Hyperkinetic movement disorders are phenotypically linked by the presence of excess unwanted movements. In addition, they share common, neural pathways involved in voluntary motor control including primary and secondary motor and sensory cortices, the basal ganglia, thalamus, and cerebellum. The pathophysiology of these disorders appears to include similar alterations in physiological properties of neurons in these areas. Phenotypic differences in the hyperkinetic disorders, however, speak to the differing infl uence and degree of each of these changes and the various motor and, in some cases, non-motor pathways involved in mediating each disorder. In support of the commonality of neural pathways that underlie the development of different hyperkinetic disorders, surgical therapies may target common regions of the brain for the treatment of each of these disorders, and pharmacological therapies are aimed at receptors that regulate these same neural pathways. Much of our understanding of the physiological differences underlying hyperkinetic move-ment disorders has stemmed from comparisons to hypokinetic movement disorders as well as comparisons across the different hyperkinetic disorders. This chapter will detail (1) the anatomy of the basal ganglia and thalamocortical circuits and their role
B. L. Walter , MD Department of Neurology, University Hospitals , Case Western Reserve School of Medicine , 11100 Euclid Ave HAN 5040 , Cleveland , OH 44106 , USA
J. L. Vitek , MD, PhD (*) Department of Neurology , University of Minnesota , 420 Delaware Street S.E., MMC 295 Mayo , Minneapolis , MN 55455 , USA e-mail: [email protected]
Chapter 1 Pathophysiology of Hyperkinetic Movement Disorders
Benjamin L. Walter and Jerrold L. Vitek
2 B.L. Walter and J.L. Vitek
in the genesis of hyperkinetic disorders and (2) describe current knowledge of the neurophysiological changes that occur in each of these disorders. We will then present a general unifi ed model of hyperkinetic movement disorders using hemibal-lism, dyskinesia, and dystonia as examples, outlining some of the differences that may occur in each. Tourette syndrome will be discussed separately since it would appear to have greater involvement of non-motor circuits. Finally, we will discuss myoclonus, a condition in which the anatomical areas involved are more diverse. While we often lose site of the role of non-motor and non-basal ganglia pathways in the development of these movement disorders, myoclonus serves as a reminder that many of these disorders have varying degrees of involvement of non-motor path-ways and extra-basal ganglia pathology. As such, the presentation of each disorder and its response to the various treatment modalities may differ.
Anatomy of the Basal Ganglia and Thalamocortical Circuits
The nuclei of the basal ganglia function as components of several segregated parallel circuits that also involve specifi c portions of the thalamus and cerebral cortex. These circuits take origin from different cortical areas, project to separate portions of the basal ganglia, which in turn project to separate portions of the thalamus, returning to the same areas of the frontal cortex from which they took origin. These parallel circuits are believed to include at least four distinct circuits that are critical to unique functions related to (1) skeletomotor, (2) oculomotor, (3) associative, and (4) limbic modalities.
Of these, the skeletomotor, or “motor” circuit, has been considered most impor-tant in the pathogenesis of hypokinetic movement disorders such as Parkinson’s disease and hyperkinetic movement disorders including dystonia, hemiballismus, and Huntington’s chorea [ 28 ] . However, it is increasingly clear that many of these disease processes also affect non-motor function, often in an analogous way to the disruption of motor function. This may be due in part to similar physiological dys-function in the non-motor portions of the basal ganglia–thalamocortical circuits (i.e., associative and limbic circuits) and/or to the involvement of other brain regions involved in non-motor function.
Cortical input to the basal ganglia occurs predominantly through the striatum (see Fig. 1.1 ). Thus, the striatum serves as the predominant input nuclei of the basal ganglia. The striatum itself is functionally segregated in an anterior to posterior direction with each circuit receiving projections into the striatum from functionally related cortical areas. In the case of the motor circuit, cortical inputs from precentral motor and postcentral somatosensory cortex project onto the posterior putamen. Subnuclei of the thalamus also project onto the striatum; these projections arise mostly from intralaminar nuclei with centromedian thalamic nucleus (CM) project-ing to motor putamen and the parafascicular thalamic nucleus (Pf) projecting to associative and limbic areas within the caudate [ 89 ] . Thalamic projections to the striatum are one route by which cerebellar information may be integrated into
31 Pathophysiology of Hyperkinetic Movement Disorders
the basal ganglia circuit as neurons in the motor region of the cerebellar dentate nucleus project to thalamic subnuclei, including centrolateral (CL), CM/Pf, ven-troanterior (VA), and ventrolateral (VL) which project directly to various regions of the striatum (see Fig. 1.1 ) [ 45, 48 ] .
The internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr) are functionally homologous and remain as distinct nuclei due to their separation by corticospinal fi bers passing through the internal capsule. They serve as the predominant output nuclei of the basal ganglia.
