism. Hypokinetic disorders include akinesia and hypokinesia.

Chorea manifests as rapid, involuntary, dance-like movements, whereas athetosis consists of slow, writhing, continuous movements. Initially, movements in chorea and athetosis may resemble voluntary actions, but they rapidly transition into involuntary, disorganized patterns. In ballism, the involuntary movements are sudden, forceful, and violent.

Akinesia refers to difficulty initiating movement coupled with a reduction in spontaneous activity, whereas bradykinesia denotes a slowness of execution.

Huntington's Disease

The earliest detectable neuropathological changes in Huntington's disease involve the loss of medium spiny neurons in the caudate nucleus and putamen. An early clinical sign is dysmetria—jerky, uncoordinated limb movements when reaching for a target, which become particularly pronounced near the end of the movement. Over time, progressive hyperkinetic choreiform movements develop, eventually exhausting the patient. Speech becomes slurred and ultimately unintelligible, followed by progressive dementia and death (typically 10–15 years after the onset of symptoms). Under normal conditions, three biochemically distinct pathways maintain a delicate balance within the basal ganglia: the nigrostriatal dopaminergic system, the intrinsic striatal cholinergic system, and the GABAergic system connecting the striatum to the globus pallidus and substantia nigra. In Huntington's disease, the intrinsic striatal GABAergic and cholinergic neurons degenerate. The loss of GABAergic projections to the lateral globus pallidus reduces its inhibitory output, thereby precipitating the hyperkinetic symptoms. Conversely, degeneration of the nigrostriatal dopaminergic system underlies Parkinson's disease (see below).

Huntington's disease is inherited in an autosomal dominant manner, with symptoms typically manifesting between the ages of 30 and 50. The mutant Gene responsible for the disorder is located near the telomere of the short arm of chromosome 4 and normally contains 11–34 cytosine-adenine-guanine (CAG) repeats, each encoding glutamine. In patients with Huntington's disease, the number of these codons expands to 42–86 or more. A greater number of repeats correlates with an earlier age of onset and a more rapid disease progression. The gene encodes huntingtin, a protein whose precise physiological function remains elusive. It is hypothesized that a toxic loss of function of this protein is proportional to the expansion of the CAG repeats. Currently, there is no effective Treatment for Huntington's disease, and it is invariably fatal. However, experimental research offers some hope: in animal models of the condition, transplantation of embryonic striatal tissue into the recipient's striatum has been shown to improve cognitive performance. Furthermore, The activity of tissue caspase-1—an enzyme that regulates apoptosis—is elevated in the brains of affected humans and animals. Knocking out the gene for this apoptosis-regulating enzyme in mice has been shown to slow disease progression.

Huntington's disease belongs to an expanding class of Genetic Disorders characterized by trinucleotide repeat expansions. Most of these involve expansions of CAG repeats (Table 12-4), though one involves a CGG repeat expansion and another a CTG repeat expansion, all of which affect coding regions of their respective genes. However, a GAA trinucleotide expansion located within a non-coding region is also implicated in a genetic disorder—Friedreich's ataxia. Preliminary evidence also suggests that an expansion of a 12-nucleotide repeat sequence is associated with a rare form of Epilepsy.

Parkinson's Disease (Paralysis Agitans)

Both hypokinetic and hyperkinetic signs are manifested in Parkinson's disease. In the cases originally described by James Parkinson (after whom the disease is named), the pathogenetic basis was the degeneration of dopaminergic neurons within the nigrostriatal system. In this condition, the fibers projecting to the putamen are particularly severely affected. Parkinsonism, which was a frequent late complication of Influenza epidemics during World War I, today presents as a sporadic, idiopathic form in many middle-aged and elderly individuals. At this age, a steady decline in dopamine levels and dopamine receptors in the basal ganglia is observed, and the acceleration of this process is presumably the underlying cause of the disease.

Parkinsonism may also arise as a complication following treatment with phenothiazine tranquilizers and other agents that block D₂ dopamine receptors, or in an acute and severe form following MPTP injections (Fig. 12-11). This effect was discovered serendipitously when a drug dealer in Northern California supplied clients with a bootleg "synthetic heroin" preparation containing MPTP. MPTP is a precursor to the highly active oxidant MPP⁺, which is metabolized in astrocytes by the enzyme monoamine oxidase B. In rodents, MPP is rapidly cleared from the Brain; however, its elimination in primates is much slower. It is taken up by the dopamine transporter and enters the dopaminergic neurons of the substantia nigra, causing their destruction. Other dopaminergic neurons are not affected to the same degree. Therefore, MPTP can be used to model parkinsonism in monkeys, a property that has greatly accelerated research into basal ganglia function.

