Abnormalities in the Basal Ganglia Motor Circuit Result in a Wide Spectrum of Movement Disorders
Movement disorders arise from dysfunction of the basal ganglia–thalamocortical motor circuit, ranging from hypokinetic disorders, of which Parkinson disease is the best-known example, to hyperkinetic disorders, exemplified by Huntington disease, dystonia, and hemiballism.
Pathological changes in specific regions of the basal ganglia strongly affect neuronal activity throughout the entire basal ganglia–thalamocortical network and the activity of descending projections to the brain stem. The most severe and disruptive movement disturbances result from dysfunction in the striatum and subthalamic nucleus. By contrast, interruption of the major output nucleus of the basal ganglia, the internal segment of the globus pallidus, has little or no effect on movement. The reasons for these different effects are not understood. It seems, however, that the clinical features of specific disorders depend on unique combinations of changes in discharge rates and patterns, synchronization of discharge, and varying degrees of involvement of individual motor subcircuits.
Hypokinetic disorders are characterized by impairments of movement initiation (akinesia), reduction in the amplitude and velocity of voluntary movements (bradykinesia), muscular rigidity (increased resistance to passive displacements), and a 4–6 Hz tremor at rest and flexed posture. Hyperkinetic disorders, in contrast, are characterized by involuntary movements, such as chorea (random fragmented movements of individual body parts), ballism (large-amplitude movements particularly of the proximal limbs), and dystonia (slower, twisting movements and sustained abnormal postures).
A Deficiency of Dopamine in the Basal Ganglia Leads to Parkinsonism
Parkinson disease, first described by James Parkinson in 1817, affects over one million people in North America alone. In addition to the cardinal features of this condition—akinesia, bradykinesia, muscular rigidity, and tremor—other prominent motor features include a shuffling gait, flexed posture, reduced facial expression, decreased blinking, and small handwriting. These motor features are summarily referred to as parkinsonism.
Another clinical aspect of Parkinson disease is a loss of the automaticity of movement and the need for increased voluntary control manifested as difficulty carrying out simultaneous movements. The disruption of automatic and well-learned movements is believed to reflect a loss of the basal ganglia's role in procedural learning.
The salient pathological feature of idiopathic Parkinson disease is degeneration of the dopaminergic cells in the substantia nigra pars compacta that project to the striatum and to a lesser extent to other basal ganglia nuclei. Dopamine loss in these areas is considered to cause most of the movement abnormalities in this disorder, since they respond to dopamine replacement therapies. Nonmotor features of the disease include depression and anxiety, cognitive impairment, sleep disturbances, and autonomic dysfunction. These nonmotor signs and symptoms respond poorly or not at all to dopamine replacement therapy.
According to recent studies these features may be caused by additional pathological changes that affect widespread areas of the brain, with a slowly progressive ascending involvement of the lower brain stem nuclei, including the dorsal motor nucleus of the vagus nerve, locus ceruleus, nucleus gigantocellularis, raphe nuclei, amygdala, and thalamus, as well as portions of the cerebral cortex. Because little is known about the specific physiologic changes produced by these nonmotor signs, we focus here on the better-known causes and effects of dopaminergic cell loss in Parkinson disease.
The etiology of Parkinson disease is uncertain in most patients, who are said to suffer from "sporadic" Parkinson disease. Nevertheless, the disorder is believed to result from a combination of environmental and genetic factors. Exposure to environmental toxins, such as pesticides, is thought to underlie the association of Parkinson disease with rural living and consumption of well water. Several such compounds are mitochondrial toxins that may damage dopaminergic cells by interfering with their energy metabolism. Other environmental factors, such as a history of smoking or caffeine consumption, are known to lower the risk of developing Parkinson disease.
Single-gene mutations may also result in parkinsonism. For example, in several families with autosomal dominant parkinsonism the disorder is linked to a defect in the gene on chromosome 4 encoding α-synuclein or to duplication or triplication of the gene. This protein is one of the major components of eosinophilic inclusions (Lewy bodies) that are found in degenerating neurons in the substantia nigra pars compacta. In both sporadic and hereditary forms of Parkinson disease the accumulation of α-synuclein appears to be a major factor accounting for neuronal dysfunction and cell death. More common than mutations in the α-synuclein gene are parkinsonism-causing defects in the parkin gene on chromosome 6, or the more recently identified LRRK2 gene mutation. The pathogenetic mechanisms triggered by these mutations are not clear. However, it appears that factors such as oxidative damage, dysfunction of cellular mechanisms involved in the removal of toxic metabolites, and abnormal cellular calcium handling may contribute to the loss of dopaminergic cells in parkinsonism.
