MOVEMENT DISORDERS

SURGERY FOR MOVEMENT DISORDERS Ali R. Rezai, M.D. Center for Neurological Restoration, and MOVEMENT DISORDERS, SUCH as Parkinson’s disease, tremor, and dystonia, are Department of Neurosurgery, among the most common neurological conditions and affect millions of patients. Cleveland Clinic, Cleveland, Ohio Although medications are the mainstay of therapy for movement disorders, neurosurgery has played an important role in their management for the past 50 years. Surgery is now Andre G. Machado, M.D., Ph.D. a viable and safe option for patients with medically intractable Parkinson’s disease, Center for Neurological Restoration, and essential tremor, and dystonia. In this article, we provide a review of the history, neuro- Department of Neurosurgery, Cleveland Clinic, circuitry, indication, technical aspects, outcomes, complications, and emerging neuro- Cleveland, Ohio surgical approaches for the treatment of movement disorders. KEY WORDS: Deep brain stimulation, Dystonia, Essential tremor, Globus pallidus pars interna, Movement Milind Deogaonkar, M.D. disorders, Parkinson’s disease, Stereotaxis, Subthalamic nucleus, Ventralis intermedius nucleus Center for Neurological Restoration, and Department of Neurosurgery, Neurosurgery 62[SHC Suppl 2]:SHC809–SHC839, 2008 DOI: 10.1227/01.NEU.0000297003.12598.B9 Cleveland Clinic, Cleveland, Ohio

Hooman Azmi, M.D. Historical Perspective predominantly limited to thalamotomy (8, Center for Neurological Restoration, and arious surgical approaches, such as 115–117, 149, 167, 254, 275, 343) for the treat- Department of Neurosurgery, resection, lesioning, stimulation, and ment of tremor and pallidotomy and thalamo- Cleveland Clinic, tomy for dystonia (224, 341, 371, 383). PD sur- Cleveland, Ohio others, have been used to treat patients V gery was rarely performed during this time. It with movement disorders. Craniotomies were Cynthia Kubu, Ph.D. performed for the resection of the motor cortex was not until the late 1980s that there was a Center for Neurological Restoration, and (68), cerebral peduncles (381, 382), and a vari- reemergence of interest in the neurosurgical Department of Psychiatry, ety of subcortical lesioning procedures (326). treatment for PD due to the increasing realiza- Cleveland Clinic, Irving Cooper (72a) first reported the effects of tion of the limitations of PD medications and Cleveland, Ohio ligation of the choroidal artery for Parkinson’s the side effects of L-dopa. This led to a resur- gence of lesioning surgeries such as pallido- Nicholas M. Boulis, M.D. disease (PD) in 1953. Six patients were treated tomies for PD. The initial Leksell (336) target of Center for Neurological Restoration, and with eight ligations, which resulted in signifi- Department of Neurosurgery, cant alleviation of rest tremor, rigidity, and pallidal lesions for treatment of PD was modi- Cleveland Clinic, contralateral cogwheeling. It was not until the fied and repopularized by Laitinen et al. (196, Cleveland, Ohio introduction of stereotaxis by Spiegel et al. 197). Original analytical descriptions of thala- (328) in 1947, and later by Leksell (206) in 1949, mic nuclei and circuitry by Hassler (142), Reprint requests: Hassler et al. (143), and Macchi and Jones (230) Ali R. Rezai, M.D., that a more accurate, less invasive, and more Center for Neurological Restoration, consistent placement of lesions in various sub- and basal ganglia circuitry by Delong et al. (81, 9500 Euclid Avenue, Desk S31, cortical locations became feasible. 82) also served as a foundational substrate for Cleveland OH 44122. The development of stereotaxy led to a vari- newer targets for therapeutic interventions Email: [email protected] ety of lesioning procedures of the basal ganglia using stereotactic techniques. The ability of electrical impulses to modify Received, May 30, 2007. and the thalamus for the treatment of rigidity functional outcome in certain brain regions Accepted, November 1, 2007. and tremor in the 1950s and 1960s. Various sur- gical techniques, lesion locations, lesion sizes, was identified almost 200 years ago, in 1809, and outcomes were reported (77, 256, 327, 392). by Rolando (98). Aldini had previously ONLINE The motor thalamus and the pallidal targets attempted to stimulate the brains of executed DIGITAL criminals immediately after death by applying VIDEO lying in the ventral and posterior portions of the globus pallidus internus (GPi) as well as current from voltaic piles (98). The use of elec- the pallidal projections were considered to be trical stimulation to understand and map the the most effective targets. However, it was the function of the human brain and its circuitry advent of L-dopa in the mid-1960s and its sig- became commonplace in the 20th century (4, nificant clinical benefits that led to a dramatic 64, 65, 291). Early explorations by Hassler et al. decrease in surgery for PD. For the next 20 revealed that acute low-frequency stimulation years, surgery for movement disorders was during stereotactic exploration for ablation of

