The basal ganglia has dense internuclear connections (see Fig. 71.1). Five parallel and separate closed circuits through the basal ganglia have been proposed. These are the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and limbic loops (Rodriguez-Oroz et al., 2009). It is now generally agreed that these loops form three major divisions—sensorimotor, associative, and limbic—that are related to motor, cognitive, and emotional functions, respectively (Table 71.1). The functions of the sensorimotor striatum are subserved mainly by the putamen, which derives its afferent cortical inputs from both motor cortices. Sensorimotor pathways are somatotopically organized, and the pathway ultimately terminates in the premotor and primary motor cortices and the supplementary motor area. Cognitive functions are largely mediated by the associative striatum, particularly the dorsal caudate nucleus, which receives afferent input from the homolateral frontal, parietal, temporal, and occipital cortices. Projections from this pathway ultimately terminate in the prefrontal cortex. The limbic striatum subserves emotional and motivational functions. Its input derives from the cingulate, temporal, and orbitofrontal cortices, the hippocampus, and the amygdala. It mainly comprises the ventral striatum, with ultimate projections to the anterior cingulate and medial orbitofrontal cortices (Rodriguez-Oroz et al., 2009). Whether these divisions are interconnected or organized in parallel remains a topic of debate.

Table 71.1 Divisions of the Striatum

Within each basal ganglia circuit lies an additional level of complexity. Each circuit contains two pathways by which striatal activity is translated into pallidal output. These two pathways are named the direct and indirect pathways, depending on whether striatal outflow connects directly with the GPi or first traverses the GPe and STN before terminating in the GPi. The direct and indirect pathways have opposite effects on outflow neurons of the GPi and SNr (Fig. 71.2, A).

Fig. 71.2 Schematic drawing of internuclear connections of basal ganglia, including (A) direct and indirect pathways and (B) direct pathway. (See Fig. 71.3 for depiction of indirect pathway.) Excitatory pathways in solid lines, inhibitory pathways in dotted lines. D₁, Dopamine D₁ receptor; D₂, dopamine D₂ receptor; GABA, γ-aminobutyric acid; glu, glutamate; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; MC, motor cortex; PMC, premotor cortex; SMA, supplementary motor area; SN, substantia nigra; STN, subthalamic nucleus; VA/VL, ventral anterior/ventrolateral thalamic nuclei.

In the motor direct pathway, excitatory neurons from the cerebral cortex synapse on putamenal neurons, which in turn send inhibitory projections to the GPi and its homolog, the SNr. The GPi/SNr sends an inhibitory outflow to the thalamus (see Fig. 71.2, B). Activity in the direct pathway disinhibits the thalamus, facilitating the excitatory thalamocortical pathway and enhancing activity in its target, the motor cortices. Thus, the direct pathway constitutes part of an excitatory cortical-cortical circuit that likely functions to maintain ongoing motor activity. In the indirect pathway, excitatory axons from the cerebral cortex synapse on putaminal neurons. These neurons send inhibitory projections to the GPe, and the GPe sends an inhibitory projection to the STN. The net effect of these projections is disinhibition of the STN. The STN in turn has an excitatory projection to the GPi (see Fig. 71.2, C). Activity in the indirect pathway thus excites the GPi/SNr, which in turn inhibits the thalamocortical pathway. Thus, the net effect of increased activity in the indirect pathway is cortical inhibition.

The striatum also receives robust afferent input from the SNc. This projection from the SNc, an important modifier of striatal activity, facilitates activity in the direct pathway, mediated via D₁ dopamine receptors, and inhibits activity in the indirect pathway via D₂ dopamine receptors (see Fig. 71.2, A).