Linking the input and output areas of the basal ganglia are two parallel pathways. These are the so-called “direct” and “indirect” striatofugal pathways. The “direct” pathway is believed to take origin from striatal medium spiny neurons that project directly to the output nuclei—GPi and SNr. The “indirect” pathway is believed to
Fig. 1.1 Basal ganglia–thalamocortical circuitry. Excitatory projections are represented with gray arrows and inhibitory projections are represented with black arrows . GPE globus pallidus par externa, GPI globus pallidus pars interna, STN subthalamic nucleus; SNr substantia nigra pars reticulata; SNC substantia nigra pars compacta; PPN pedunculopontine tegmental nucleus, MEA mesencephalic extrapyramidal area. Individual thalamic subnuclei shown include VA ventralis anterior; VLo ventralis lateralis, pars oralis; VPLo ventralis posterior lateralis, pars oralis; CL cen-tral lateral; CM centromedian; Pf parafascicular. Dopamine (DA) receptor subtypes 1 and 2 on striatal projection neurons are represented as D1 and D2, respectively
4 B.L. Walter and J.L. Vitek
originate from distinctly different striatal medium spiny neurons that project to the external segment of the globus pallidus (GPe), which projects to the subthalamic nucleus (STN), which in turn projects to the basal ganglia output nuclei—GPi and SNr. There is a second arm of the indirect pathway as some GPe neurons also proj-ect directly to GPi. Additionally, there are collateral projections from the STN pro-jecting back on GPe.
Cortical regions may also affect basal ganglia activity via the “hyperdirect” pathway. This pathway consists of somatotopically organized projections directly to the STN from the cortical sensorimotor areas that project to the putamen [ 81, 82, 110 ] . In summary, both direct and indirect pathways as well as the “hyperdirect pathway” have a fi nal common output through GPi and SNr which projects to the thalamus and brainstem.
Using Olszewski’s terminology, basal ganglia projections to the thalamus are predominately to ventralis anterior (VA) and ventralis lateralis pars oralis (VLo). In the stereotactic surgery literature using Hassler’s terminology, these are known as lateropolaris (Lpo ) and ventrooralis anterior (Voa) and ventrooralis posterior (Vop) (Voa and Vop are analogous to VLo in the animal) and are collectively referred to as the pallidal-receiving area. Just posterior to Voa/Vop in the thalamus is the ventral intermediate nucleus (Vim), the cerebellar-receiving area (analogous subnuclei in the animal is ventralis posterior lateralis pars oralis [VPLo]). Anatomical tracing studies in non-human primates show that pallidal- and cerebellar-receiving areas in the thalamus are largely segregated; GPi projects to VA and VLo, which predomi-nately projects to the SMA, with lesser projections to premotor cortex and primary motor cortex. The cerebellum predominately projects to VPLo and area X (analo-gous to the Vim/Voi subnuclei in human), which then project to the motor cortex and arcuate premotor area, respectively [ 92, 94 ] .
Brainstem projections from the basal ganglia are less well understood, but there is increasing evidence that these regions likely play a critical role in the pathophysi-ology of movement disorders [ 83 ] . Most GPi and SNr neurons projecting to the ventral thalamus are believed to send axon collaterals to the pedunculopontine nucleus (PPN) and midbrain extrapyramidal area (MEA) [ 88 ] . These areas project to the thalamus, as well as the locus coeruleus (LC), which has widespread projec-tions to the thalamus and cerebellum. The MEA sends glutamatergic projections back to the GPi and SNr, as well as to the brainstem and spinal cord, whereas the PPN has extensive projections to the thalamus [ 39, 60, 87, 103 ] . Cholinergic projec-tions from the PPN have a differential effect on thalamic relay (e.g., ventrolateral thalamus) and reticular neurons, depolarizing relay neurons and hyperpolarizing reticular neurons [ 66– 69 ] . Thus, cholinergic brainstem projections from the PPN are generally excitatory to thalamic relay neurons and inhibitory to reticular neu-rons. The extensive projections from Rt and PPN throughout the motor thalamus may explain the observed changes in neuronal activity reported in both pallidal- and cerebellar-receiving areas in animal models of PD [ 39, 60, 87, 102, 114 ] as well as the existence of abnormal activity in cerebellar-receiving areas in hyperkinetic disorders such as dystonia [ 55, 123 ] .
51 Pathophysiology of Hyperkinetic Movement Disorders
Functional Role of the Basal Ganglia–Thalamocortical “Motor” Circuit
It has been proposed that the basal ganglia–thalamocortical motor circuit may func-tion to scale and focus motor activities through the opposing effect of the direct and indirect striatopallidal pathways. Scaling of movement could occur if both pathways projected to the same neurons. In such a case, increased direct pathway activity would lead to increased inhibition of GPi neurons and promote movement through disinhibition of movement-related thalamocortical neurons, while activation of the indirect pathway would suppress movement by increasing excitatory activity from the STN to the GPi and increasing inhibition of movement-related thalamocortical neurons. Balancing the amount of activity in the direct and indirect pathways once could thus “scale” movement. Focusing of movement may occur when these path-ways project to different neurons. Neurons controlling agonist activity would be facilitated through the direct pathway while neurons controlling antagonist activity would be inhibited by the indirect pathway [ 117 ] .