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the pallidum could augment tremor, whereas high-frequency neurocircuitry of PD and other movement disorders (2, 29, 39, stimulation at 25 to 100 Hz had the opposite effect (143). These 41, 53, 56, 62, 83, 99, 120, 133, 135, 144, 152, 204, 205, 209, 223, observations paved the way for the future development of 234, 239, 241, 246, 248, 249, 262, 273, 283, 292, 320, 325, 332, 340, chronic electrical stimulation therapies for the management of 343, 385, 391). These data provided support for the concept of movement disorders. the cortico-striatal-pallidal-thalamic-cortical (CSPTC) circuits. The first systematic use of chronic deep brain stimulation Alexander et al. (7) hypothesized that a network of five parallel, (DBS) for the treatment of movement disorders is attributed to segregated circuits exists that underlies a variety of functions. Bechtereva et al. (22) in Russia. Beginning in 1967, they These circuits originate in various regions of the frontal lobes reported benefits with chronic DBS of the thalamus, striatum, and then traverse through different nodes in the striatum, pal- and pallidum. But it was not until the 1980s that Brice and lidum, and thalamus before returning to their cortical points of McLellan (54), Blond and Siegfried (52), Siegfried and Shulman origin. One of these circuits underlies complex motor function (319), and Benabid et al. (34, 36) published reports of the use of and is implicated in the pathophysiology of PD. chronic electrical stimulation or DBS for the treatment of move- The concept of a CSPTC motor circuit or loop implies that a ment disorders, thus ushering in a new era of functional neu- number of the nodes involved in the circuit are potential targets rosurgery for movement disorders. for neuromodulation including neurosurgical procedures such DBS has similar efficacy as that reported with various lesion- as lesioning and DBS, somatic or stem cells, or gene therapy. ing procedures (e.g., pallidotomy, thalamotomy). However, the In the CSPTC circuitry model, the striatal structures, such as superior safety profile of DBS relative to lesioning procedures, the caudate and putamen, serve as the input structures, particularly bilateral thalamotomy and pallidotomy, has made whereas the GPi and substantia nigra pars reticulata (SNr) are it the procedure of choice in countries where access to this tech- the primary output structures. The motor circuit originates in nology is available the precentral motor regions (especially Brodmann areas 4 and DBS, with its inherent features of reversibility and adjustabil- 6). Information passing through the basal ganglia is organized ity, has gained popularity and emerged as the neurosurgical anatomically though “direct” and “indirect” pathways within standard of care for movement disorders such as PD, dystonia, the CSPTC circuit (Fig. 1). Information in the direct pathway and essential tremor over the past 20 years (6, 9, 25, 32, 33, 37, passes monosynaptically from the putamen to the output struc- 70, 101, 187, 193, 201, 202, 227, 252, 268, 274, 280, 293, 294, 343, tures of the basal ganglia, the GPi, and the SNr. Information 351, 357, 394). Since its inception, more than 40,000 DBS from the indirect pathway passes multisynaptically through implants have been performed in more than 500 centers world- the globus pallidus externa (GPe) and the subthalamic nucleus wide (28). In addition to the widespread use of DBS for move- (STN) before terminating on the GPi/SNr. The information ment disorders, a number of clinical investigations using DBS from both the direct and indirect pathways then projects to are under way to explore its safety and efficacy for conditions various thalamic relay nuclei, including the ventral oralis ante- such as Tourette’s syndrome (14, 88, 111, 155, 243, 266, 322, rior (Voa) and ventral oralis posterior (Vop) nuclei (in Hassler’s 366), chronic pain (48, 69, 119, 188, 210, 295), and psychiatric nomenclature) (230). This information is then projected back to disorders such as depression (60, 109, 238, 310, 314) and the frontal region of origin, thereby closing the circuit. The obsessive-compulsive disorder (OCD) (73, 121, 122, 190, 242, direct and indirect pathways appear to balance one another. 