Brain stimulation: current applications and future prospects

Thalamus & Related Systems 1 (2001) 255–267

Brain stimulation: current applications and future prospects Alon Y. Mogilner a , Alim-Louis Benabid b , Ali R. Rezai c,∗ a

b

Department of Neurosurgery, New York Medical College, Valhalla, New York, NY, USA Department of Neurosurgery, Université Joseph-Fourier-INSERM, 38043 Grenoble, France c Department of Neurosurgery, S/80 Center for Functional and Restorative Neuroscience, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA Accepted 2 October 2001

Abstract Advances in the neurosciences and functional neurosurgery have led to a renaissance in the use of brain stimulation technology. A number of intractable neurological disorders can now be safely and successfully treated with brain stimulation. Although this technique was first performed over 50 years ago, it has only now begun to reach its vast clinical potential. This article will provide a historical overview of brain stimulation, describe state-of-the-art clinical applications, and discuss future prospects in this rapidly advancing field. © 2001 Published by Elsevier Science Ltd. Keywords: Electrical stimulation; Deep-brain stimulation; Thalamus; Globus pallidus; Subthalamic nucleus

1. Introduction We are now entering a new era in the use of brain stimulation techniques to treat a variety of neurologic and psychiatric disorders. While functional neurosurgery has traditionally involved lesioning of the nervous system, brain stimulation provides a reversible and adjustable means of obtaining similar or improved clinical results with less morbidity. The dramatic clinical effects of brain stimulation in the treatment of movement disorders has spurred renewed interest in the use of this technology for the treatment of chronic pain, epilepsy, psychiatric disorders, and other emerging areas. Although first performed over 50 years ago, a number of factors have propelled this technology to the forefront of functional neurosurgery. Improvements in imaging, stereotactic surgical targeting and navigation allow us to target the nervous system with millimeter precision and increased safety. Advances in neurophysiology, ranging from improved understanding of single-cell physiology to functional imaging studies, have helped elucidate the pathophysiology and the circuitry underlying a number of disease states and are providing new targets for intervention. Finally, current stimulation devices allow for precise tailoring of stimulation

∗ Corresponding author. Tel.: +1-216-444-8001; fax: +1-216-444-1015. E-mail address: [email protected] (A.R. Rezai).

1472-9288/01/$ – see front matter © 2001 Published by Elsevier Science Ltd. PII: S 1 4 7 2 - 9 2 8 8 ( 0 1 ) 0 0 0 2 4 - 3

parameters to maximize clinical benefit while minimizing complications.

2. Historical overview The first therapeutic use of brain stimulation was by Pool (1954) of Neurological Institute, Columbia University, who considered brain stimulation as an alternative to the ablative psychosurgical procedures of his era. In 1948, via the traditional open craniotomy, Pool implanted a silver electrode in the caudate nucleus of a woman suffering from depression and anorexia, who, incidentally, suffered from advanced Parkinson’s disease. Electrical stimulation via an implanted induction coil was carried out over a period of 8 weeks, and improved her mood as well as her appetite. Similar psychiatric neurosurgical procedures began to be performed by others, most notably by Heath (1954) at Tulane University, starting in 1950. During the same time period, another technical development in neurosurgery significantly influenced the evolution of brain stimulation. Stereotactic neurosurgery, introduced by Spiegel et al. (1947), offered a less invasive and more precise alternative to open neurosurgical ablative procedures pioneered by Moniz in Portugal for the treatment of psychiatric and movement disorders. It soon became evident that this technology was well suited for the placement of stimulating electrodes into the brain (Spiegel and Wycis, 1961)

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with decreased risk to the patient as compared to traditional open procedures. Consequently, the histories of brain stimulation and stereotactic neurosurgery became inextricably linked. Stereotactic lesioning of subcortical structures including the thalamus and globus pallidus were the only available treatment options for Parkinson’s disease until the advent of levodopa in the late 1960s. Electrical stimulation of these targets was routinely performed prior to placement of a lesion, both to verify the efficacy of the planned lesion as well to detect any adverse side effects (Spiegel and Wycis, 1961). Hassler et al. (1960), and Hassler (1966) had reported his observations that electrical stimulation of the globus pallidus had opposite effects on tremor, depending on the frequency of stimulation. Stimulation at lower frequencies was noted to evoke tremor, while higher frequency stimulation could reduce or even arrest it. Spiegel et al. (1960) reported that low frequency stimulation of the globus pallidus could elicit or augment tremor. As neurosurgery for psychiatric disorders fell out of favor by the 1960s, chronic pain became the sole indication for brain stimulation. The advent of levodopa for the treatment of Parkinson’s disease in the late 1960s resulted in a significant reduction in the number of functional neurosurgical procedures, although such procedures continued to be performed by a handful of neurosurgeons throughout the world. The modern era of stimulation for movement disorders began in the late 1980s, when Benabid et al. (1987) reported the use of high-frequency (130 Hz or greater) ventralis intermedius (Vim) thalamic stimulation for the treatment of tremor. As the use of brain