Direct evidence for the reduction of dopaminergic inputs to the striatum comes from postmortem biochemical analyses and from PET studies in humans with Parkinson disease (Figure 43–8). With PET the dopaminergic system can be visualized in vivo. Such studies have demonstrated that the reduction of dopamine is most severe in the caudal putamen, the portion of the striatum containing the motor circuit. This result is consistent with the observation that the earliest and most prominent manifestations of the disease involve the development of motor signs and symptoms.
Loss of dopamine in the striatum in Parkinson disease.
Positron emission tomography (PET) images of 18F-DOPA uptake in the striatum in a normal subject and in a twin of a Parkinson patient show the extent of dopamine metabolism. In the twin, 18F-DOPA uptake in the putamen was reduced when the subject was asymptomatic and more severely reduced five years later when symptomatic. (Adapted, with permission, from Brooks 2000.)
Postmortem studies that have compared the brains of parkinsonian and control patients, as well as studies in experimental animals, have shown that the first overt motor signs of the disease occur when 70% or more of striatal dopamine are lost, attesting to a significant capacity of the basal ganglia–thalamocortical network to compensate for changes in dopamine levels. The presymptomatic compensation for dopamine loss may occur within the dopaminergic system itself, through increased activity of healthy dopaminergic neurons, sprouting of remaining dopaminergic fibers, and changes in the synthesis, release, or metabolism or receptor sensitivity. Mechanisms independent of dopamine, such as synaptic changes in the thalamus or cortex, may also play a role.
Dopamine loss in other nuclei of the basal ganglia (specifically the subthalamic nucleus, the internal pallidal segment, and the substantia nigra pars reticulata) may also contribute to the manifestations of Parkinson disease. Whether dopamine loss in regions outside the basal ganglia, such as the thalamus and frontal cortex, is a factor in the development of parkinsonism has not been examined in detail.
In the early 1980s a group of drug addicts injected themselves with a synthetic opioid that was contaminated with the meperidine analog MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a potent mitochondrial toxin. Soon after the exposure some of these individuals developed profound and irreversible parkinsonism. Investigations by William Langston and others revealed that MPTP is a potent neurotoxin able to destroy selectively the dopaminergic neurons in the midbrain. An important consequence of this discovery was that it allowed researchers to develop a phenotypically and anatomically convincing animal model of dopamine depletion, the MPTP-treated primate. Anatomical and electrophysiological studies in these animals have contributed greatly to circuit models of the pathophysiology of Parkinson disease.
Early microelectrode recordings and neuro-imaging studies in MPTP-treated primates demonstrated that induction of parkinsonism is accompanied by a decrease in the discharge rates of neurons in the external pallidal segment and an increase in activity the subthalamic nucleus and internal pallidal segment. These changes, along with the motor signs of parkinsonism, can be reversed by systemic administration of dopamine receptor agonists. These findings led to the development of a highly influential pathophysiologic model in which loss of dopaminergic input to the striatum led to increased activity in the indirect pathway and decreased activity in the direct pathway. Both of these changes are thought to lead to a net increase of the activity of neurons in the internal segment of the globus pallidus and the substantia nigra pars reticulata. This increase in basal ganglia output would result in increased inhibition of thalamocortical and midbrain tegmental neurons and account for the hypokinetic features of the disease.
This so-called "rate model" of Parkinson disease has now been largely supplanted by models that place greater emphasis on changes in neuronal firing pattern and synchrony. The rate model cannot account for the lack of akinesia following thalamic lesions and of involuntary movements following lesions of the internal pallidum, as demonstrated in both experimental animal models and surgically treated patients.
Electrophysiological recordings from the basal ganglia in parkinsonian animals and in humans undergoing neurosurgical procedures have shown obvious abnormalities of firing patterns (Figure 43–9). Abnormal burst discharges and synchronized oscillatory neuronal activity throughout the basal ganglia– thalamocortical circuitry are now thought to be at least as important for the development of parkinsonian akinesia and tremor as the changes in discharge rates. It is important to emphasize that the abnormalities that result in parkinsonism in the earlier rate model as well as in the newer models that emphasize pattern abnormalities are primarily found in the indirect pathway of the basal ganglia.