386). Because DBS is the most commonly used neurosurgical The direct pathway is presumed to be responsible for the initi- procedure for the treatment of movement disorders, it is the ation of action and the indirect pathway for the braking of major focus of this article. action or the ability to switch from one action to another. Inhibitory γ-aminobutyric acid (GABA)ergic projections pre- Neural Circuitry of Movement Disorders dominate in these pathways. Other than the excitatory gluta- matergic projections from the cortex to the basal ganglia and Traditionally, surgical procedures have targeted the known the returning excitatory thalamocortical projections, the only anatomic subcortical gray or white matter regions implicated in projections within the deep subcortical brain structures that the circuitry and the pathophysiology of movement disorders. are excitatory are the glutamatergic projections coursing from As discussed above, a long history of lesioning procedures for the STN to the GPi/SNr. The most common surgical targeted the treatment of movement disorders has provided a wealth of regions in this circuit are the STN, the GPi, and their associated empirical evidence supporting the presumed underlying neu- CSPTC motor circuit white matter inputs and outputs. There rocircuity associated with the aberrant motor symptoms. are other emerging targets in the CSPTC motor loop that are During the past two decades, technological advances in struc- being further investigated, but, given the scope of this review, tural and functional brain imaging and physiological brain they will not be discussed. mapping, coupled with animal research, have further advanced Dopamine is one of the most powerful neurotransmitters our understanding of the underlying neurocircuitry of specific influencing the motor CSPTC circuit. Dopamine can have either movement disorders, and led to additional refinement of the an excitatory or inhibitory role on striatal neurons, depending surgical targets. on the dopamine receptor subtype: D1 receptors are associated The use of animal models has contributed significantly to a with an excitatory effect, whereas D2 receptors are inhibitory. better understanding of the pathophysiology and underlying In general, dopaminergic inputs to the striatum serve to reduce

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(353) and correlated to bradykinesia. These results corroborate A B the recent view that the pathology of PD extends beyond abnormal frequencies and involves more complex interactions within the CSPTC circuit. Although the pathophysiology of dystonia may be related to a disruption of the activity within the CSPTC circuit, the exact mechanisms are still uncertain. No gross morphological changes involving specific components of the CSPTC motor circuit or links to specific neurotransmitters have been consis- tently identified for dystonia. Electrophysiological studies indi- cate that the abnormality is not as simple as increased or decreased communication rates between the motor CSPTC loop components, but rather, a disruption of the communica- FIGURE 1. A, cortico-striato-pallido-thalamo-cortical (CSPTC) neural tion pattern between two structures (370). Under this perspec- circuitry in normal state. B, CSPTC in Parkinson’s disease (PD). SNc, tive, the effects of DBS could be mediated by a lesion-like effect substantia nigra pars compacta; GPe, globus pallidus externus; STN, that disrupts abnormal connectivity, similar to that which subthalamic nucleus; GPi, globus pallidus internus; SNr, substantia nigra reticulata. might occur after DBS for the treatment of PD. Thus far, the motor GPi and ventral lateral (Voa/Vop) thalamus have been the primary surgical targets for dystonia. basal ganglia output and subsequently disinhibit thalamocor- The pathophysiology of essential tremor most likely involves tical activity. Dopaminergic activity may also ultimately facili- components of the cerebellum, motor thalamus, and relevant tate activity through the direct pathway over the indirect path- frontal cortices, and, unlike PD and dystonia, it does not neces- way, but this hypothesis is still under debate (110). sarily involve the CSPTC circuit. Essential tremor is probably PD is a disorder characterized primarily by dopamine loss in related to frontocerebellar circuits in which axons from the cere- the substantia nigra pars compacta, which results in the classic bellum synapse on thalamic neurons that project to the cortex. motor symptoms of PD, including tremor, rigidity, bradykine- Studies of patients with essential tremor who are undergoing sia, gait difficulties, and postural changes. The reduced