Consistent with the focusing hypothesis, Mink has hypothesized that the basal ganglia serve to facilitate desired movements while suppressing competing move-ment programs [ 75, 78 ] . With attention to the same point of integration, that is, where GPi receives excitatory input from STN and inhibitory input from the direct striatopallidal projections, Mink points out that signifi cant divergence may occur in the STN–GPi projections and convergence in the striatopallidal projection. Given that these projections are somatotopically organized, activation of the direct path-way may inhibit a somatotopically focused area of GPi, which in turn has inhibitory projections to the thalamus resulting in disinhibition of thalamocortical projections, and allow a desired movement in a specifi c body part. At the same time, STN–GPi projections may cause widespread activation of inhibitory projections to specifi c portions of the thalamus that control competing movements creating a “surround inhibition.” Based on this hypothesis, a cortical area can select a movement program by activation of the direct pathway, while the competing programs are inhibited by cortical projections through the indirect as well as the hyperdirect pathways. Given the large number of corticothalamic relative to pallidothalamic projections and the time lag for basal ganglia projections to reach the thalamus relative to those from the cortex, the role of the basal ganglia in motor control, although debated, has been considered to be modulatory. This may account for the observations that pallido-tomy (where GPi output is removed) and deep brain stimulation (where GPi output is relatively fi xed) do not abolish movement.
Functional Neurochemistry of the Basal Ganglia Circuits
The striatum, as the primary input center of the basal ganglia, receives extensive converging projections from most of the cortical mantle. These excitatory gluta-matergic corticostriatal projections terminate on the heads of dendritic spines of
6 B.L. Walter and J.L. Vitek
medium spiny projection neurons. Projections to the striatum from thalamic intralaminar nuclei (CM and Pf) are also glutamatergic but differ from corticostriatal projections in that they terminate on the dendritic shafts of the striatal projection neurons [ 24, 36, 105 ] .
The medium spiny striatal projection neurons have a distinct connectivity and neuropharmacology. While both populations of neurons release GABA as their principal neurotransmitter, their similarities end with this point. Direct pathway projection neurons en route to GPi also carry substance P and dynorphin, whereas indirect pathway neurons projecting to GPe also release enkephalin [ 29 ] .
The direct and indirect pathway projection neurons are also differentially modu-lated by dopamine; direct pathway medium spiny neurons express D1 receptors, which are coupled to Gs proteins and are excitatory, whereas indirect pathway projec-tions express D2 receptors, which are coupled to G0 proteins and are inhibitory [ 37 ] .
Dopaminergic innervation to the striatum comes from the substantia nigra pars compacta (SNpc). SNpc projections end on medium spiny projection neurons. These dopaminergic terminals express nicotinic acetylcholine receptors which are believed to facilitate the release of dopamine and are under the control of striatal cholinergic interneurons [ 122 ] .
Four major classes of interneurons exist within the striatum. These include (1) large cholinergic interneurons, known as TANs or tonically active neurons due to their 2–10 Hz tonic irregular activity or LA cells due to their long-lasting after hyperpolarizations, (2) nitric oxide/somatostatin/neuropeptide Y containing GABAergic interneurons that have low-threshold spiking ( LTS cells ), (3) parvalbu-min-positive fast-spiking ( FS cells ) GABAergic interneurons, and (4) calretinin-positive GABAergic cells [ 51 ] .
The large cholinergic interneurons receive mostly thalamic glutamatergic input and some glutamatergic cortical projections. Recent attention has been directed toward D2 dopamine receptors on these striatal cholinergic interneurons which may be poised to play a more global role by regulating activity of multiple projection neurons by depressing activity via M1 receptors [ 15, 119 ] .
NO positive striatal interneurons are also regulated by nigral dopaminergic projec-tions via D1/D5 class receptors. These interneurons modulate activity of other striatal neurons, most importantly medium spiny projection neurons, via soluble guanylyl cyclase . These interneurons receive cortical but not thalamic projections [ 15 ] .
The corticostriatal synapses onto striatofugal projection neurons are an impor-tant site of integration of multimodal information from various cortical regions and are regulated by dopaminergic projections from the SNpc and modulated by the intrinsic cholinergic and nitric oxide interneurons present in the striatum [ 21 ] . This is a candidate area where sensorimotor integration may occur and may also play a critical role on motor learning, cognitive performance, and reward mechanisms [ 15 ] . These corticostriatal synapses display both major types of synaptic plasticity, that is, long-term depression (LTD) and long-term potentiation (LTP). Unique to this circuit, dopamine is required for the induction of both LTD and LTP [ 14, 15 ] .
LTD of the corticostriatal synapse may also be evoked experimentally by stimulating corticostriatal fi bers at 100 Hz in association with activation of the postsynaptic
71 Pathophysiology of Hyperkinetic Movement Disorders
striatal projection neuron [ 14, 58, 117 ] . Both D1 and D2 receptor activity has been found to be required for the induction of LTD. However, the relative balance toward D2 receptor activity over D1 activity is believed to be particularly critical in the induction of LTD as mutant mice lacking D2 receptors fail to show LTD after tetanic corticostriatal stimulation and instead show LTP [ 16 ] . There are a number of possible mechanisms by which D2 activation in the striatum may lead to LTD, and together these mechanisms may result in a complex array of feed-forward and feed-back control of neuroplasticity of the corticostriatal synapse. First, activation of D2 receptors on cholinergic interneurons would lead to reduced release of Ach onto M1 receptors residing on the striatal projection neuron, which would then lead to disin-hibition of inward Ca currents, resulting in increased production of endocannabi-noids (ECBs). ECBs released locally are believed to directly act to promote LTD. A second mechanism may occur by D5 activation on NOS interneurons leading to release of NO locally which may lead to LTD in local neurons. A third mechanism may occur by direct activation of D2 receptors on the striatal projection neuron leading to release of ECBs [ 15 ] .