Disorders of the basal ganglia result in prominent motor dysfunction, though not generally in frank weakness. The absence of direct primary or secondary sensory input and lack of a major descending pathway below the level of the brainstem suggest that the basal ganglia moderates rather than controls movement. The direct pathway is important in initiation and maintenance of movement, and the indirect pathway apparently plays a role in the suppression of extraneous movement. From this model of basal ganglia connectivity, hypotheses about the motor function of the basal ganglia have been proposed. One hypothesis is that the relative activities of the direct and indirect pathways serve to balance the facilitation and inhibition of the same population of thalamocortical neurons, thus controlling the scale of movement. A second hypothesis proposes that direct pathway-mediated facilitation and indirect pathway-mediated inhibition of different populations of thalamocortical neurons serve to focus movement in an organization reminiscent of center-surround inhibition. These hypotheses relate activity in the direct and indirect pathways mainly to rates of firing in the STN and GPi. Thus, death of neurons in the SNc, as in nigrostriatal degeneration associated with PD, decreases activity in the direct pathway and increases activity in the indirect pathway. These changes cause an increased rate of firing of subthalamic and GPi neurons, with excessive inhibition of thalamocortical pathways, and produce the behavioral manifestations of bradykinesia in PD (Fig. 71.3, A) (Hallett, 2011).

Fig. 71.3 Schematic drawing of functional activities in the direct and indirect pathways in Parkinson disease (PD) and Huntington disease (HD). A, In PD, reduced dopaminergic facilitation of direct pathway and inhibition of indirect pathway due to death of dopaminergic neurons causes increased firing and increased inhibition of thalamocortical pathways, producing bradykinesia. B, In HD, loss of striatal neurons leads to reduced activity in indirect pathway, causing reduced inhibition of thalamocortical pathways, with production of excessive or involuntary movements. (See Fig. 71.2 for explanations to abbreviations.)

On the other hand, predominant loss of indirect pathway neurons, as in HD, interferes with suppression of involuntary movements. Choreic involuntary movements are the usual result (see Fig. 71.3, B). Direct electrophysiological recordings of the STN and GP during stereotactic functional neurosurgical procedures confirm that the GPi and STN are overly active in patients with PD. The activity of these nuclei returns toward normal with effective pharmacotherapy, and chorea is associated with lower firing rates of neurons in these nuclei. Unfortunately, this model does not completely explain some important features of movement disorders. For example, bradykinesia and chorea coexist in HD and in patients with PD treated with levodopa (LD). Thalamic lesions that might be expected to worsen parkinsonism by reducing excitatory thalamocortical activity do not do so. Pallidal lesions that might be expected to worsen chorea by decreasing inhibition of thalamocortical pathways instead are dramatically effective at reducing chorea. The model is even more problematic when applied to dystonia. It has been suggested that in dystonia, there is overactivity of both the direct and indirect pathways. Yet, intraoperative recordings in dystonia have shown low rates and abnormal patterns of neuronal firing in the GPi. A simple change in firing rate of the STN or GPi is thus insufficient to explain the underlying physiology of dystonia. It is likely that disordered patterns and synchrony of pallidal firing, as well as changes in sensorimotor integration and the control of spinal and brainstem reflexes, are important. These factors are under investigation, but current models remain useful for understanding the rationale of pharmacological and ablative surgical procedures for certain movement disorders.

Although much of the emphasis has been on GPi and SNr efferents to the thalamocortical system, there is growing evidence that descending pathways, particularly to the zona incerta and PPN, are important in movement disorders. The PPN appears to play a role in locomotion, muscle tone, and akinesia. A number of other pathways also seem particularly relevant to myoclonus, including a corticolemniscal-thalamocortical circuit and a spinobulbar-spinal circuit that primarily involves the spinoreticular tracts, nucleus reticularis gigantocellularis of the medullary reticular formation, and the reticulospinal tracts. The Guillain-Mollaret triangle is a network connecting the red nucleus, dentate nucleus, and inferior olive, which has been implicated in palatal myoclonus (also known as palatal tremor). The propriospinal pathways and segmental spinospinal loops are important in the genesis of propriospinal and spinal segmental myoclonus, respectively.