positron emission tomography and functional magnetic reso- dopaminergic input associated with PD causes an increase in nance imaging (MRI) indicate hyperactivity of the cerebellum activity through the indirect rather than the direct pathway. and thalamus (58, 387). These findings provide support to the This results in hyperactivity of the GPi/SNr and subsequent well-established clinical knowledge that ablation of the cerebel- inhibition of thalamocortical activation further downstream, lar thalamus is highly effective in alleviating tremor. DBS of the which leads to reduced frontal cortical activity and the classic ventralis intermediate nucleus (VIM) is demonstrated to be motor symptoms of PD (261, 263). The STN is one of the major equally effective (275, 343) in alleviating tremor, and a recent driving forces behind the increased activity of the GPi and SNr study demonstrated that VIM DBS affects the excitability of output nuclei. Given their unique role in the CSPTC motor cir- the cerebellothalamocortical pathway (247). cuit, the most common surgical targets are the STN, GPi, and The concept of CSPTC circuits and other neurocircuits is crit- their associated CSPTC motor circuit white matter inputs and ically important in functional neurosurgery with respect to pro- outputs. There are other emerging targets in the CSPTC motor viding guidance regarding targets and sites of intervention. loop which are being further investigated, but, given the scope These circuits are a model of a network of interconnected of this review, they will not be discussed. regions that is implicated in normal motor functioning and Recent advances in the pathophysiology of PD reveal that in abnormal functioning associated with various disease processes. addition to the abnormal frequency (hyper- or hypoactivity) The surgically accessible components of this network are poten- between the structures of the CSPTC circuit, there is disordered tial targets of intervention, which can include lesioning proce- neurophysiological rhythmic activities and patterns in these dures, DBS, or other neurorestorative approaches involving regions as well. Hashimoto et al. (141) assessed the effects of somatic or stem cells and gene therapy. high-frequency (HF) STN DBS in the primate 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism. HF Mechanism of DBS Action DBS resulted in modifications in the pathological pattern of The placement of stereotactic lesions and DBS reflect two pallidal activity. Before stimulation, spontaneous pallidal activ- different methods of neuromodulation. Whereas lesioning ity was irregular, with varying intervals. Stimulation resulted in destroys a given volume of tissue, DBS exerts a reversible a higher frequency and regular pattern of spike activity, which electrical field on the surrounding nervous tissue elements. correlated with improvements in parkinsonian signs. Further The underlying mechanism of action of DBS remains a point investigation on activity patterns has also been pursued by of debate and active research. There appears to be a combina- other groups. Synchronous low-frequency activity (in the tion of inhibition of neurons, modulation of abnormal pat- β band) has been identified in the basal ganglia by Brown (55), terns of activity, and activation of axons. Initial observations Kühn et al. (189), Pogosyan et al. (287), and Trottenberg et al. suggested that HF stimulation caused inhibition of the cellu-

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lar activity in the nucleus, thereby mimicking a transient Surgical Patient Selection Criteria lesion-like effect. Studies show that DBS can induce inhibition In general, patients must be able to tolerate the various com- of cellular activity or of neural network functions by either the ponents of surgery and have the cognitive skills and social sup- “jamming” of neural transmission through stimulated nuclei, port structure to comply with the demands of surgery and the by direct inhibition of membrane action potentials, by retro- postoperative care. For those undergoing DBS surgery, both grade activation of upstream neuronal structures, or by the the patient and the family members need to have a detailed shutting down of neurotransmitter release in the STN (38). understanding of reasonable outcomes, potential complica- Recent experiments demonstrate that HF stimulation of the tions, and the multiple steps involved in the preoperative STN is accompanied by increased release of glutamate and assessments, surgery, and perioperative and follow-up care. dopamine in the STN and striatum, respectively (203, 338). The patient needs to cooperate with follow-up