Deep Brain Stimulation in Movement Disorders: Parkinson’s Disease, Essential Tremor, and Dystonia

Published on 13/03/2015 by admin

Filed under Neurosurgery

Last modified 13/03/2015

Print this page

This article have been viewed 2369 times

Chapter 114 Deep Brain Stimulation in Movement Disorders

Parkinson’s Disease, Essential Tremor, and Dystonia

Louis A. Whitworth, Kim J. Burchiel

History

The treatment of movement disorders has intrigued neurosurgeons for more than a century. One of the first case reports, by Horsley ¹ in 1909, described a resection of the precentral gyrus in a patient with hemiathetosis. The procedure relieved the patient of the athetosis but left him with permanent hemiparesis and dyspraxia. A few decades passed before a renewed interest in this field led Bucy to perform a similar procedure for treatment of tremor. In 1937, Bucy and Case² resected the motor and premotor regions in a patient with an incapacitating post-traumatic tremor. The procedure abolished the tremor and led Bucy to apply the same technique to parkinsonian tremor. Although effective in treating the tremor, the procedure left patients with impairment of dexterous movements and varying degrees of hemiparesis. Subsequently, locations were sought for interruption of the corticospinal tract that might be associated with less morbidity. Walker³ described sectioning of the lateral two thirds of the cerebral peduncle to treat parkinsonian tremor. Again, this procedure was associated with postoperative hemiparesis, although dexterity seems to have been less affected.

It was not until the 1940s that surgeons first performed surgery on the basal ganglia to treat movement disorders. Before then, most physicians shared Dandy’s view that this region of the brain was the center of consciousness and that damage to the basal ganglia could lead to vegetative states. Meyers ⁴ performed the first direct operation on the basal ganglia in 1939 to treat a patient with postencephalitic tremor. In this procedure, via a transcortical, transventricular approach, he resected two thirds of the caudate nucleus, resulting in good control of the patient’s contralateral tremor. Subsequent surgeries by Meyers for Parkinson’s disease (PD), hemiballism, and choreoathetosis included resections of the caudate, along with portions of the putamen, globus pallidus, and/or ansa lenticularis. By 1949, he had performed 58 such procedures.⁵ Of his patients, 62% had significant improvement in their tremor and rigidity; however, there was a 12% rate of operative mortality. Meyers determined that the mortality rate was excessive for elective surgery and concluded that open surgery on the basal ganglia had a limited role, although he showed that surgery in this region did not lead to alterations in consciousness or coma.

A few years later, Cooper ⁶ discovered an alternate way of performing Meyers’s procedure. While attempting to perform a pedunculotomy on a patient with PD, he inadvertently transected the anterior choroidal artery and was forced to abandon the operation. However, when the patient awoke from surgery, he had no neurologic deficit and his tremor and rigidity were much improved. Cooper reasoned that sacrificing the artery led to a circumscribed infarct within the basal ganglia and the subsequent improvement of the patient’s symptoms. He went on to perform anterior choroidal artery ligation in a series of 55 patients. Tremor and rigidity were improved in approximately 70% of patients; however, there was an 11% rate of postoperative hemiplegia and a 10% rate of operative mortality.⁷ The high complication rate was attributed to the great variability in the vascular territory of the artery, and the procedure was soon abandoned.

Perhaps the most significant development in movement disorder surgery came in 1947 when Spiegel and Wycis introduced their stereotactic apparatus.⁸ Their first cases involved pallidal lesions in patients with Huntington’s chorea and choreoathetosis. This was followed by similar procedures for patients with PD and tremor. In their series of 50 patients, 78% had significant improvement in their tremor, whereas there was only a 4% rate of hemiplegia and 3% rate of operative mortality.⁹ Spiegel and Wycis proved their stereotactic technique was at least as effective as open resections, with far less morbidity and mortality. They were soon followed by Hassler and Riechert,¹⁰ who performed the first stereotactic thalamotomy in 1952. The ventral lateral thalamus soon became the target of choice for the treatment of PD. Thalamotomy proved more effective than pallidotomy for treating tremor and was arguably as effective for rigidity.