Table 1 Current stimulation targets for various disease states Condition

Stimulation targets

Movement disorders: Tremor

Ventral intermediate nucleus of thalamus (Vim)

Parkinson’s disease

Ventral intermediate nucleus of thalamus (Vim) Subthalamic nucleus (STN) Globus pallidus internus (Gpi)

Dystonia

Ventral intermediate nucleus of thalamus (Vim) Globus pallidus internus (Gpi)

Chronic pain

Ventralis caudalis nucleus of thalamus (VC) Periacqueductal/periventricular gray (PAG/PVG) Medial lemniscus (ML) Internal capsule (IC) Motor cortex (MC)

Epilepsy

Centromedian nucleus of thalamus (CM) Anterior nucleus of thalamus (AN) Subthalamic nucleus (STN)

Psychiatric disorders

Internal capsule (IC) Cingulate gyrus

Brain injury states

Intralaminar nucleus of the thalamus (IL) Midbrain reticular formation (RF)

stimulation for the treatment of movement disorders has now become part of mainstream neurosurgical practice, other indications and stimulation loci for treatment of chronic pain, epilepsy, and psychiatric disorders have been revisited.

Fig. 1. Quadripolar DBS electrode. Photograph of the four pole/contact electrode. Each contact is made of platinum/iridium alloy and is 1.5 mm in length and 1.27 mm in diameter. The insulated inter-pole distance is 1.5 mm or 0.5 mm depending on the model (courtesy of Medtronic).

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3. Clinical indications and modern stimulation devices A summary of the common clinical indications for brain stimulation is provided in Table 1. Patients who are disabled with a significant compromise in quality of life despite optimal medication therapy are candidates for deep-brain stimulation surgery. While the treatment of tremor and Parkinson’s disease is the most common indication for brain stimulation and has the most robust clinical outcome data, an increasing number of disease states are being treated with this technology. The devices used for brain stimulation, also referred to as “pacemakers for the brain”, are manufactured by Medtronic Inc. (Minneapolis, MN, USA.) The electrode used, known as a “deep-brain stimulating” or DBS electrode, is a 1.27 mm diameter quadripolar platinum/iridium lead (Fig. 1). Each of the four contacts is 1.5 mm long, and, depending on the model of the electrode, is separated by either 0.5 or 1.5 mm of insulation. The electrode is connected via an extension lead tunneled subcutaneously to an implanted pulse generator (Fig. 2A and B). Stimulation can be unipolar, bipolar or multipolar, as each of the electrode contacts can be used as an anode or cathode providing a variety of different electrical field patterns. Stimulation parameters include frequency ranges of 2–185 Hz, voltage range of 0–10.5 V, and square wave pulse widths ranging from 60 to 450 ␮s. The stimulators is programmed via a portable device which communicates with the implanted generator via telemetry. Stimulation can be performed continuously or intermittently, and can be programmed to cycle ‘on’ and ‘off’ during fixed time intervals. Patients are able to activate and deactivate the stimulator via handheld controllers, and can modify a subset of the stimulation parameters within given limits set by the medical team.

4. Mechanisms of action The exact mechanism of action of brain stimulation remains unknown. Most likely, brain stimulation exerts its effects via a number of differing but interrelated mechanisms which come in to play depending on the site being stimulated, the disease entity being treated, and the stimulation parameters used. Undoubtedly, the clinical effects seen with brain stimulation reflect the complex combination of inhibition and activation of cell bodies and axons, and depend on the orientation of the electrode, the cytoarchitecture of the structure being stimulated as well as the frequency, pulse width, and duration of stimulation. The similar clinical effects of high-frequency stimulation (HFS) and lesioning of the Vim thalamus and globus pallidus in man, as well as of the subthalamic nucleus (STN) in animal models, strongly suggest that HFS effects a reversible inhibition of the target structure being stimulated