programming Similarly, increased release of GABA in axons from afferent and medication adjustments in the outpatient setting. Ad- connections was observed in the GPi of parkinsonian patients ditionally, the patient and family should have realistic expecta- during DBS surgery (40). It has also been demonstrated that tions about surgical outcome, and they should understand that activation of a DBS lead placed in the ventral thalamus can the surgery will not cure the disease or stop its natural progres- rapidly disrupt local synaptic function and neuronal firing, sion. Neurosurgery for movement disorders can provide and thereby lead to a “functional deafferentation” and/or improvements in disabling motor symptoms and motor func- “functional inactivation” (13). A recent study of PD patients tion. It is important to provide accurate information to the after placement of DBS electrodes in the STN suggests that HF patient and family members regarding those symptoms that stimulation produces early inhibition with subsequent are likely to respond to surgery versus those that are not. rebound excitation and another period of inhibition. These Patients should be in stable overall health with respect to findings suggest that the observed inhibitory activity reflects cardiac, pulmonary, and systemic conditions such as hyperten- neuronal hyperpolarization (96). These data further suggest sion, diabetes, and cancer. Patients who require anticoagulants, that STN neuronal inhibition may be accompanied by direct such as warfarin or antiplatelet medication, must be able to excitation of the cell and/or its axon. tolerate complete withdrawal from these medications before In summary, the growing literature demonstrates the com- surgery. Consultation with other medical specialists may be plexity of the motor system and the potential mechanisms of required before proceeding with surgery. DBS action. The prevailing hypotheses postulate inhibition at In recent years, there has been increasing recognition of the the neuronal level, activation at the axonal level, as well as neurobehavioral changes associated with PD and other move- interruption of excessive and abnormally patterned neuronal ment disorders, including cognitive, mood, and personality activity in the STN, GPi, and the interconnected components of changes. Neuropsychological assessment is recommended as the CSPTC network (20, 39, 133, 135, 264, 309, 385). part of the preoperative assessment to determine candidacy Surgery: The Team for neurosurgical intervention for the treatment of movement disorders. The neuropsychological assessment should include Surgery for movement disorders is most optimally man- assessment of cognition, neuropsychiatric symptoms, social aged in the context of a multidisciplinary team. In addition to support, and goals for surgery. Patients with severe cognitive the neurosurgeon, this team should include a movement dis- dysfunction or dementia on neuropsychological examination orders neurologist, a neuropsychologist, a neurophysiologist, should be excluded from surgical intervention. Patients with and physician extenders such as nurse practitioners and mild cognitive impairment or frontal dysexecutive syndrome physician’s assistants. The movement disorders neurologist may still undergo surgery, but these individuals should have can help confirm an accurate diagnosis and rule out atypical a strong social support structure and receive extra counseling, parkinsonism or psychogenic movement disorders. The ben- along with family members, regarding the potential for efit of surgery for a particular movement disorder is largely increased risks for cognitive impairment and confusion post- dependent on accurate diagnosis, as it is the underlying surgery. Psychiatric conditions such as anxiety, depression, pathophysiology and neurocircuitry of the specific move- and mania must be identified and medically optimized by a ment disorder that is influenced by surgery. The movement specialist preoperatively. Neurosurgical intervention in disorders neurologist can also optimize medications for indi- patients with delusional psychosis or severe personality dis- viduals who have not had adequate medication trials. order, such as borderline personality disorder, is generally Occasionally, medication adjustments by an expert can signif- not recommended. icantly improve the functioning of a patient such that he or she no longer requires surgery. The DBS programming can be PD: Selection Criteria performed by the neurosurgeon, neurologist, or physician extenders. As DBS programming results in changes in motor PD is a progressive neurodegenerative disorder resulting in symptoms, there must be close attention to concomitant med- prominent motor abnormalities such as bradykinesia (slow- ication adjustments coupled with rehabilitation (e.g., physi- ness of movement), rigidity (muscle stiffness), tremor, and gait cal and occupational therapies) to optimize an individual and postural instabilities. In PD, there is progressive degener- patient’s motor outcome. ation of dopaminergic neurons. Administration of L-dopa and