The introduction of levodopa in the 1960s led to a sharp decline in surgery for PD. It was not until a few decades later, when the long-term complications of levodopa became apparent, that interest was rekindled in movement disorder surgery. Many technical advances were made in the interim. The use of computed tomography and magnetic resonance imaging (MRI) supplanted ventriculography for target localization. The use of microelectrode recording (MER) became more prevalent and provided an additional method for target confirmation. Even the targets for the lesions themselves had become better defined. The ventral intermediate nucleus (Vim), a portion of the ventral lateral nucleus, became the preferred target for tremor control, and the posteroventral portion of the internal segment of the globus pallidus (GPi) became the preferred target for bradykinesia and rigidity.

The use of subcortical or deep brain stimulation (DBS) is the most recent advance in the treatment of PD and other movement disorders. Since the introduction of stereotactic surgery, electrical stimulation has frequently been performed to improve target localization and predict potential adverse effects before creating a lesion. For example, it was recognized that high-frequency stimulation (more than 100 Hz) in the Vim could suppress tremor. Because of the risk of irreversible neurologic injury and the complications associated with bilateral thalamic lesions, Benabid et al.¹¹ carried out the first large-scale series of thalamic DBS for tremor. The safety and efficacy of this technique fueled interest in applying DBS to other targets such as GPi and the subthalamic nucleus (STN). The remainder of this chapter focuses on the use of DBS at these three sites to treat PD, disabling tremor, and dystonia.

Pathophysiology of PD, Tremor, and Dystonia

Parkinson’s Disease

Although a comprehensive review of the extrapyramidal motor system is beyond the scope of this chapter, a fundamental understanding of the basal ganglia and basal nuclei in regard to their physiologic function and the pathophysiology of movement disorders is important. The basal ganglia integrate and modulate cortical information along multiple parallel channels. Three main parallel systems can be delineated: sensorimotor, associative, and limbic.¹² The best understood functions of the basal ganglia are those of the sensorimotor system. The role of the associative and limbic loops in causing the cognitive and behavioral disturbances associated with basal ganglia syndromes is less clear. These systems affect behavior indirectly by feedback to the cerebral cortex and directly by providing information to subcortical centers that influence movements. Their function is primarily through disinhibition of neural activity. Disruption of these channels by disease or injury results in disruption of movement and may be associated with significant deficits in cognition, perception, and mentation.

The basal ganglia can be divided into dorsal and ventral divisions. The dorsal basal ganglia include the caudate and putamen (neostriatum) and the globus pallidus (paleostriatum). Associated with the dorsal group are the substantia nigra (SN) and the STN. The ventral basal ganglia are located inferior to the anterior commissure (AC) and include the substantia innominata, nucleus basalis of Meynert, and nucleus accumbens. The ventral region is intimately associated with the amygdala and the limbic system. The striatal complex (caudate and putamen) serves as the primary input into the motor circuit of the basal ganglia. The majority of afferent projections to the striatum are from the cerebral cortex, but there are also projections from the thalamus, substantia nigra pars compacta (SNc), and parabrachial pontine reticular formation. Afferents from the prefrontal area terminate preferentially in the caudate nucleus, whereas projections from the motor and sensory cortices terminate primarily in the putamen. The output nuclei of the basal ganglia consist of the GPi and the substantia nigra pars reticulata (SNr). Output neurons from the GPi project primarily to the ventral anterior, ventral lateral, and centromedian nuclei of the thalamus. These fibers exit the GPi as two bundles: the ansa lenticularis and lenticular fasciculus. The ansa lenticularis originates from the lateral portion of the GPi and curves around the internal capsule to enter the Forel fields, whereas the lenticular fasciculus originates from the dorsomedial portion and traverses the internal capsule as small groups of axons. Within the Forel fields, these two fasciculi join to form the thalamic fasciculus, which courses dorsal to the zona incerta en route to the thalamus. The SNr has more diffuse projections, which provide afferent input to the thalamus, superior colliculus, and parabrachial pontine reticular formation.