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(Benabid et al., 1998). Indeed, a recent in vitro study in the rat demonstrated that high-frequency (100–250 Hz) stimulation of STN resulted in a transient blockade of the persistent sodium current as well as L- and T-type calcium currents (Beurrier et al., 2001). The terms “depolarization blockade” or “functional lesion” have been used in this regard to describe the effects of HFS but are currently only hypotheses about the intimate mechanism which has still to be deciphered, whether it has one or several components. While simple inhibition can be used to understand the similar clinical effects of HFS to lesioning in selected cases, it cannot explain the beneficial effects of HFS in situations such as globus pallidus (Gpi) stimulation for dystonia. The Gpi in dystonia is clearly hypoactive, in sharp contrast to the hyperactivity of Gpi seen in Parkinson’s disease. Nonetheless, chronic high-frequency stimulation of Gpi is beneficial in dystonia. It has been suggested that HFS, rather than simply inhibiting a hyperactive structure, acts via as a resynchronization of abnormal output patterns present in disease (Montgomery and Baker, 2000; Vitek, 1998), or via a “jamming” of these abnormal patterns by HFS acting as a blank noise. This could also mimic the effects of ablative procedures, the results of which are to suppress abnormal firing patterns. Furthermore, Benabid has recently suggested that high-frequency stimulation may have opposing effects on structures being stimulated, depending on that structure’s cellular architecture. Stimulation of structures composed mainly of cell bodies such as nuclei or ganglia results in inhibition of those structures, while stimulation of fiber bundles results obviously in excitation (Benabid et al., 2000), as observed in the operating room where HFS of internal capsule, medial lemniscus and optic tract as well as third nerve fibers results in symptoms (contractions, paresthesias, visual flashes and ocular deviations) consistent with activation of these structures. The mechanism of action of low-frequency stimulation (LFS), used currently for pain control as well as certain instances of refractory epilepsy, is even more enigmatic. LFS of the sensory thalamus results in pain relief while inducing paresthesias similarly to what happens during stimulation of the dorsal columns of the spinal cord, while LFS of the motor cortex affords pain relief at stimulation thresholds below those of inducing motor activity. Moreover, LFS is occasionally effective in the treatment of tremor and other movement disorders, seemingly when it is applied to the sensory-motor thalamus in cases of abnormal movements of the stump in cases of phantom limb pain (Mazars et al., 1980). Overall, there is a crucial necessity for further research in understanding the mechanisms of action of brain stimulators.

5. Surgical procedure Modern stereotactic techniques combine multiple imaging modalities, physiological mapping and high speed surgical navigation computers, to allow for targeting of any

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Fig. 2. Pulse generator and DBS electrode. (A) Photograph of the pulse generator device which is implanted in the infraclavicular region. (B) Photograph showing the overall configuration/positioning of the implanted bilateral electrodes and pulse generators.

intracranial structure with millimeter precision. Subcortical nuclei such as the Gpi, STN, and thalamus are routinely localized during functional surgical procedures. Anatomic localization is achieved with stereotactic imaging via MRI, CT and ventriculography. Advances in image processing

technology allow for rapid, automated fusion of different imaging modalities. For example, multiple high-resolution MRI scans obtained prior to stereotactic frame placement can be fused with a CT scan obtained with the frame in place, allowing for both increased patient comfort as well

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as removing any potential MRI image distortion induced by the frame. In addition, stereotactic atlases, in which cadaver brains were sliced and oriented with respect to landmarks such as the anterior and posterior commissures (Andrew and Watkins, 1969; Morel et al., 1997; Schaltenbrand and Bailey, 1959; Schaltenbrand and Wahren, 1977; Talairach et al., 1957), can be “morphed” to a particular patient’s anatomic imaging data, allowing for further increased ease of target selection. Patient-specific segmentation algorithms are further advancing anatomical localization capabilities (Fig. 3). The routine use of intraoperative physiological mapping has been instrumental in the growth of functional neurosurgery. A number of methods of intraoperative physiologic verification of the anatomical target exist: microelectrode recording (MER), semimicroelectrode recording, and macrostimulation. Both microelectrode and semimicroelectrode recording attempt to define the boundaries of a given structure based on the known spontaneous and/or evoked electrical activity of that structure and surrounding structures. The latest image-guided systems allow real-time visualization of both anatomic and physiologic data during the course of a recording trajectory, providing further confirmation of target localization (Fig. 4). Macrostimulation, stimulation through a relatively large diameter electrode

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Fig. 3. Patient-specific segmentation atlas. Three-dimensional reconstruction of the thalamus, subthalamic nucleus and the basal ganglia in a patient using patient-specific segmentation atlas.

Fig. 4. Computer-guided brain targeting and navigation. Operative computers combine different imaging modalities such as CT and various MRI sequences, along with brain and patient-specific atlases, to provide the target and best trajectory of approach to that target. In this case, an actual path in the brain is shown in the axial, sagittal, coronal and three-dimensional planes, toward the target—the subthalamic nucleus—in a patient with intractable epilepsy.