LTP of the corticostriatal synapse can be evoked experimentally by repetitive activation of cortical inputs if combined with postsynaptic depolarization [ 22 ] . A major difference between striatal LTD and LTP is that while in LTD, D1 and D2 activation synergistically promotes LTD; in contrast, D1 activation promotes LTP while D2 activation opposes it.
Thus, the striatum, and particularly the corticostriatal synapse, is a point of con-vergence of several different neurotransmitter systems leading to neuroplastic changes that may underlie learning within this circuit. ECBs and NO have a local role in neuroplasticity. Cortical and thalamic input arrives via glutamatergic projec-tions, and the opposing modulatory effects of dopamine and acetylcholine regulate the overall activity of these circuits. The intrinsic and efferent circuits of the striato-pallidothalamic connections are predominately GABAergic with the exception being projections from the STN which are glutamatergic. These major transmitter systems therefore are the principal pharmacological targets for treatment of basal ganglia disorders, and there is a particularly critical role of modulatory effects of acetylcholine and dopamine.
Neurophysiology of Hyperkinetic Movement Disorders in Dyskinesia Hemiballism and Dystonia: Toward a Unifying Basal Ganglia Model
The rate model : The development of an animal model of PD using the neurotoxin MPTP together with an understanding of the anatomical connectivity of the basal ganglia–thalamocortical motor circuit led to the development of the rate model for movement disorders in the late 1980s and early 1990s [ 3, 29 ] . Detailed studies of the parkinsonian MPTP monkey led to the fi nding that mean fi ring rates of neurons in GPi were increased, while those downstream in the pallidal-receiving area of the
8 B.L. Walter and J.L. Vitek
thalamus were reduced [ 29, 33, 34, 74 ] . This led to the proposal that excessively increased mean discharge rates in GPi led to suppression of thalamocortical activity and the development of parkinsonian motor signs [ 3, 29 ] . Similarly, from this model of hypokinetic disorders, it was proposed that the opposite would be true for hyper-kinetic disorders, i.e. mean discharge rates in GPi would be reduced leading to excessive increases in thalamocortical activity and increased movement (see Fig. 1.2 ). Support for this hypothesis was derived from human and animal studies of hypokinetic and hyperkinetic disorders including PD, hemiballism, levodopa-induced dyskinesia, and dystonia [ 71, 86, 101, 112, 116 ] .
Thus, in hyperkinetic disorders, reduced tonic inhibitory control of GPi on thalamic relay nuclei was theorized to lead to increased adventitious movements, whereas in hypokinetic disorders, increased inhibition of thalamic activity is believed to produce paucity of movement or slowed movement.
Problems with the rate model : Patient and experimental animal responses to surgical interventions, however, contradict some of the predictions of the rate model. The rate model would predict that pallidotomy would worsen dyskinesias in PD patients and exacerbate the involuntary movements that occur in hyperkinetic disorders by disin-hibiting the thalamus. Pallidotomy, however, does not produce a hyperkinetic state or worsen drug-induced dyskinesia in PD patients. In fact, pallidotomy is very effective in alleviating drug-induced dyskinesias as well as the involuntary movements associ-ated with hemiballismus and dystonia. The rate model also predicts that lesions within the motor thalamus should worsen or induce parkinsonian motor signs. Lesions in the motor thalamus, however, do not exacerbate or induce parkinsonian motor signs but, instead, are reported to improve or abolish parkinsonian tremor, rigidity, and drug-induced dyskinesias [ 42, 84, 85 ] . These contradictions of the rate model have led to the development of an alternative pattern model [ 113, 116– 118, 121 ] .
Fig. 1.2 Model for hyperkinetic disorders based on observed changes in mean discharge rate and altered patterns of neuronal activity. The width of the lines in the model represents the relative change in mean discharge rate compared with normal. Increased rates are represented with wider arrows , while decreased rates are represented with thin arrows . Disrupted lines represent the altered patterns and suggested increase in synchronization of neuronal activity in the basal ganglia–thalamocortical circuit leading to unregulated cortical output
91 Pathophysiology of Hyperkinetic Movement Disorders
The pattern model : While many predictions of the rate model do not occur, this model has provided the framework upon which subsequent hypotheses have been developed. Physiological recordings from animal models and from humans undergo-ing intraoperative mapping during stereotactic procedures have provided evidence that other features of basal ganglia neural activity are also changed in Parkinson’s disease [ 7, 33, 90 ] as well as in patients with hemiballismus, dystonia, and dyskinesia [ 55, 57, 101, 116, 123 ] . These include increase in the incidence of busting activity, synchronization, and the development of oscillatory activity at particular frequency ranges. Alterations in the receptive fi elds of neurons in the motor circuit and changes in the pattern of spontaneous neuronal activity have all been described in these dis-orders. The net effect of these changes in producing the particular type of movement disorder remains unclear; however, the fact that lesions which remove this altered activity, or deep brain stimulation that modulates it, lead to improvement in the movement disorder provides compelling evidence for a causal relationship and sup-port for the pattern model [ 117 ] . Relative differences between the type and severity of these changes in neuronal activity may underlie the development of individual hyper-kinetic disorders. A greater understanding of these differences would provide the ratio-nale for the development of new medical and surgical therapies directed at modifying this activity in order to reduce or eliminate its disruptive effect on motor control.