Motor input to the striatum from the neocortex is via excitatory glutamatergic projections that terminate on spiny cells in the putamen; dopaminergic terminals from the SNc coterminate on these cells. Neurons within the putamen send inhibitory γ-aminobutyric acid–ergic (GABAergic) axons to the external segment of the globus pallidus (GPe), GPi, and SNr. Although a matter of some debate, it appears that dopamine increases striatal output to the GPi and SNr (the direct pathway) and decreases transmission to the GPe (the indirect pathway) via subtype-1 and subtype-2 dopamine receptors, respectively ¹³ (Fig. 114-1A).

FIGURE 114-1 Functional anatomy of the basal ganglia. A, Normal physiologic state with balance between the direct and the indirect pathways. B, Parkinson’s disease. Loss of dopaminergic input from the SNc leads to increased activity along the indirect pathway and decreased activity along the direct pathway, resulting in increased inhibitory input to the ventral lateral thalamic nucleus (VL). C, Effects of an STN lesion in parkinsonism, decreasing inhibitory input to the VL. D, Effects of a GPi lesion in parkinsonism, decreasing inhibitory input to the VL. E, Dystonia. Increased activity along the direct pathway, leading to excessive inhibition of the GPi and decreased inhibitory input to the thalamus. Black arrows indicate excitatory connections, and light gray arrows indicate inhibitory connections. CM, centromedian nucleus of the thalamus; D₁, dopamine receptor subtype 1; D₂, dopamine receptor subtype 2.

The direct pathway begins as an excitatory, glutamatergic projection from the cerebral cortex to the putamen. GABAergic projections from the putamen inhibit cells of the GPi and SNr. Cells of the GPi and SNr are also GABAergic and project to the ventral lateral thalamus. These fibers have a high rate of spontaneous activity and thus tonically inhibit thalamic neurons. Inhibition of these pallidal and nigral projections by afferents from the striatum decreases the inhibitory inputs to the thalamic neurons (thalamic disinhibition). Because the ventral lateral thalamic neurons have excitatory projections to the cerebral cortex, the net effect of the direct pathway is to increase the activity of the thalamus, excite the cortex, and facilitate movement. By contrast, the indirect pathway sends its GABAergic projections from the putamen to the GPe, which in turn has projections to the STN. These pallidosubthalamic fibers are also GABAergic and tonically inhibit cells of the STN. Inhibition of these fibers by the striatum releases these subthalamic cells from their tonically inhibited state. The STN sends excitatory glutamatergic projections to the GPi, which increases the firing rates of pallidothalamic fibers. Because the fibers from the GPi to the thalamus are inhibitory, this leads to a decrease in thalamic output to the cortex (thalamic inhibition). The net effect of the indirect pathway is to decrease activity of the thalamus and, consequently, decrease activity of the cerebral cortex.

This represents a simplified description of the basal ganglia motor loop and omits several pathways, such as those from the cortex to the subthalamus and from the subthalamus to the external segment of the globus pallidus. Nevertheless, it provides a basic framework for understanding the basal ganglia’s role in the extrapyramidal system. A delicate balance exists between the direct and the indirect pathways, with the former increasing thalamocortical activity (thalamic disinhibition) and the latter decreasing it (thalamic inhibition). It has been proposed that these two pathways may be involved with scaling or termination of movements.¹⁴ Striatal output would first inhibit GPi and SNr neurons via the direct pathway (facilitating movement), followed by disinhibition of the same neurons via the indirect pathway (terminating movement). Alternately, these pathways may be involved in the focusing of movements by simultaneously targeting separate populations of neurons in the GPi and SNr.¹⁵ Activity along the direct pathway would lead to inhibition of select GPi and SNr neurons, facilitating an intended movement, whereas activity along the indirect pathway would target surrounding neurons in the GPi and SNr, inhibiting unintended movements.