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(on the order of 1 mm diameter), is used in all DBS cases prior to final implantation of the electrode. Macrostimulation allows the physician to assess for both the therapeutic effects of stimulation (reduction of tremor, rigidity, or pain), as well as for possible untoward effects (i.e. paresthesias, motor contractions, ocular deviation). As the stimulation parameters used during this testing phase are usually similar to those which will be used for chronic stimulation, macrostimulation should approximate the effects of chronic therapy.

6. Brain stimulation for movement disorders As mentioned previously, the effects of electrical stimulation of the thalamus and globus pallidus have been recognized since the dawn of stereotactic movement disorder surgery (Hassler, 1966; Hassler et al., 1960; Spiegel et al., 1960). The first systematic use of chronic deep-brain stimulation for the treatment of movement disorders is attributed to Bechtereva et al. (1972a,b, 1975a,b). A total of 24–40 gold electrodes in four to six bundles were implanted stereotactically into the thalamus, striatum, and pallidum (more specific locations were not given). Therapeutic stimulation consisted of 30–40 trains of 3–5 s bursts at 50 Hz, with a 1 min interstimulus interval. Stimulation sessions were held once or twice a week. In some patients, multiple brain sites were stimulated simultaneously. They reported successful therapeutic effects, lasting for up to 3 years, in patients with Parkinson’s disease, Wilson’s disease, and torsion dystonia, although detailed outcome measures and complications were not provided. Stimulation of the cerebellar cortex for control of movement disorders was first performed by Cooper et al. (1976a,b), with the rationale that increased inhibitory output from cerebellar Purkinje cells could treat a number of neurologic conditions thought to be caused by a disinhibition of motor or behavioral activity. Stimulation frequency was 200 Hz. He applied this technique in 141 patients with cerebral palsy, and found that overall condition, defined to include a variety of symptoms and functional assessments, was improved moderately to markedly in 46% of patients. Vim thalamic stimulation for the treatment of movement disorders was performed by Cooper starting in 1976, reporting his initial results in 1980 and long-term follow-up of 49 patients in 1982 (Cooper et al., 1980, 1982). Stimulation was performed at a frequency of 70 Hz with 500 ␮s pulses. 55% of patients experienced useful improvement (defined via a combination of clinical exam, gait evaluation, video evaluation, and somatosensory evoked potentials) with thalamic stimulation. Further reports surfaced in the early 1980s describing the beneficial effect of chronic stimulation for the treatment of movement disorders. Again, however, these isolated case reports lacked systematic descriptions of clinical indications, exact target locations,

consistent stimulation parameters, as well as objective clinical outcome. 6.1. Thalamic stimulation for tremor It can be said that the modern era of deep-brain stimulation for movement disorders began in 1987, when Benabid et al. (1987) began the systematic use of chronically implanted Vim electrodes for long-term tremor control in patients with Parkinsonian and essential tremor. Benabid et al. (1987, 1989) initial reports suggested that chronic Vim stimulation may be useful in those patients who have already undergone unilateral thalamotomy with persistent symptoms on the non-operated side. As bilateral thalamotomy is associated with increased morbidity including speech dysfunction (Louw and Burchiel, 1998), a contralateral non-destructive thalamic procedure was envisioned as appropriate. Benabid was one of the first to recognize the importance of high-frequency stimulation (130 Hz or greater) for a consistent beneficial effect. At the present time, Vim thalamic DBS has been well-established as a safe and effective modality for the treatment of Parkinsonian and essential tremor of the upper extremity, with equal efficacy to thalamotomy but with fewer complications. Approximately 80–90% of patients with Parkinson’s disease and essential tremor obtain significant benefit from the procedure (Benabid et al., 1996, 1998; Koller et al., 1997; Limousin et al., 1999; Schuurman et al., 2000). The mechanism of action of Vim DBS is thought to be similar to that of thalamotomy, which, in turn, is thought to reflect the interruption of a cerebellar–thalamic-motor cortical circuit or of a spino–thalamo–cortico–spinal circuit. Positron emission tomography (PET) studies of Vim stimulation have consistently demonstrated a decrease in contralateral cerebellar metabolic activity (ipsilateral to the side of the tremor) with Vim stimulation. A reduction in primary sensorimotor cortex as well as premotor cortex activity was seen in one study (Davis et al., 1997; Deiber et al., 1993; Parker et al., 1992). These findings suggest that one of the mechanisms of action of Vim DBS is via a suppression of activity in a cerebellar–thalamic-motor cortex circuit, although a reduction of the cerebellar evoked activity by the stimulation-induced reduction of tremor cannot be ruled out. A single MRI study revealed an increase in activity in lateral thalamus, Gpi, and primary somatosensory cortex ipsilateral to the side of stimulation (Rezai et al., 1999). 6.2. Globus pallidus stimulation for Parkinson’s disease Given the known beneficial effects of lesioning of the posterior ventral globus pallidus in alleviating many of the cardinal symptoms of Parkinson’s disease including rigidity, bradykinesia, gait dysfunction, tremor, as well as reducing the severity of levodopa-induced dyskinesias (Laitinen et al., 1992), the Gpi became the next target for chronic