Physiological Changes in the BG–TC Circuit in Movement Disorders
Grouped discharges and bursting. In normal animals, GPi neurons fi re with a tonic, relatively regular pattern at approximately 80 Hz [ 101 ] . The regularity of these discharges is degraded in both hypokinetic and hyperkinetic movement disorders. In Parkinson’s disease, GPi cells fi re with increased bursting and grouped discharges [ 101 ] . Irregular bursting or grouped discharges have also been reported when parkinso-nian patients became dyskinetic [ 61, 71 ] , in hemiballism and dystonia [ 101, 107, 116 ] .
Oscillations and synchrony. Synchronized oscillations become prominent at 4–30 Hz in the parkinsonian animal and in PD patients. They are particularly prominent in the low beta frequency end of this spectrum (at 11–30 Hz) in untreated PD patients. While transient synchronization likely has a physiological role in motor control, uncon-trolled synchronized oscillations are likely to interfere with normal movements. In PD patients, synchronized oscillations in the 11–30 Hz range have been theorized to have disruptive or anti-kinetic properties. In contrast, high-frequency synchronization >60 Hz may facilitate dynamic task related cortical activity [ 12 ] . Consistent with these observations, therapeutic doses of dopaminergic medications have been reported to reduce such synchronized oscillations in the low beta range coincident with improvement in parkinsonian motor signs [ 19 ] (see Table 1.1 ).
The origin of synchronization of basal ganglia neurons is unknown; however, the large number of reciprocal connections between nodal points (GPe ↔ STN; GPi → CM → Striatum → GPi) makes this structure highly susceptible to such activity
10 B.L. Walter and J.L. Vitek
Table 1.1 Summary of altered rates and patterns pallidal activity in hypo- and hyperkinetic movement disorders
(see Fig. 1.1 ). New evidence also suggests that there may be pallidal–striatal projections from GPe and possibly GPi as well, which may also serve as reentrant circuits [ 8, 93, 100 ] .
In addition, TANs interneurons in the striatum, which normally do not show sig-nifi cant oscillatory behavior, become highly oscillatory in the parkinsonian animal [ 90 ] , and TANs and pallidal cells which normally show poor synchrony have highly correlated synchronous 3–19 Hz periodic oscillations in the parkinsonian state [ 91 ] .
Altered receptive fi elds. The selectivity of basal ganglia neurons to passive joint movements may also be altered in movement disorders. While a single GPi or thal-amic neuron normally responds to movement in the contralateral limb about one joint in one direction, in both the parkinsonian and dystonic states, the “receptive fi eld” of these cells may be widened, responding to movement from both ipsilateral and contralateral limbs about multiple joints in multiple directions [ 35, 50, 55 ] .
Pathophysiology of Hemiballism
Hemiballism consists of involuntary, often violent, movements of the limbs on one side. These movements are most closely associated with inactivation or destruction of the STN or its efferent pathway on the side contralateral to the involuntary movements [ 18 ] . Hemiballismus has been observed in humans after vascular lesions restricted to the STN, as well as in monkeys after selective lesioning of the STN [ 17, 41 ] . Based on the previously proposed rate model, these movements were thought to occur predomi-nantly as a result of disinhibition of the thalamus (see Fig. 1.2 ) [ 40, 41 ] .
111 Pathophysiology of Hyperkinetic Movement Disorders
This model received support from both experimental studies in the monkey and studies of patients with intractable hemiballismus [ 18, 40, 41, 49, 65, 120 ] who underwent microelectrode-guided pallidotomy [ 49 ] . In both the human and the monkey, there is a signifi cant reduction in the tonic discharge rate in GPi after an STN lesion and the development of hemiballismus. Consistent with this observa-tion, monkeys with hemiballismus after inactivation of STN show decreased meta-bolic activity in both GPi and the ventral lateral thalamus [ 26 ] . However, the reduced rate in GPi would suggest that thalamotomy and not pallidotomy would effectively treat hemiballism, yet lesions in either site alleviate the involuntary movements associated with this disorder [ 6, 31, 63, 106, 115, 116 ] .
Observations that either pallidotomy or thalamotomy was an effective treatment for hemiballism led to the reevaluation of the rate model and to the proposal that altered patterns of neuronal activity underlie the development of this movement disorder [ 116 ] and to the subsequent consideration that such alterations may also contribute to the altered movement that occurs in hypokinetic disorders as well. In the case of hemiballism, in addition to decreased GPi fi ring rates, there is also evidence of increased irregular grouped discharges and bursting in GPi [ 107 ] , as well as increased synchrony and decreased somatosensory responses [ 116 ] .
Few patients with hemiballism have been studied, but data from cross-correla-tional analysis of multiple GPi neurons and EMG activity show remarkable high correlations suggesting that a state of increased synchronization existed in this con-dition [ 116 ] .
Receptive fi elds in hemiballism have been reported to be dramatically reduced [ 116 ] . This may not be surprising as the pathological lesion that produces hemibal-lism is ablation of the STN, a critical nodal point in the basal ganglia pathway through which proprioceptive information may reach the GPi and pallidal-receiving area of the motor thalamus [ 40, 41 ] .