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synthetic dopamine agonists is the mainstay of medical treat- Patients who are refractory to all conservative measures, ment of PD. However, over time, patients experience a less including medication trials (anticholinergics, baclofen, benzodi- favorable response to medications and may begin a cycle that azepines, or other muscle relaxants) and botulinum toxin injec- includes increasing medication doses and multiple medica- tions are potential candidates. tions with disabling side effects. Dose escalations can be asso- Dystonia is a heterogenous condition with variable expres- ciated with motor fluctuations and troublesome dyskinesias sion. It can be classified into primary or secondary dystonia (83, 251, 260). Despite major advances in the understanding of according to etiology. Primary idiopathic dystonia refers to the pathophysiology of PD and improvements in pharmaco- dystonia with no discernible etiological factor responsible for logical management, there are a substantial number of patients its onset. Patients with primary idiopathic dystonia have nor- who are considered refractory to medical management. Such mal imaging findings, cerebrospinal fluid composition, and medically refractory patients with significant motor complica- laboratory test examinations. A subset of patients with pri- tions and disability can benefit from DBS of the STN or GPi. mary dystonia have a DYT-1 mutation on chromosome 9q (12). Neurosurgery has been shown to consistently benefit only Secondary dystonia refers to dystonia that is associated with a patients with idiopathic PD. Atypical parkinsonism (supranu- clearly preexisting, identifiable brain insult such as perinatal clear palsy, nigrostriatal degeneration, etc.) or other disorders hypoxia, stroke, trauma, toxin exposure, or infectious sequelae. with parkinsonian features have not been shown to respond Tardive dystonia is another subset of dystonia that results from favorably to surgery. super-sensitivity of the postsynaptic dopamine striatal recep- In general, surgery is most likely to benefit symptoms affect- tors due to long-term administration of dopamine receptor- ing the extremities rather than axial symptoms that involve blocking agents such as neuroleptics (105, 219, 395). posture, balance, gait, and speech. Surgical candidates typi- Dystonia can also be classified according to the affected body cally have more than one of the following symptoms: severe part. In focal dystonia, a single region of the body is affected, tremors; off-medication-related rigidity, freezing, dystonia, and such as in blepharospasm (eyes), cervical dystonia/torticollis bradykinesia; on-medication-related dyskinesias; and signifi- (neck), and spasmodic dysphonia or laryngeal dystonia (182). cantly disabling on-off-medication motor fluctuations. One of In segmental dystonia, two or more adjacent body parts are the most important predictors of neurosurgical treatment affected, such as cranial-cervical dystonia, crural dystonia, or response is the patient’s response to L-dopa. Patients who brachial dystonia. Generalized dystonia refers to dystonia demonstrate a significant improvement in motor symptoms involving most body parts. during L-dopa off-medication versus on-medication states are Primary, generalized dystonia of DYT-1-positive (184, 195, most likely to benefit from surgery. The only exception to this 201) or non-DYT-1 types, as well as patients with idiopathic general rule involves tremor. Tremor is the only identified cervical dystonia can obtain the best motor benefits with bilat- motor symptom that can improve with DBS regardless of eral GPi DBS (363). Patients with juvenile-onset idiopathic response to off-on-medication testing. Consequently, a formal dystonia whose age of onset is older than 5 years and who do off-on test of L-dopa responsiveness can be very helpful in the not have multiple orthopedic deformities also have a good selection of the best surgical candidates. response to surgery (280). Appendicular symptoms (e.g., those affecting the limbs) appear to respond better than axial Tremor: Selection Criteria symptoms (201). With regard to focal dystonia, ideal surgical Essential