Biochemistry

Our understanding of basal ganglia pharmacology is growing rapidly. Along with this growth is an expanding spectrum of practical applications for pathology, neuroimaging, and therapeutics. For example, catecholamine and amino acid neurotransmitters coexist with peptides. This co-localization may allow histopathological differentiation among medium spiny striatal projection neurons that secrete γ-aminobutyric acid (GABAergic neurons), further elucidating the specific nature and progress of striatal neurodegeneration. Neuroimaging technology has been aided by the development of radiopharmaceutical ligands with such discrete targets as the dopamine transporter on the presynaptic dopamine neuron and subpopulations of dopamine receptors on the postsynaptic neuron. The pharmaceutical industry is searching for ways to provide better-targeted and more physiological stimulation of neurotransmitter receptors and is expanding its investigations from the primary targets themselves to approaches that may modify responsiveness of the primary targets.

The major neurotransmitters of the basal ganglia are outlined in Table 71.2 (see also Fig. 71.2). Most excitatory synapses of the basal ganglia and its connections—including those from the cerebral cortex to the striatum, the STN to the GPi, and the thalamocortical projections—use glutamate. Projections from the striatum to the GPe and GPi, from the GPe to the STN, and from the GPi to the thalamus are inhibitory and employ GABA. Medium spiny GABAergic neurons in the direct pathway co-localize substance P and dynorphin. GABAergic neurons in the indirect pathway co-localize enkephalin. Dopamine is the major neurotransmitter in the nigrostriatal dopamine system; it has excitatory or inhibitory actions depending on the properties of the stimulated receptor. Acetylcholine is found in large aspiny striatal interneurons and the PPN. Norepinephrine, important in the autonomic nervous system, is most concentrated in the lateral tegmentum and locus ceruleus. Serotonin is found in the dorsal raphe nucleus of the brainstem, hippocampus, cerebellum, and spinal cord.

Table 71.2 Pharmacology of the Basal Ganglia

Pathway	Transmitter
STRIATAL AFFERENTS
Cerebral cortex → striatum	Glutamate
Cerebral cortex → STN	Glutamate
Locus ceruleus → striatum	Norepinephrine
Locus ceruleus → SN	Norepinephrine
Raphe nuclei → striatum	Serotonin
Raphe nuclei → SN	Serotonin
Thalamus → striatum	Acetylcholine?
SNc → striatum	Glutamate?
	Dopamine, cholecystokinin
INTRINSIC CONNECTIONS
Striatal interneurons	GABA, acetylcholine
Striatum → GPi	Somatostatin, neuropeptide Y
Striatum → SNr	Nitric acid, calretinin
Striatum → GPe	GABA, substance P
GPe → STN	GABA, dynorphin, substance P
STN → GPi, SNr, GPe	GABA, enkephalin, glutamate
STRIATAL EFFERENTS
GPi → thalamus	GABA
SNr → thalamus	GABA

GABA, γ-Aminobutyric acid; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SN, substantia nigra; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.

For each of these neurotransmitters, multiple types of receptors may exist. Glutamate is active at a number of types of ligand-gated ion channel receptors named for their selective agonists: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate. The NMDA receptor has been the focus of particular attention because of its potential role in excitotoxic neuronal injury. There are also metabotropic glutamate receptors. There are two classes of GABA receptors, GABA_A and GABA_B. GABA_A receptors are ligand-gated chloride channels and have many subtypes. The GABA_B receptor is a metabotropic receptor. Five types (D₁ through D₅) and two families (D₁ and D₂) of dopamine receptors have been identified. The D₁ family of receptor is adenylate cyclase dependent and contains subtypes D₁ and D₅. D₁ receptors reside primarily in the direct pathway, cerebral cortex, and limbic system. D₂ receptors are located primarily in the indirect pathway, cerebral cortex, and limbic system, as well as in the pituitary gland. There are two families of acetylcholine receptors, nicotinic and muscarinic. There are two subtypes of nicotinic and five subtypes of muscarinic receptors. Most striatal cholinergic receptors are muscarinic. In the norepinephrine system, there are two primary receptor systems, α and β. There are many distinct receptor subtypes of serotonin receptors, including G protein–coupled receptors in the 5-HT₁, 5-HT₂, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇ families and the 5-HT₃-type ligand-gated ion channels. Adenosine A_2A receptors are co-localized with striatal dopamine D₂ receptors on GABAergic medium spiny neurons, which project via the indirect striatopallidal pathway to the GPe. Drugs targeting specific subpopulations of receptors are in use or under development for movement disorders, but there remains a knowledge deficit about the relative clinical utility of specific receptor agonists and antagonists.