Pathophysiology of Dystonia
Reports of neuropathological examination of patients with suspected PGD are lim-ited. Standard MRI scans have been reported as normal in cases of DYT1 dystonia. Until recently, limited neuropathological studies have reported no pathological changes in the brains of DYT1 patients [ 27 ] . A recent study, however, revealed perinuclear inclusion bodies in the PPN, cuneiform nucleus, and griseum centrale mesencephali, which stain positive for TorsinA, ubiquitin, and nuclear envelope protein laminin A/C [ 70 ] .
Whether or not these anatomical changes underlie the development of dystonia or are epiphenomenon remains unclear. What is clear, however, is that there are physiological changes in the pallidum and thalamus that bear features common to both hypokinetic and hyperkinetic disorders. In common with other hyperkinetic movement disorders, there is a decrease in the mean discharge rate of GPi neurons and enhanced synchrony at low frequencies (see Fig. 1.2 ). Similar to PD however,
12 B.L. Walter and J.L. Vitek
GPe mean discharge rates are reduced and receptive fi elds are both widened and more frequent. Present models suggest there is increased inhibitory input through the direct and indirect pathways [ 116 ] , with the direct pathway taking a predomi-nate role leading to the reduced mean discharge rates and likely contributing to the development of altered patterns of neuronal activity in GPi [ 101, 116 ] .
Altered patterns of activity in GPi were originally described as consisting of irregular grouped discharges and bursting [ 116 ] . Starr et al. further characterized the burst discharges in dystonia and reported that GPi but not GPe had increased burst-ing when compared to the normal non-human primate. Further, there was no differ-ence by subtype of dystonia, and the only difference in GPi burst characteristics between dystonia and PD was a relatively greater intra-burst fi ring rate in PD that was proportional to the relatively increased overall fi ring rate [ 101 ] . In dystonia, recordings in STN [ 123 ] have shown similar fi ndings with increased grouped dis-charges and pauses, and the same follows for pallidal-receiving areas Voa and Vop [ 55, 123 ] .
Synchronized oscillations have also been demonstrated in the pallidum of dys-tonic patients. Both GPi and GPe cells showed signifi cantly increased synchronous oscillations in the 2–10 Hz range in dystonia patients—activity not seen in the nor-mal non-human primate [ 101 ] . Analysis of power spectra of local fi eld potentials from DBS electrodes in GPi in dystonia patients has revealed a peak in the <10 Hz range that is greater than that found in PD patients treated with dopaminergic medi-cations which in turn was greater than untreated PD patients [ 98, 101 ] .
Responses of GPi neurons to passive movement are abnormally unselective, i.e., receptive fi elds are widened [ 116 ] . Likewise in the thalamus, somatosensory responses in both Vop and Vim were distorted in patients with dystonia compared to a control group comprised of chronic pain or tremor (non-PD) patients [ 54, 56, 58 ] . The number of sensory cells responding to movement of more than one joint was signifi cantly higher in dystonic than in control patients, and the representations of the dystonic body parts were increased. These observations provide compelling evi-dence that both pallidal (Vop)- and cerebellar (Vim)-receiving areas of the motor thalamus are involved in the pathogenesis of at least some types of dystonia.
There is evidence that the development of motor symptoms in dystonia is infl u-enced by a neuroplastic process. PGD often begins to express in early childhood, when the nervous system is most adaptable, and typically generalizes in a gradual fashion following a caudal–rostral somatotopic progression suggesting that plastic-ity of the nervous system may be important in the genesis of the fully generalized presentation. When primary dystonia occurs later in life, it tends to remain focal [ 11 ] . Focal dystonia may also occur in patients who repetitively perform skilled tasks such as musicians and has been modeled in primates by training the animals to repetitively perform a task, suggesting that either altered regulation of neuroplas-ticity or redundant reinforcement of movement programs may have a role in the genesis of focal dystonia [ 13 ] . The corticostriatal synapse is a key site for plastic learning, and the evolution and treatment of dystonic symptoms suggest that a neu-roplastic process may play a role in the pathogenesis of this disorder.
131 Pathophysiology of Hyperkinetic Movement Disorders
Compared to other movement disorders, dystonia responds differently to functional surgery. In comparison to DBS for Parkinson’s disease and essential tremor, GPi DBS for dystonia has been reported to have a longer latency to peak benefi t. These patients also typically have a period of prolonged benefi t after cessation of stimula-tion. Progression of benefi t from GPi DBS has been described to begin with improvement in pain at 1–2 days, hyperkinetic or phasic dystonia improving by 1 week, and tonic fi xed dystonia improving from 1 month to 2 years after stimula-tion onset [ 53 ] . One large case series reported maximum improvement in the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) around 1 year postoperatively [ 25 ] . There is little amount of data on what occurs with cessation of DBS in dystonia; however, most reports show partial return of dystonic symptoms after several hours to 1 week [ 25, 30 ] . While there may be signifi cant variability from patient to patient, delays to onset of improvement and longer washout periods when DBS is stopped compared to PD suggest there are different regulatory factors that are at play in the dystonic condition.
The most effective pharmacological therapy for generalized dystonia is treat-ment with anticholinergic medications. The TANs neurons of the striatum are the most likely candidate for this drug action; alternatively, PPN projections to the thal-amus could also be involved. These neurons are intimately involved with nigrostri-atal dopamine projections, and together they carefully regulate the corticostriatal synapse, a major site of multimodal integration and a synapse that displays strong capability for LTP and LTD.