tremor is a benign condition (32, 173, 198, 222) that candidates are those with cervical dystonia (201, 331). The can be managed for many years with medications. In those results of DBS for secondary dystonia are inconsistent. In gen- patients who have disabling extremity tremor despite optimal eral, DBS for secondary dystonia is less effective than for pri- medication management, surgery using the VIM target mary generalized dystonia, particularly in those patients with becomes an option. In general, patients with resting and distal an identifiable structural brain abnormality. The only excep- postural tremor fare the best with surgery, followed by those tion is tardive dystonia, which has been reported to respond with proximal postural tremor. Patients with intention/action well to surgery in a small number of patients (92, 331, 396). tremor tend to benefit to a lesser degree. The more proximal and the action/intention features of tremor are the most diffi- Surgical Targets cult and challenging tremor characteristics to treat surgically The three most common targets for movement disorder sur- (44, 85, 169). Head, neck, and lower-extremity tremors are also gery are the STN, GPi, and VIM thalamus. GPi and STN DBS more difficult to treat than upper-extremity tremors. Tremors improve PD symptoms (e.g., tremor, rigidity, and bradykinesia) involving the head, neck, and axial regions usually require and also reduce drug-induced dyskinesias. STN DBS also bilateral surgery. reduces the medication burden, thereby reducing medication- associated side effects (80, 59, 368). Both the STN and the GPi Dystonia: Selection Criteria have corresponding associative (cognitive), limbic, and motor DBS offers a therapeutically viable option for patients with territories that require accurate surgical targeting of the motor severe, primary dystonia and also for a small subset of patients component. Presently, the most commonly used target for DBS with secondary dystonia. The key to favorable responses after therapy to treat PD is the STN, followed by the GPi. The GPi is DBS in patients with dystonia is proper patient selection. also the most commonly used target for dystonia (66, 100, 159,

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185, 201, 280, 312, 331, 350, 351, 355, 396). The VIM target is the main target used for non-parkinsonian tremor. The VIM is very effective in alleviating PD-associated tremors, but is not effec- tive in the treatment of other cardinal PD symptoms. (342, 343). Thus, VIM DBS surgery is rarely performed for PD treatment. The STN Target The STN was previously not considered a target because of the fear of causing hemiballismus. However, in 1990, Bergman et al. (42) showed that a lesion in the STN of a nonhuman pri- mate model could reverse the symptoms of PD. This early work, coupled with the evolving concept of the flexibility (e.g., reversibility and adjustability) inherent in DBS for the treat- ment of movement disorders, resulted in Benabid et al. (34) and Pollak et al. (288) applying STN DBS for the treatment of PD initially in 1993, with report of a subsequent case series in 1995 (215). Since that time, STN DBS has become the most com- mon target for DBS surgery for PD. Targeting the STN has been demonstrated to effectively treat the entire spectrum of advanced PD symptoms of tremor, rigidity, bradykinesia, motor fluctuations, and drug-induced dyskinesias, while also FIGURE 2. A three-dimensional depiction of the STN and structures around it in the midbrain-diencephalic consistently reducing the need for dopaminergic medication region. Note the close proximity of the STN to the red postoperatively. nucleus (RN), cerebral peduncles, and substantia nigra Anatomically, the STN (also called the corpus luysi) is an (SN). almond-shaped nucleus located on the inner surface of the peduncular portion of the internal capsule. The STN is sur- rounded by several key structures that need to be considered carefully (Fig. 2). This includes the anterior and laterally situ- afferents coming from the intralaminar nuclei of the thalamus ated internal capsule, through which corticospinal and corti- and STN. Pallidal efferents pass through the major routes of cobulbar fibers pass. Anteromedially lie the fibers of Cranial pallidal outflow (the ansa lenticularis and lenticular fasciculus) Nerve III, the posteromedial hypothalamus, and portions of primarily to the Vop nucleus of the thalamus, but they also the fields of Forel. The red nucleus, fibers with cerebellothala- interdigitate with the afferents to the VIM. mic projections, and the prelemniscal radiations are situated posteromedially. Dorsal to the STN is the zona incerta and The VIM Target Forel’s field H2 that separate it from the ventral border of the The VIM is the common lesioning and DBS target used for motor thalamus. The cerebral peduncle and the substantia the treatment of tremor (Fig. 3, B and C) (1, 6, 25, 33, 35–37, 63, nigra are situated ventral to the STN (Fig. 3, A–C). 