PD, whose hallmarks include bradykinesia, akinesia, and rigidity, is the most common and best understood disorder of the basal ganglia. The disease correlates with a loss of dopaminergic neurons in the SNc that project to the striatum. According to the DeLong model,¹⁶ this loss of dopaminergic input to the putamen leads to increased activity of the indirect pathway while decreasing activity along the direct pathway (Fig. 114-1B). The net effect of this change results in overexcitation of GPi and SNr neurons, which in turn increases their tonic inhibition of thalamocortical cells. This deficit of dopamine in the basal ganglia circuitry leads to the development of the cardinal symptoms of PD. Positron emission tomography studies in parkinsonian patients have demonstrated decreased activity in the supplementary motor area, dorsal prefrontal cortex, and frontal association areas that receive subcortical input from the basal ganglia.¹⁷

According to the DeLong model, the increased basal ganglia output causing PD is primarily due to overactivity of the STN and GPi. As such, these nuclei have become the surgical targets for the treatment of PD. Ablation of the GPi ¹⁸ and more recently the STN¹⁹ has been shown to ameliorate many cardinal symptoms associated with the disease. The effects of such ablations in regard to the DeLong model can be seen in Fig. 114-1C and D. Recent surgical treatments have focused on the use of DBS in these nuclei to reduce their overactivity.

Tremor

The pathophysiologic basis of tremor is less well known. Animal models of PD, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–treated monkeys, rarely exhibit significant tremor, and no animal model exists for essential tremor (ET). In humans, tremor can manifest in a variety of conditions, with the most common being PD and ET. Tremor may also been seen in the setting of various injuries or insults to the central nervous system. These secondary tremor disorders, which often are associated with other neurologic deficits, include multiple sclerosis, cerebrovascular accident, and traumatic brain injury. The characteristics of the tremor vary by disease process. Parkinsonian tremor occurs at rest and has a frequency of 4 to 5 Hz. In contrast, ET is primarily a postural and/or action tremor with a slightly higher frequency. Secondary tremors (e.g., multiple sclerosis and traumatic brain injury) tend to be both postural and kinetic, have high amplitude with low frequency, and often affect the proximal limb as much as the distal. Interestingly, despite the varying etiologies and presentations, the same operations tend to benefit all types of tremor; the consensus is to target the Vim of the thalamus for ablation or high-frequency stimulation.

The Vim has been extensively mapped using MER during thalamic procedures. Two subsets of tremor cells have been identified: kinesthetic cells, which simply fire in response to somatotopographically organized contralateral movements, and autonomous tremor cells, which fire synchronously with the tremor.²⁰ Tremor cells can also be found in other brain structures, such as the GPi and STN, but their relationship to thalamic tremor cells is unclear. The Vim does not receive direct projections from the GPi and appears to receive principally cerebellar input. It has been proposed that Vim thalamotomy or thalamic stimulation may be targeting pallidal outflow fibers en route to other thalamic regions.²¹ Cells discharging at rates similar to the tremor have been identified in regions of the thalamus that receive input from the basal ganglia.²² The increased inhibition on the thalamus from GPi and SNr in parkinsonian patients may promote bursts in thalamocortical cells,²³ and periodic bursting of the reticular nucleus during periods of immobility may enhance this rhythmic oscillation.

Dystonia

Dystonia is a heterogeneous condition characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The age of onset reveals a bimodal distribution, with modes at 9 and 45 years and a nadir at 27 years.²⁴ Various schemes have been proposed for its classification, including (1) age of onset (early onset or late onset), (2) distribution of affected body regions (focal, segmental, multifocal, or generalized), and (3) etiology (idiopathic, genetic, or secondary). Although 15 subtypes of dystonia can be distinguished genetically, the most common mutation is the deletion of a GAG triplet from the DYT1 gene.²⁵ It is likely that many dystonias currently classified as idiopathic will also have a genetic basis. The causes of secondary dystonia are numerous and include vascular insults, trauma, Wilson’s disease, Huntington’s disease, tardive dystonia, and demyelination.