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stimulation. Gpi stimulation is currently used by a number of centers for the treatment of refractory Parkinson’s disease, with beneficial effects on these cardinal manifestations of PD and reduction in dyskinesias similar to that obtained by pallidotomy. The discovery of the effects of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) in inducing a Parkinson’s disease-like state in humans as well as in primate models has allowed for dramatic advances in our understanding of normal and pathological basal ganglia functional anatomy (Lozano and Lang, 1998; Wichmann and DeLong, 1998). A reduction in dopaminergic output from the Substantia nigra pars compacta results in increased activity in the Gpi, which thus exerts an increased inhibition on its downstream targets including thalamus and cortex. Thus, inactivation of the Gpi should ameliorate Parkinsonian symptomatology. Functional imaging studies of Parkinson’s patients have demonstrated a hyperactivity of the lentiform nucleus, consistent with these assumptions. Improvement following pallidotomy has been correlated with a post-operative decrease in lentiform hypermetabolism, as well as increases in supplementary motor cortex activity (Eidelberg et al., 1996, 1997). A PET study of Gpi stimulation have demonstrated increased regional cerebral blood flow (rCBF) to the ipsilateral supplementary motor area and putamen/Gpi, consistent with a restoration of cortical motor activity following deactivation of the overly inhibitory Gpi (Davis et al., 1997).

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6.3. Subthalamic nucleus stimulation for PD Unlike the Vim thalamus and globus pallidus, the STN was previously not considered for stereotactic lesioning procedures in Parkinson’s disease. This was due to fear of causing hemiballism, a well-documented effect of STN lesions in previously normal individuals (Lee and Marsden, 1994) experiencing intracerebral hemorrhage in this area. The impetus for targeting the subthalamic nucleus resulted from a number of studies in the MPTP-lesioned primate model of PD, beginning in the midlate 1980s. Whereas initial studies suggested a hypoactivity of STN in PD (Crossman et al., 1987), later studies confirmed the opposite, i.e. an increased glutaminergic (excitatory) STN output in Parkinson’s. After STN lesions in MPTP-treated monkeys were clearly demonstrated to alleviate the symptoms of PD (Aziz et al., 1991, 1992; Bergman et al., 1990a,b), in 1993 Benabid implanted a stimulating electrode in the STN of a 51-year patient with severely disabling akinetic-rigid PD with severe on–off fluctuations (Pollak et al., 1993). Chronic high-frequency stimulation at 130 Hz resulted in alleviation of contralateral akinesia without inducing any dyskinesias. Since that time, the STN is increasingly becoming the preferred target for chronic electrical stimulation in PD at most centers (Fig. 5), effective in treating the cardinal manifestations of the disease, with improvements in motor function of approximately 60% using the standardized UPDRS rating scale.

Fig. 5. Post-operative MRI. Post-operative sagittal T1 MRI demonstrating the implanted DBS electrode in the subthalamic nucleus of a patient with Parkinson’s disease.