Pathophysiology of Tourette Syndrome
Tourette syndrome (TS) is a neuropsychiatric disorder that predominates in children and adolescents and often improves with maturity. It manifests as a constellation of motor and psychiatric abnormalities, including motor and vocal tics, and may be comorbid with prominent obsessions, compulsions, and attention defi cit disorder. As such, TS is a prime example of a movement disorder that involves both motor and non-motor circuits.
A number of lines of evidence support the notion that tics fi t within the family of hyperkinetic movement disorders and thus may involve dysfunction of the basal ganglia–thalamocortical “motor” circuit. A theoretical “center-surround” model popularized by Mink and coworkers provides a theoretical basis for the develop-ment and expression of tics [ 79 ] . Based on the model, a focal area of striatum becomes hyperactive, which leads to disinhibition of a motor program resulting in unwanted stereotyped movements. Support for this model comes from the observa-tion that stimulation in the motor putamen in non-human primates may evoke ste-reotyped movements [ 5 ] . Based on this model, Mink and colleagues also proposed that simple tics originate in areas of the motor circuit projecting to the primary motor cortex, while complex tics originate in regions with projections to SMA, CMA, and premotor cortex [ 76, 79 ] . In addition to the motor circuit, however, a role
14 B.L. Walter and J.L. Vitek
for non-motor circuits in the development and manifestation of tics also seems likely. An essential clue to the pathogenesis of tics and involvement of limbic- and reward-related circuitry may be that patients with TS have diffi culty suppressing these unwanted motor activities and tics are often associated with a premonitory urge. The psychiatric comorbidities may refl ect dysfunction in the parallel-arranged non-motor circuits similar to that which occurs in the motor circuit in this condition [ 4 ] . Obsessions and compulsions may originate in the limbic portions of the circuit projecting to the orbitofrontal cortex, and the symptoms of attention defi cit may originate in associative potions of circuit projecting to dorsolateral prefrontal cortex.
In PD, HB, and dystonia, non-motor symptoms may be mild and may be over-looked particularly in early stages of the disease. In TS however, there is a profound presence of non-motor comorbidities present at the onset of the disorder. As such, non-motor pathways of the basal ganglia may play a signifi cant role in this condi-tion. Non-motor portions of the basal ganglia include the nucleus accumbens and the rostroventral extensions of the caudate and putamen. These areas receive input related to limbic function from the hippocampus and amygdala. The ventral stria-tum projects to portions of the ventral pallidum [ 77 ] . Ventral pallidum projects to medial dorsal thalamus as has been shown in the rat; however, in primates, the prominence of this pathway is unclear and output of this circuit may infl uence motor outcome via projections from ventral striatum to dopaminergic cells of substantia nigra [ 38 ] . In addition to modulatory dopaminergic input from SNpc, the ventral striatum also receives prominent input from the ventral tegmental area (VTA). Dopamine receptor antagonists as a class are the most potent medications for tic suppression [ 52 ] , implicating the striatum in the pathogenesis of TS with its rich dopaminergic innervation from SNpc and the VTA.
Evidence that these “non-motor” circuits are involved in TS also comes from pharmacological therapies, functional surgical therapies, and functional imaging studies. In the modern era of stereotactic functional surgery, approaches to the treat-ment of tics associated with TS are still in its infancy. There is insuffi cient amount of physiological data to glean evidence of its pathophysiology. However, there have been reports of tic reduction in the 1970s with intralaminar thalamic ablation [ 43 ] and, more recently, with DBS in this same target [ 46, 111 ] providing compelling evidence for a role of these subnuclei in tic mediation. Furthermore, DBS in either motor or non-motor portions of the GPi has also been reported effective in amelio-rating tics associated with TS, suggesting tic generation may involve both motor and non-motor pathways. While outcome data are limited, both approaches have been reported to improve motor tics, as well as neuropsychiatric symptoms [ 96 ] . Most reports have focused on motor symptoms and reduction of tics following sur-gical intervention, and consistent improvement across the varied neuropsychiatric comorbidities has yet to be demonstrated.
Functional imaging studies implicate the striatum in TS [ 9, 10, 32 ] . Neuroimaging studies of dopamine function have been mixed; however, recent studies are consis-tent with increased striatal dopaminergic innervation particularly in the ventral striatum in patient with TS [ 1, 23, 95 ] (see [ 2 ] for a review). Postmortem data suggest
151 Pathophysiology of Hyperkinetic Movement Disorders
that nigrostriatal projection density peaks in mid-adolescence and then declines [ 44 ] , which may parallel the typical natural history of tic symptomatology.
In addition to the striatum multiple, other brain regions have been implicated in tic development. A PET study of tics compared to stage II sleep showed signifi cant involvement of the cerebellum and insula, as well as thalamus and putamen during tic release [ 59 ] . If the cerebellum is involved in the pathophysiology of tics, these results could suggest an important role of cerebellar projections to the CM thalamus which project to the putamen. The CM thalamus is part of the thalamic region tar-geted by surgeons for the treatment of tics [ 111 ] .