Mechanisms of Neurodegeneration

Many of the neurodegenerative movement disorders share the property of neuronal damage caused by the accumulation of aggregation-prone proteins that have toxic effects (Table 71.3). For a protein to function normally, it must be properly synthesized and folded into its normal three-dimensional structure. Nascent proteins are aided in folding by molecular chaperones. Proteins that are not properly folded, are otherwise damaged, or are beyond their useful lives are degraded by the ubiquitin-dependent proteasome protein degradation system (Gupta et al., 2008). In the ubiquitin-dependent proteasome system, proteins are first labeled for degradation by attachment of a polyubiquitin chain (Fig. 71.4). This three-step process involves activation, conjugation, and ligation steps catalyzed by three types of enzymes—E1, E2, and E3, respectively. Polyubiquinated protein enters the 26S proteasome, a cylindrical complex of peptidases. The end products of proteasome action are protein fragments and polyubiquitin. The polyubiquitin is then degraded and recycled to the cellular ubiquitin pool, a process requiring enzymatic action by ubiquitin carboxyterminal hydrolase 1.

Table 71.3 Toxic Proteins and Neurodegenerative Movement Disorders

α-Synuclein	Tau	Polyglutamine Tract
Parkinson disease	Four-repeat tau	Huntington disease
Diffuse Lewy body disease	Progressive supranuclear palsy	Spinocerebellar ataxias
Multiple system atrophy	Corticobasal degeneration Frontotemporal dementia with parkinsonism (chromosome 17) Parkinsonism dementia complex of Guam Postencephalitic parkinsonism	Dentatorubral-pallidoluysian atrophy

Fig. 71.4 Ubiquitin-dependent proteasome proteolysis. Once a protein is tagged for degradation, it is tagged with a polyubiquitin chain, a three-step process involving first activation, then conjugation, then ligation. Ubiquinated protein enters 26S proteasome where it is degraded into protein fragments, and polyubiquitin chain is degraded back to monomeric ubiquitin. E, Enzyme; U, ubiquitin; UCHL1, ubiquitin carboxy terminal hydrolase.

The cascade of pathogenic events linking abnormal protein aggregation to cell death is the subject of intense investigation. Although aggregates are the most striking physical change in surviving cells, the actual role of the aggregate remains a mystery. Indeed, many now believe that the formation of aggregates may be a protective mechanism sequestering the wayward protein from vulnerable cell processes. Misfolded proteins may produce the most mischief as they form protofibrils. A number of mechanisms have been described. In some cases, these are specifically related to the type of protein, but in many other cases, they are nonspecific mechanisms shared by all the misfolded protein diseases. Some potential mechanisms of neurodegeneration related to misfolded protein stress are listed in Box 71.1. The mutant protein may be unable to perform a vital function or may interfere with the function of the wild-type protein. Mutant protein, protofibrils, or aggregates might interfere with other proteins. Interference with transcription factors may be particularly important in this regard. Mutant proteins may activate caspases or in other ways activate the apoptotic cascade. They may interfere with intracellular transport or other vital processes. They may suppress activity of the proteasome, enhancing protein aggregation. They may interfere with mitochondrial function, making cells more vulnerable to excitotoxicity. In addition to the ubiquitin-proteasome system, lysosomes play an important role in degrading intracellular proteins by a process termed autophagy (Pan et al., 2008). When the function of the ubiquitin proteosome system is not sufficient to clear the accumulating cellular proteins, the autophagy lysosome pathway becomes the other important route for degradation of aggregated/misfolded proteins as well as sick or abnormal mitochondria. Accumulation of iron, increased oxidative stress, and microglial activation have also been thought to play important roles in the pathogenesis of various neurodegenerative disorders (Zhu et al., 2010).