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Furthermore, levodopa intake is reduced following surgery by approximately 50%, resulting in a significant decrease in drug-induced dyskinesias (Krack, et al., 1997a,b; Limousin et al., 1995a,b, 1998; Pollak et al., 1996). The presumed mechanism of action of STN stimulation is a deactivation of the hyperactive STN, and a concomitant reduction of the excitatory output from STN to both Gpi and SNr. PET studies of STN stimulation have demonstrated activation of the supplementary motor area (SMA) and the dorsolateral prefrontal cortex, also consistent with a functional disinhibition provided by STN stimulation. While the Vim thalamus is clearly the stimulation target for non-Parkinsonian tremor, i.e. essential tremor (Hubble et al., 1996, 1997), the optimal surgical target for Parkinson’s disease is still a subject of debate. In those patients with tremor-predominant PD, thalamic stimulation is clearly efficacious in relieving tremor. Since, however, PD involves a spectrum of symptoms including rigidity, akinesia, bradykinesia, drug-induced dyskinesias, as well as tremor, a more appropriate target may be STN or Gpi which can treat all PD symptoms, particularly as symptoms progress over time. 6.4. Other movement disorders Dystonia, defined as an abnormal sustained contraction of various body parts usually involving both agonist and antagonist musculature, encompasses a heterogeneous group of disorders. It can be present without a known cause (primary or idiopathic dystonia), or may be secondary to events such as trauma, anoxia or metabolic, toxic or pharmacologic insults. It may be focal, involving a localized group of muscles, or generalized. Clearly, the heterogeneous nature of this disease suggests varying etiologies and thus would necessitate varying treatment strategies. It comes as no surprise, therefore, that a variety of surgical interventions, including lesioning and stimulation of the thalamus and globus pallidus, have been attempted for the treatment of dystonia, with varying results (Vitek, 1998). Neurophysiologic studies performed during ablative procedures for dystonia have demonstrated abnormal activity in the Gpi, as well as motor thalamus (Lenz et al., 1998, 1999; Vitek, 1998; Vitek and Giroux, 2000; Vitek et al., 1999). Pallidal firing rate was decreased, and the overall firing pattern highly irregular, in patients with generalized dystonia. Despite this decreased pallidal activity, interventions which block Gpi activity such as pallidotomy and pallidal stimulation are clinically effective in some forms of dystonia, suggesting that a removal of abnormal patterns of neuronal activity, rather than a complete abolition of activity, can improve dystonia. Recent reports have demonstrated the efficacy of deep-brain stimulation of the thalamus and Gpi for various forms of dystonia, with more beneficial effects on primary and generalized dystonias as opposed to secondary and focal dystonias (Islekel et al., 1999; Krauss et al., 1999;

Kumar et al., 1999; Lozano et al., 1997; Sellal et al., 1993; Thompson et al., 2000; Tronnier and Fogel, 2000). Vandewalle recently reported relief of motor tics in a patient with Tourette’s syndrome with bilateral medial thalamic deep-brain stimulation (Vandewalle et al., 1999). Undoubtedly, with increasing use of the technique, emerging applications of DBS for other movement disorders will surface.

7. Brain stimulation for chronic pain Unlike the history of stimulation for movement disorders, the history of brain stimulation for chronic pain is filled with initial promising reports of a particular technique, followed by frequent disappointment upon careful review of results and outcomes. The early literature is marred by a dearth of systematic patient selection criteria, target selection, surgical technique, and long-term objective outcome reporting. The increasing use of brain stimulation for movement disorders, however, will assure that the technology to perform these procedures will be routinely available, and may thus result in a return to favor of some of these procedures. Alternatively, the increasing use of motor cortex stimulation may well obviate the need for subcortical stimulation procedures for pain control. 7.1. Subcortical targets The initial use of brain stimulation for pain control by Pool, Heath and others targeted the so-called “affective” state of the individual and thus was viewed more as a psychosurgical intervention. Targets stimulated included the septal region, cingulate gyrus, and caudate nucleus. At the present time, however, two major subcortical targets are used for the treatment of refractory pain conditions—sensory thalamus (ventralis caudalis, VC), and periacqueductal/periventricular gray (PAG/PVG). Sensory thalamic stimulation, first reported by Mazars (1975), and Mazars et al. (1973, 1974) results in the production of paresthesias in the area of pain, associated with pain relief, similar to that obtained with stimulation of the dorsal columns of the spinal cord. The exact mechanism by which paresthesia-evoking thalamic stimulation results in pain relief is not known. One concept is that deafferentation causes an abnormal firing pattern in thalamic neurons and that thalamic stimulation inhibits this abnormal neural activity (Lenz et al., 1987; Lis-Planells et al., 1992; Rinaldi et al., 1991). Gerhart et al. (1983) showed that stimulation of the VPL in monkeys caused inhibition of spinothalamic neurons’ evoked responses to noxious cutaneous stimulation. Benabid et al. (1983) demonstrated that VPL stimulation inhibited the response of parafascicular nucleus (Pf) cells to noxious stimuli. Stimulation of the periacqueductal gray, first reported in 1969, provided yet another proposed pathway of analgesia,