Abnormalities in the pattern of neuronal firing in the basal ganglia of parkinsonian monkeys.
Raster plots show continuous data recordings from selected representative neurons situated in the structures portrayed at the left.
Recording of cells in vitro and related neural network modeling studies have elucidated some of the mechanisms that may underlie these abnormal patterns of activity in the basal ganglia. Because most pathways in the basal ganglia are GABAergic, the role of rebound bursting, triggered by prolonged and pathological GABAergic inhibition of basal ganglia cells, has been extensively studied. One of the connections studied in detail is the interaction between the external segment of the globus pallidus and the subthalamic nucleus. Subthalamic nucleus neurons fire spontaneously as a result of the interplay between a persistent depolarizing Na+ current and after hyperpolarization, both of which follow each action potential and are in part caused by a K+ current that is activated by Ca2+ entry into the cell associated with the action potential. These normal oscillations are reset by single inhibitory postsynaptic potentials evoked by pallidal inputs. In the presence of stronger inhibition, as may occur when the synchronicity of pallidal activity is increased in parkinsonism, the hyperpolarization may be sufficient to trigger rebound depolarization, a phenomenon that appears to be central to the generation of bursts of action potentials in subthalamic nucleus neurons.
In recent years oscillatory activity in the basal ganglia has also been assessed by recording of local field potentials. Such recordings, reflecting the activity of larger ensembles of neurons and their synaptic inputs, can be made in parkinsonian patients implanted with macroelectrodes. It was found that parkinsonism is associated with high-amplitude oscillation in the high alpha and beta frequencies (10–30 Hz) in the subthalamic nucleus, internal pallidal segment, and cerebral cortex. Such oscillation may prevent the circuitry (specifically in the cortex) from engaging in oscillations at higher (gamma-band) frequencies. Gamma-band oscillatory activity in frontal cortex and related areas is seen as a prerequisite for normal movement, and lack of gamma-band oscillations may contribute to akinesia and bradykinesia.
Changes in the cortical activity of parkinsonian patients that may result from disordered subcortical inputs have also been evaluated by functional imaging. The time resolution of such imaging is too low to show directly any changes in firing patterns. However, PET scans of patients performing a movement show decreases in synaptic activity in the anterior cingulate, supplementary motor area, and dorsolateral prefrontal cortex. In addition, brain areas that are not normally activated are recruited when patients perform visuomotor tracking. These changes may be compensatory or they may be part of the motor problem, as normal function in the newly recruited areas may be disrupted.
Progress in understanding the pathophysiology of Parkinson disease, and the finding that lesioning of motor circuit structures in parkinsonian animals has strong antiparkinsonian effects, has contributed to the resurgence of neurosurgical procedures to treat patients with advanced Parkinson disease. Initially, surgical lesioning of basal ganglia and thalamic targets was used to interrupt abnormal activity in the motor circuit, but these (irreversible) procedures have now been largely replaced by chronic high-frequency deep brain stimulation. In this less invasive and reversible procedure a programmable pulse generator, similar to a cardiac pacemaker, is placed subcutaneously and connected to a stimulating electrode inserted into the subthalamic nucleus or internal segment of the globus pallidus. Although the mechanisms of action of deep brain stimulation remain controversial, it is likely that chronic high-frequency stimulation in patients with Parkinson disease acts primarily by replacing the irregular, abnormal basal ganglia output to the cortex with a more regular and better-tolerated pattern that may then allow the cerebral cortex to function more normally. Alternatively, chronic stimulation may disrupt the abnormal and disruptive beta-frequency oscillations.
Reduced and Abnormally Patterned Basal Ganglia Output Results in Hyperkinetic Disorders
Lesions of the basal ganglia or imbalances in their neurotransmitter systems may result in involuntary movements such as hemiballism, Huntington disease, dystonia, and drug-induced involuntary movements.