Recent ultrastructural work has elucidated that many degenerative movement disorders can be linked to abnormal synthesis, folding, or degradation of specific proteins or protein families. Thus, a number of parkinsonian disorders are thought to result from neuronal accumulation of α-synuclein or tau proteins. Certain other disorders are linked to abnormalities in pathways involving proteins with expanded polyglutamine tracts (polyQ). Among these disorders, clinical and pathological differences depend on the distribution of protein aggregates or in the abnormal configuration they assume when they aggregate. The synucleinopathies include PD, Lewy body disease (LBD), and multiple system atrophy (MSA). The tauopathies include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), familial frontotemporal dementia with parkinsonism (FTDP), postencephalitic parkinsonism (PEP), posttraumatic parkinsonism, and amyotrophic lateral sclerosis (ALS)-PD of Guam. The polyQ disorders include HD, dentatorubral-pallidoluysian atrophy (DRPLA), and many spinocerebellar ataxias (Ling et al., 2010; Williams and Lees, 2009).

Within the central nervous system (CNS), certain neuronal populations seem selectively vulnerable to the various pathogenic mechanisms of cell death. This preferential degeneration of specific neuronal populations ultimately determines the phenotype of the disorder. Better understanding of the various pathogenic cellular mechanisms and selective vulnerability may lead to neuroprotective therapeutic strategies that favorably modify the natural course of the neurodegenerative disease.

Parkinsonian Syndromes

Parkinson Disease

Although the disease was described by others before him, James Parkinson is attributed with rendering the first cogent description of PD. In his monograph, The Shaking Palsy (1817), he identified the hallmark features of the illness through descriptions of cases observed in the streets of London as well as in his own patients. Over time, Parkinson disease or idiopathic PD has replaced the original term paralysis agitans as the name for the clinical syndrome of asymmetrical parkinsonism, usually with rest tremor, in association with the specific pathological findings of depigmentation of the SN due to loss of melanin-laden dopaminergic neurons containing eosinophilic cytoplasmic inclusions (Lewy bodies) (see Chapter 21). Dopamine deficiency in parkinsonian brain homogenates was described by Hornykiewicz in 1959, a discovery that ultimately led to highly effective pharmacotherapy with LD and direct-acting dopamine agonists (DAs). Recently, genetic forms of parkinsonism that are clinically indistinguishable from PD have been linked to mutations in several genes (Shulman et al., 2011). The discovery of different genetic forms of parkinsonism with variable penetrance has led to the current concept of PD as a syndrome with genetic and environmental etiologies, but overall, gene mutations are a rare cause of parkinsonism, particularly in those patients with late-onset disease (Gandhi and Wood, 2010).

Epidemiology and Clinical Features

In community-based series, PD accounted for more than 80% of all parkinsonism, with a prevalence of approximately 360 per 100,000 and an incidence of 18 per 100,000 per year (de Lau and Breteler, 2006). PD is an age-related disease, showing a gradual increase in prevalence beginning after age 50, with a steep increase in prevalence after age 60 (Driver et al., 2009). Disease before 30 years of age is rare and often suggests a hereditary form of parkinsonism. Prevalence rates in the United States are higher than those in Africa and China, but the role of race remains unclear. Within the United States, race-specific prevalence rates vary, with some studies suggesting a similar prevalence among whites and blacks. Unfortunately, blacks make up only a small fraction of most specialty clinic populations and thus are underrepresented in clinic-based studies and clinical trials. One study showed the world’s highest prevalence of PD may be among the Amish in the U.S. Northeast—nearly 6% of those 60 years of age or older, more than 3 times the prevalence for the rest of the country (Racette et al., 2009).

Typically, the onset and progression of PD are gradual. The most common presentation is with rest tremor in one hand, often associated with decreased arm swing and shoulder pain (Jankovic, 2008). Bradykinesia and rigidity are often detectable on the symptomatic side, and midline signs such as reduced facial expression or mild contralateral bradykinesia and rigidity may already be present. The presentation may be delayed if bradykinesia is the earliest symptom, particularly when the onset is on the nondominant side. The disorder usually remains asymmetrical throughout much of its course. With progression of the illness, generalized bradykinesia may cause difficulty arising from a chair or turning in bed. The gait and balance are progressively affected, and falls may occur. Sudden arrests in movement, also called freezing or motor blocks

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