The hypokinetic manifestations of Parkinson's disease are akinesia and bradykinetic disorders, whereas rigidity and tremor are hyperkinetic features. The lack of motor activity and the difficulty in initiating voluntary movements are striking. There is an impairment of associated movements, such as the normal subconscious movements of swinging the arms during walking, as well as an impoverishment of facial expressions that emotionally convey thought and speech; the numerous fidgety movements and gestures common to us all are absent. Rigidity differs from spasticity because it involves a reduction in the excitation level of motor neurons innervating both agonist and antagonist Muscles. The passivity of limb movements is combined with a diffuse muscular rigidity resembling the resistance encountered when bending a lead pipe, hence the term "lead-pipe rigidity." Superimposed on this passive resistance is a series of brief releases ("cogwheel rigidity"), although the sudden loss of resistance characteristic of spasticity does not occur. The tremor, which is observed at rest and disappears during movement, is caused by regular, alternating 8-Hz contractions of antagonist muscles. According to the prevailing view, the Pathogenesis of Parkinson's disease is rooted in an imbalance between Excitation and Inhibition within the basal ganglia, resulting from the loss of dopaminergic inhibition of the putamen (Fig. 12-12). The resulting reduction in inhibitory output to the lateral globus pallidus leads to a decrease in the inhibitory Influence of the subthalamic nucleus, which in turn enhances the excitatory effect of this nucleus on the medial globus pallidus. Consequently, the inhibitory output from the medial globus pallidus to the thalamus is reduced, as is the propagation of excitatory signals to the cerebral cortex.

Table 12-4. Examples of diseases caused by Trinucleotide Repeat Expansion

Treatment

A crucial consideration in discussing the pathogenesis of Parkinson's disease is the balance between the level of excitation in cholinergic interneurons and the inhibitory dopaminergic influence on neurons in the striatum. Some success has been achieved by reducing cholinergic activity using anticholinergic agents. A more potent effect can be attained through the administration of L-DOPA. Unlike dopamine, this precursor readily crosses the Blood-brain barrier (see Chapter 15) and helps compensate for the dopamine deficit. However, L-DOPA is converted to dopamine primarily by surviving dopaminergic neurons, while the degeneration of these neurons continues. Consequently, the efficacy of L-DOPA therapy diminishes after several years.

Surgical intervention aimed at destroying the medial globus pallidus (pallidotomy) or the subthalamic nucleus helps restore the balance of efferent impulses toward normal (see Fig. 12-12). Surgical outcomes can be augmented by the implantation of electrodes connected to a subcutaneously placed stimulator. High-frequency electrical stimulation allows for the reversible disruption of neural circuits in the vicinity of the electrode tips as needed.

Another surgical approach involves the implantation of dopamine-producing tissue into or near the basal ganglia. Autografts of adrenal medullary tissue or carotid body tissue function as cellular dopamine minipumps, yet this approach yields only short-lived benefits. Considerably better outcomes are achieved through the transplantation of fetal striatal tissue. There is evidence that the transplanted Cells not only survive under these conditions but also establish appropriate functional connections with the recipient's basal ganglia structures.

Fig. 12-11. Conversion of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenylpyridinium (MPP⁺) by monoamine oxidase B (MAO-B).

Meanwhile, research continues into agents that could prevent the degeneration of dopaminergic neurons. In this regard, it is of note that Mutations in the gene encoding a-synuclein—a synaptic protein of elusive function—are linked to a familial form of parkinsonism, and Lewy bodies, the neuronal inclusion bodies characteristic of all forms of Parkinson's disease, are largely composed of a-synuclein. Furthermore, Lewy bodies are rich in ubiquitin (see Chapter 1), and a mutation in the gene for one of the Proteins required for ubiquitination is associated with another familial form of Parkinson's disease. Nevertheless, much research remains to be done to fully elucidate the causes of dopaminergic neuron degeneration in Parkinson's disease.