Hemiballism is a hyperkinetic disorder characterized by spontaneous involuntary movements of the contralateral proximal limbs. Hemiballism most often results from lesions restricted to the subthalamic nucleus, usually as the result of small strokes. Experimental lesioning of the subthalamic nucleus in monkeys shows that involuntary movements result only when the lesion is confined to the nucleus and 20% or more of the nucleus is damaged. Such experimental lesions significantly reduce the tonic discharge of neurons in the internal segment of the globus pallidus and decrease the phasic responses of these neurons to limb displacement.
The reduced inhibitory input from the internal segment may permit thalamocortical neurons to respond in an exaggerated or abnormal manner to cortical or other inputs. If the basal ganglia inhibit planned or ongoing movements under physiological conditions, loss of this function could conceivably result in excessive movements, particularly involuntary movements. However, the finding that lesions of the internal segment relieve rather than worsen ballism and other hyperkinetic disorders argues strongly that this view is too simplistic, and that not only global activity changes but also altered patterns and synchrony of neuronal discharge in the thalamus and cortex play a major role in the generation and manifestation of hyperkinetic disorders.
Huntington disease is a hereditary disorder that affects men and women equally at a frequency of 5 to 10 per 100,000 individuals. The onset of the disease occurs most often after the third decade of life. The disease is characterized by the gradual development of motor symptoms, including chorea and eye-movement abnormalities. Nonmotor disturbances such as depression, behavioral disturbances, and cognitive impairment are also very common. Death occurs as the result of medical complications of the underlying neurological disease, in most cases 15 to 20 years after onset.
Huntington disease results from a defect on chromosome 4, affecting the gene that codes for the protein huntingtin, and is inherited in an autosomal dominant fashion. The disease is a prime example of a disorder resulting from trinucleotide repeats in a small portion of a gene (see Chapter 44). Higher numbers of trinucleotide repeats are associated with an earlier onset of the disease (anticipation).
Because of the lack of suitable animal models of Huntington disease, the pathophysiologic changes that underlie the clinical signs and symptoms in this disease are not as well established as those in Parkinson disease. The available evidence suggests that neuronal degeneration early in the disease process occurs primarily in the striatum, affecting strongly those output neurons that give rise to the indirect pathway. This reduces inhibition of neurons in the external segment of the globus pallidus leading to excessive inhibition of subthalamic nucleus neurons and a subsequent reduction in basal ganglia output. The functional inactivation of the subthalamic nucleus could explain the appearance of involuntary movements, which are similar to those seen in cases of hemiballism.
In later stages of Huntington disease a rigid and akinetic phenotype develops in most cases, possibly as the result of additional loss of the striatal neurons that project to the internal segment of the globus pallidus and substantia nigra pars reticulata. The resulting removal of inhibition from neurons of the internal segment may convert the hyperkinetic movement disorder into a hypokinetic problem with increasing rigidity and akinesia.
The gradual loss of brain stem and cortical neurons may also contribute to some aspects of the movement disorder. The profound behavioral, psychiatric, and cognitive problems seen in Huntington disease reflect the fact that nonmotor areas of the cortex and basal ganglia are involved in the pathology.
Dystonia is distinguished clinically from chorea and hemiballism by the presence of slower, twisting movements, often resulting in abnormal postures. Dystonic movements are triggered by voluntary movements. Typically, patients show co-contraction of agonist-antagonist muscle groups and an inability to restrict movements to a single body part (overflow).
Most of the pathological conditions that result in dystonia affect the functioning of the basal ganglia–thalamocortical network. Dystonia may result from genetic defects, focal lesions of the basal ganglia or other structures, or disorders of dopamine metabolism. Whereas most cases of dystonia in adults are focal and nonfamilial, dystonia starting in childhood (or in young adults) is often generalized and genetic in origin. These genetic forms of dystonia do not feature prominent neuronal degeneration. A common autosomal dominant form of generalized dystonia originates from a trinucleotide deletion on chromosome 9, leading to the formation of a mutant variant of a normal protein (torsinA). Another interesting form of dystonia is dopamine-responsive dystonia, resulting from mutations in genes involved in the production of tetrahydrobiopterin, an essential cofactor in the biosynthesis of dopamine and other biogenic amines (see Chapter 13). Similar to Parkinson disease, this disorder can be treated with dopamine replacement.