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via a presumed opioid-related mechanism (Reynolds, 1969; Richardson and Akil, 1977a,b). PAG/PVG stimulation is indicated for pain classified as nociceptive, which is defined as pain caused by direct activation of the nociceptors (mechanic, chemical, and thermal) found in various tissues. Examples of nociceptive pain include cancer pain from bone or tissue invasion, or non-cancer pain secondary to degenerative bone and joint disease or osteoarthritis. This type of pain stands in contrast to neuropathic or deafferentation pain, which results from an injury or dysfunction of the central or peripheral nervous system. Examples include thalamic pain, stroke, traumatic or iatrogenic brain or spinal cord injuries, phantom limb or stump pain, post-herpetic neuralgia and various peripheral neuropathies. The sensory thalamus is usually considered a more appropriate target for neuropathic pain conditions. The overall long-term successful pain control reported in the literature with stimulation, is approximately 60% for nociceptive pain and 30–50% for neuropathic pain (Kumar et al., 1997). 7.2. Motor cortex stimulation One of the most promising recent developments in neurostimulation for pain control is that of epidural motor cortex stimulation (MCS), discovered rather fortuitously by Tsubokawa et al. (1991, 1993). Sensory cortical stimulation was attempted to treat central pain caused by CNS subcortical lesions, with the rationale that the sensory cortex represents the final station along the spinothalamic tract, and stimulation of the structurally intact cortex may somehow modulate the pain produced by subcortical injury. Interestingly, Tsubokawa et al. (1991, 1993) found that stimulation of the precentral motor cortex, rather than the somatosensory post-central cortex, resulted in effective pain relief. Stimulation was applied for 5–10 min at a time from five to seven times during the day, with frequencies of 50–120 Hz, pulse width 0.1–0.5 ms, and current <1 mA. Stimulation parameters were adjusted to be below the threshold for a motor response. The analgesic effects had a “halo” effect, lasting at times for hours after stimulation was discontinued. Stimulation of post-central somatosensory cortex did not provide pain relief in these patients, and actually exacerbated pain in a number of cases. An increasing number of groups are now reporting promising results with this technique. The largest series with the longest follow-up in the literature comprises 32 patients spanning a 4-year period, reported by Nguyen et al. (1999). A total of 10 of the 13 patients with central pain (77%) and 10 of the 12 patients with neuropathic facial pain had experienced substantial pain relief (75%). An increasing number of groups are now reporting promising results with this technique. At this time, the questions remaining to be answered include: indications for surgery, surgical technique, and optimal stimulation parameters to maximize long-term clinical benefit. Unlike paresthesia-producing (i.e. sensory thalamic stimulation), motor cortex stimulation

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does not usually induce paresthesias, making this technique ideal for double-blinded controlled studies. The mechanism of action of MCS is a subject of debate. While some have postulated that direct projections from motor cortex to sensory cortex can provide for a stimulation-induced modulation of abnormal sensory cortical activity present in pain states, others suggest that descending corticothalamic projections play an important role in the generation of analgesia (Peyron et al., 1995; Tsubokawa et al., 1991, 1993).

8. Brain stimulation-emerging areas 8.1. Epilepsy Initial attempts at seizure control using brain stimulation utilized stimulation of the cerebellar cortex. Cooper (1973a,b, 1978), and Cooper et al. (1976a,b, 1978) was the first to employ cerebellar stimulation for epilepsy. Cooper hypothesized that the massive inhibitory Purkinje cell outflow of the cerebellum could modulate abnormal cortical epileptogenic activity “as the pedals of a mighty organ modulate the output of its chimes”. Cooper et al. (1974) reported significant seizure reduction in 56% of patients, other clinical trials failed to demonstrate any benefit (Van Buren et al., 1978; Wright et al., 1984). Stimulation of the anterior nucleus of the thalamus for epilepsy was first reported by Cooper and Upton (1985), and Cooper et al. (1980). The rationale for choosing the anterior nucleus involved its important role in the limbic circuitry, receiving projections from the mammilary bodies and projecting to the hippocampus, amygdala, cingulate, orbitofrontal cortex, and caudate. It was thought that anterior nucleus stimulation would modulate abnormal epileptiform activity within the limbic system. Although exact details of the stimulation were not provided, he reported that in five of six patients with intractable seizures, anterior nucleus stimulation reduced seizures by more than 60% in five of six cases, with 30% average decrease in medication requirements. Velasco et al. (1987, 2000) (Mexico) were the first to employ bilateral centromedian (CM) nucleus stimulation for the treatment of epilepsy, and their long-term results in 13 patients were recently reported. Stimulation parameters were 60 Hz, 4–6 V, alternating right and left sides. With a mean follow-up of 41 months, they noted a significant decrease (defined as >80% seizure reduction) in the incidence of generalized tonic-clonic seizures and atypical absence seizures, but no change, in the incidence of complex partial seizures. Recent reports by Benabid et al. (2000) of seizure control following subthalamic nucleus stimulation, combined with confirmatory data in a rat model (Deransart et al., 1998a,b; Vercueil et al., 1998), suggest that the STN may be a future target for seizure control using brain stimulation. Preliminary results of anterior thalamic nucleus and STN DBS in humans have been encouraging. Several centers are