Pathophysiology of Myoclonus
Myoclonus is a clinical sign of nervous system disease with a vast heterogeneous etiology and pathophysiology. It is characterized by brief (often <100 ms), sudden shock-like muscle jerks [ 20 ] . It is caused by sudden muscular contraction in the case of positive myoclonus or inhibition in negative myoclonus [ 20 ] . It can be caused by focal damage to the motor cortex, subcortical areas, brainstem, spinal cord, and peripheral nerve. Oftentimes, it is a result of systemic metabolic abnor-malities or widespread pathology. While the mechanisms involved in the generation of myoclonus are likely as varied as the structure involved in its genesis, what is likely is that it occurs as a result of excessive neural excitability [ 97 ] .
Myoclonus is clearly different from the other hyperkinetic movement disorders presented herein due to its heterogeneous pathophysiology. There are likely more similarities and common involvement of basal ganglia circuitry in subcortical myo-clonic syndromes. The best evidence for this exists with myoclonus-dystonia syn-drome . The concurrence of dystonia and myoclonus in this syndrome may have some common pathophysiological features localizing them to the basal ganglia. What is more signifi cant, however, is that a few patients with this syndrome have undergone DBS in the pallidum with good results. One patient who underwent bilateral GPi DBS had excellent improvement in both dystonia and myoclonus [ 62 ] . Furthermore, intraoperative physiology revealed 4 Hz oscillatory discharges of GPi neurons that preceded and signifi cantly correlated with contralateral EMG bursts, suggesting a pathogenic role of GPi in this syndrome. Another patient with Vim DBS had resolution of the myoclonus but not the dystonic symptoms. Given the role of the pallidal-receiving area Voa and Vop in the development of dystonia, its exclu-sion in this case supports the role of these thalamic subnuclei in the pathophysiol-ogy of dystonia present in this syndrome. This case also illustrates some similarities between myoclonus and tremor, which is believed to predominately involve abnor-malities in cerebellothalamic pathways, and can be dramatically improved by stimulation involving the cerebellar-receiving area of the thalamus—Vim. The cer-ebellum itself has also been implicated in some cases of myoclonus; in one case, a child had a myoclonic syndrome and a cerebellar tumor, with resolution of the myo-clonus after removal of the tumor [ 80 ] . Thus, while there is some evidence that
16 B.L. Walter and J.L. Vitek
myoclonus can occur from basal ganglia pathology, likening it to other hyperkinetic movement disorders, it may also result from alterations in cerebellar pathways and other areas throughout the central and possibly the peripheral nervous system.
Conclusion
Underlying the pathophysiology of hyperkinetic disorders is the common feature of decreased neural fi ring rates in the inhibitory basal ganglia output nuclei—GPi and SNR—leading to a disinhibition of thalamocortical activity. This alone, however, does not fully explain the phenotypic differences between hyperkinetic movement disorders or their response to therapies. In each of these disorders, there is an altera-tion in information processing in the basal ganglia circuits that interferes with nor-mal thalamocortical, corticothalamic, and corticocortical signal processing leading to alterations in movement as well as the development of non-motor comorbidities. These abnormal signals may manifest as changes in rate or bursting patterns of individual neurons or may be seen as an overall pattern change in fi ring of ensem-bles of neurons seen as changes in synchrony of oscillations in different frequency bands. Changes in the somatotopic representation of information as is it distributed topographically across neurons within basal ganglia output nuclei likely also con-tribute to the development of these disorders.
In dyskinesia, there appears to be increased bursting of output neurons, widened receptive fi elds, and reduced synchrony. In hemiballism, there is also increased bursting but reduced or absence of somatosensory responses and increased syn-chrony. In dystonia, there appears to be abnormal bursting, increased, widened somatosensory representations, and increased synchrony with 4–10 Hz oscillations. In Tourette syndrome, theories suggest there would be restricted abnormalities in sensorimotor circuits pertaining to the neurons somatotopically related to the abnor-mal tics with signifi cant similar dysfunction seen in non-motor circuitry. Similarly, the other hyper- and hypokinetic movement disorders often are associated with non-motor cognitive or psychiatric disturbances that may be a result of a similar pathophysiology in both motor and non-motor pathways. Myoclonus can be a symptom of dysfunction in many different nodes of the nervous system as can dys-tonia and tics; these disorders serve as a reminder that many of these disorders can arise from abnormalities in parts of the nervous system other than the basal ganglia.
Neuroplastic mechanisms must be kept in mind when considering the pathophys-iology or treatment of hyperkinetic movement disorders. This is particularly true for dystonia but is also likely involved in Tourette syndrome, and dyskinesias clearly occur as a result of synaptic remodeling or receptor changes. The corticostriatal synapse is a key candidate for plastic learning in the basal ganglia circuit as it has demonstrable LTP and LTD and is regulated by dopamine and acetylcholine.
In considering targets for pharmacological interventions in these disorders, the functional neuropharmacology should be kept in mind, particularly of the modulatory
171 Pathophysiology of Hyperkinetic Movement Disorders
role of dopamine and acetylcholine in the striatum, the differential role of D1 and D2 dopamine receptors in the direct and indirect pathways, respectively, and the prominence of GABA in the intrinsic nuclei within the basal ganglia. The functional role and connectivity of the nuclei within these circuits should also be kept keenly in mind when considering targets for functional surgery such as deep brain stimula-tion. While we are just beginning to understand how DBS may work in these cir-cuits, future modes of therapy can benefi t from advancing our understanding of the underlying physiology of these circuit disorders.
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