Dystonia is a hyperkinetic movement disorder whose pathophysiology is best appreciated in relation to the aforementioned sensorimotor circuit of the basal ganglia. Although the lack of a suitable primate model has limited investigations into the circuit abnormalities, available data indicate that dystonia and PD are roughly similar with regard to their indirect pathway overactivity. However, in contrast to PD, the direct pathway appears to be overactive in dystonia, resulting in a net reduction in GPi activity and subsequent increases in thalamocortical activation (Fig. 114-1E). Reductions in the mean discharge rates in the GPi have been reported in humans with dystonia.²⁶ Based on the previous models of hyperkinetic movement disorders, we could not have predicted that GPi lesions (pallidotomy) would improve dystonia; rather, we would have predicted that GPi lesions would make dystonia worse. Yet ample evidence exists that pallidotomy (and pallidal stimulation) improve symptoms in dystonic patients.²⁷ Because of this, it is unlikely that alterations in firing rates alone explain the benefits of pallidotomy. The patterning and synchrony of the discharge, rather than the frequency alone, are pathophysiologically relevant to dystonia and explain the improvement following pallidotomy or GPi DBS.²⁸

Physiologic Effects of Stimulation

Despite its use for more than 20 years, much is still unknown about the in vivo mechanism of action for DBS. Four theories have been proposed to explain the effects of the stimulation: (1) depolarization blockade, (2) synaptic inhibition, (3) synaptic depression/depletion, and (4) stimulation-induced modulation of pathologic neural networks. Because high-frequency stimulation has demonstrated clinical effects comparable with lesioning, it has been postulated to exert its effect via a depolarizing blockade or synaptic inhibition of the cells within the target nucleus. The limitation of these first two theories is that they do not take into account the possible independent activation of the efferent axon of local cells or the axons of remote cells traversing the area of stimulation.

In the region of stimulation, three general classes of neurons can be affected: local cells, afferent inputs, and fibers of passage. Based on animal data, average stimulation currents used in DBS may affect the preceding neural elements for a distance of 2 to 5 mm from the active cathode.²⁹ During stimulation, the firing of the cell body is not necessarily representative of the efferent output via the axon. Work by Holsheimer et al.³⁰ and Mclntyre and Grill³¹ would suggest that, at the pulse widths and amplitudes used in DBS, stimulation is likely affecting myelinated axons as opposed to cell bodies. Fibers running parallel to the direction of the stimulating current would be preferentially activated as opposed to those running transversely. In addition, given the short refractory period of myelinated axons, frequencies in the 100- to 200-Hz range are unlikely to inhibit conduction. Using a primate model of PD, Hashimoto et al.³² demonstrated that stimulation of the STN produced short-latency excitatory responses that increased the average firing rate and altered the pattern of neuronal activity in both the GPi and the GPe. These results would seem to argue against stimulation-induced blockade in the target nucleus.

Likewise, the theory of synaptic depression due to neurotransmitter depletion has been called into question. in vivo experiments have shown increases in neurotransmitter release and changes in firing of efferent nuclei consistent with activation of neurons around the electrode and subsequent synaptic action on their targets during stimulation.^32,³³ Given the similar effects of ablation and DBS, it was not unreasonable to assume that stimulation had an inhibitory effect on the target nucleus. However, there appears to be mounting evidence that the effects of DBS are not due to depolarizing blockade, synaptic inhibition, or synaptic depression.

Thus, although it appears that DBS preferentially stimulates axons, the ultimate effect that it produces is difficult to predict. The variable volume of the neuropil that is affected by stimulation further confounds this. However, work done by Deuschl et al.³⁴ and Vitek and Giroux³⁵ suggests that the effects are generated by altered firing patterns, increased neuronal synchronization, and low-frequency rhythmic oscillation of neurons within the basal ganglia and thalamus. While ablation and DBS result in similar therapeutic benefits, it is likely that they achieve their results through very different mechanisms.