The exact role of the basal ganglia in dystonia remains poorly defined, at least in part because existing animal models of the disease do not fully replicate the phenotype. Some of the evidence regarding the role of the basal ganglia in dystonia comes from recordings in a small number of human patients undergoing neurosurgical procedures and from PET scans of dystonic patients. These studies have found that the average discharge rate in both segments of the globus pallidus is low. As in the other movement disorders, abnormally patterned or synchronized activity of the basal ganglia output neurons may play an important role in the pathophysiology of dystonia. In some cases dopaminergic dysfunction may also contribute to the development of dystonia. This view is supported by the findings that alterations in striatal dopamine transmission are seen in some forms of dystonia, that dystonia may occur in untreated Parkinson disease, and that dystonia can be seen in some patients receiving dopamine receptor-blocking drugs.
Dystonia has also been interpreted as a disorder of abnormal synaptic plasticity in the basal ganglia. A key finding supporting this view is that sensorimotor maps in the basal ganglia–thalamocortical circuits are less defined in patients with focal hand dystonia than in controls. Because focal hand dystonia is often seen in the hands of patients with writer's cramp or musician's dystonia, it is interpreted as the end product of pathological synaptic plasticity in subcortical or cortical regions. Evidence for disordered plasticity in the cortico–basal ganglia–thalamocortical circuits also comes from the finding that the beneficial effects of surgical treatments such as lesioning or chronic electrical stimulation of the globus pallidus require weeks or months to develop.
Abnormal Neuronal Activity in Nonmotor Circuits Is Associated with Several Neuropsychiatric Disorders
Disturbances of the nonmotor basal ganglia–thalamocortical circuits may contribute to the development of cognitive and behavioral problems accompanying movement disorders and to primary psychiatric disorders, such as obsessive-compulsive disorder, Tourette syndrome, and depression. Although processes outside the basal ganglia–thalamocortical loop systems may also contribute to the psychiatric disturbances, we concentrate here on the possible involvement of the basal ganglia circuitry.
The evidence for the functional relevance of the nonmotor areas comes mostly from clinical observations. In addition, animal studies employing microinjections of a GABA receptor antagonist, bicuculline, into motor, associative, and limbic portions of the external pallidal segment in primates have provided evidence for the notion that different neurobehavioral syndromes arise from dysfunction of different basal ganglia–thalamocortical circuits. Injections in the limbic part of the external segment of the globus pallidus induced stereotypic movements, whereas injections in the associative part induced hyperactivity. As predicted, abnormal movements were observed only when bicuculline was injected into the motor territory. These studies provide experimental support for the proposed behavioral domains in the basal ganglia and their role in abnormal motor and nonmotor behaviors.
Damage to the dorsolateral prefrontal cortex or subcortical portions of the prefrontal circuit results in a variety of abnormalities related to cognitive or executive functions, whereas damage to the lateral orbitofrontal circuit (for example, in stroke patients) is associated with lack of empathy, emotional lability, irritability, and failure to respond to social cues.
One of the best-studied psychiatric disorders arising from pathology in a nonmotor circuit is obsessive-compulsive disorder. The stereotypic behaviors (rigid behavioral patterns) and compulsions that are characteristic of this disorder have been interpreted as evidence for dysfunctional procedural learning. Functional imaging studies of patients with this disorder have demonstrated abnormalities in activity in the basal ganglia–thalamocortical limbic circuits that originate in portions of the orbitofrontal and anterior cingulate cortices. The most prominent changes are seen in the ventral striatum, specifically in the nucleus accumbens and ventromedial caudate nucleus, and in the midbrain. The beneficial outcome of neurosurgical treatments directed at the limbic circuitry, such as lesioning or stimulation of the anterior limb of the internal capsule and the ventral striatum, or lesions involving fibers emanating from orbitofrontal or anterior cingulate cortex, is evidence that the limbic circuit is involved in obsessive-compulsive disorder.
Tourette syndrome, in which obsessive-compulsive symptoms are associated with motor or vocal tics (brief involuntary movements or vocalizations), is also characterized by abnormalities in the limbic circuit. The fact that dopamine receptor-blocking drugs suppress tics implicates the basal ganglia in these disorders. Additional changes in brain activity occur in cortical areas associated with motor functions, particularly in the sensorimotor cortex and supplementary motor area. Chronic stimulation of the limbic and motor circuit at the pallidal and thalamic levels is now being explored as a treatment of severe, refractory Tourette syndrome.