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performing long-term protocols for DBS of the STN and the anterior thalamic nucleus for intractable epilepsy. One area of future developments for DBS and epilepsy is the potential use of “closed-loop” systems which have sensing mechanisms coupled with the stimulation function. In this regard, future generation systems will be able to sense abnormal electrical activity similar to a cardiac pacemaker. 8.2. Psychiatric disorders Since 1948, when Pool treated psychiatric disorders with brain stimulation, there have been few reports of the use of brain stimulation to treat psychiatric conditions. While lesioning procedures including cingulotomy, capsulotomy, subcaudate tractotomy and limbic leukotomy have all been employed for the treatment of refractory obsessive-compulsive disorder (OCD) and, to a lesser degree, major affective disorder, chronic electrical stimulation of these lesioning targets has only recently been reported. Nuttin et al. (1999) placed quadripolar electrodes bilaterally in the anterior limbs of the internal capsules of four patients suffering from severe OCD. Beneficial effects were seen in three patients. A number of clinical trials with DBS for OCD and depression are underway. A recent report of transient depression induced by high-frequency stimulation of the Substantia Nigra pars reticulata (Bejjani et al., 1999), using the lower poles of an electrode placed for subthalamic nucleus stimulation, raise the intriguing possibility that STN and/or SNr stimulation may be a putative target for future intervention. 8.3. Eating disorders A long history of animal studies of hypothalamic function has elucidated two hypothalamic regions related to food intake: the ventromedial nucleus as a satiety center, and lateral nucleus as a hunger center (Anand and Brobeck, 1951a,b; Anand and Dua, 1955). Destruction of the ventromedial nucleus in animals leads to hyperphagia and obesity, while lesions of the lateral nucleus lead to weight loss. Over 25 years ago, Quaade et al. (1974) performed low-frequency stimulation of the lateral hypothalamic nucleus in morbidly obese patients as a prelude to electrocoagulation, without significant long-term benefit. Benabid et al. (2000) have reported preliminary work with both lateral and ventromedial hypothalamic stimulation in an animal model. Others are also beginning investigation of this potential application of brain stimulation.

centromedian) was noted to be effective in eliciting these responses in animals (Magoun, 1958). Based on these observations, a number of targets have stimulated in comatose patients in an attempt to increase their level of consciousness. The midbrain reticular formation, intralaminar thalamus, other thalamic nuclei, and the globus pallidus all have been stimulated with mixed results (Cohadon and Richer, 1993; Hassler et al., 1969; Sturm et al., 1979; Tsubokawa et al., 1990). Critical shortcomings of work in this field include a lack of a standardized classification scale, as well as a lack of a historical control group in any of these studies. The severe degree of brain damage in these groups of patients may preclude any means of functional recovery whatsoever with such procedures. A recent proposal to revisit intralaminar stimulation in a less severely disabled group of patients, described as minimally conscious (Schiff et al., 2000) appears promising. Since these patients may not be able to provide informed consent, ethical issues will most likely limit the number of these surgeries performed until that time where a strong multidisciplinary effort is made to address the use of these techniques in these patients (Fins, 2000).

9. Conclusions Functional neurosurgery involves close collaboration among neurosurgeons, neurophysiologists, neurologists, psychiatrists, and neuroradiologists. It is important to underscore that we are at the beginning of a newly emerging therapy—the era of neuromodulation. Advances in anatomical and functional imaging, improvements in device technology, coupled with an increased understanding of the pathophysiology of various neurologic disorders, have provided us with the ability to reversibly modulate the nervous system. It is now possible to treat a number of chronic and disabling neurologic disorders. However, much remains to be done. In order to ensure continued progress in this field, we need to have a better understanding of the pathophysiology of disease, as well as of the mechanism of action of brain stimulation at all levels ranging from single ion channels to systems physiology. Surgical techniques will continue to become safer and less invasive. There is a crucial need to develop next generation stimulation devices with combined closed-loop electrical and chemical sensing and output functions. Only with every-improving implantable devices and continued advances in our understanding of nervous system function and dysfunction will the future of this therapy be as fertile as our present optimism suggests.

8.4. Brain injury states The seminal work of Moruzzi and Magoun (1949) described the reticular activating system of the brainstem, an area which when stimulated evokes arousal responses and EEG desynchronization. Within the thalamus, stimulation of the midline projection nuclei (i.e. intralaminar and

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