108, 113, 126, 164, 173, 174, 191, 221, 222, 226, 231, 267, 297, 377). In the somatotopic organization of the VIM nucleus face, The GPi Target responsive cells lie medially, followed by the upper extremity The GPi target is used for PD treatment less commonly than more lateral, and the lower extremity is the most lateral, situ- the STN. However, the GPi is currently the most common target ated closely to the internal capsule (Fig. 6). The VIM nucleus for treating dystonia (364) despite reports of using thalamic of the thalamus has neurons that fire in synchronous bursts (Voa, ventrolateral) (92) and subthalamic DBS targets (162, 373) with the tremor frequency and are called tremor cells (TCs). for dystonia. The GPi DBS target is the posteroventrolateral GPi, TCs are believed by some to act as tremorigenic pacemakers which is the predominant motor territory of the nucleus (Fig. 4). (178, 222). There is a significant confusion and controversy The globus pallidus is divided into two anatomic segments: surrounding the nomenclature of the thalamic nuclei (178, internal (GPi) and external (GPe). Although these segments 179). The DBS target for tremor control is the electrophysio- are separated by the medial medullary lamina, the pallidal logically defined VIM (178). This electrophysiologically neurons from each segment are similar and, for the most part, defined motor thalamus (VIM) has TCs and kinesthetic cells, morphologically indistinguishable. The GPi is bound laterally and it lies immediately anterior to the cutaneous receptive and dorsally by the GPe. Medially, the GPi is bound by the cells, which lie in the sensory thalamus (178). The somatosen- internal capsule. Ventrally, it is close to the optic tracts (Fig. 5, sory relay nucleus ventralis caudalis (VC) of the thalamus lies A and B). The therapeutic sensorimotor territory of the GPi is immediately posterior to VIM. The VC has specific neurons ventral and posterior, and the somatotopy places the face and that respond to tactile stimulation in small, receptive fields. arm posterior and ventral, and the leg central and more dorsal The Vop nucleus lies immediately anterior to the VIM. The (350). The striatal afferents terminate in the GPe, as do the internal capsule lies lateral to the VIM. The Vop receives affer-

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A B

FIGURE 3. Location of the STN and its relation to the surrounding C FIGURE 4. Location of the GPi structures is depicted on axial (A), coronal (B), and sagittal (C) sec- and its relation to the surrounding tions of the Schaltenbrand and Wahren atlas. Note the close proxim- structures as depicted on the axial ity of the STN to the internal capsule (IC), red nucleus (RN), and section of the Schaltenbrand and substantia nigra (SNR). The coronal (B) and sagittal (C) sections Wahren atlas. Note the close prox- also show the ventral and dorsal tier of thalamic nuclei, including imity of the GPi medially to the the ventral caudal nucleus (VC), ventral intermediate nucleus IC and laterally to the GPe. The (VIM), and ventral oralis anterior and posterior nuclei (Voa and dark boundary between the GPi Vop, respectively). ATh, anterior thalamic nucleus complex; MTh, and GPe is the external lamina. medial thalamic nucleus complex. (From, Schaltenbrand G, Wahren (From, Schaltenbrand G, Wahren W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme W: Atlas for Stereotaxy of the Medical Publishers, 1977. Reproduced with permission [313].) Human Brain. Stuttgart, Thieme Medical Publishers, 1977. Repro- duced with permission [313].)

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FIGURE 5. High-resolution axial magnetic resonance imaging (MRI) scans showing the globus pallidus and optic tract. A, inversion recovery sequence showing the caudate nucleus, putamen, globus pallidus (GP), IC, and thalamus. B, axial T2-weighted MRI scan showing the trajectory of the intended placement of the deep brain stimulation (DBS) lead with its tip just dorsal to the optic tract. FIGURE 6. Somatotopic arrangement of the ventral relay nuclei shown on an axial section including VC, VIM, Voa, and Vop. The general scheme in the ents from pallidal neurons (230) and the VIM receives affer- thalamic somatotopy includes having the leg placed more laterally and the face placed more medial with ents from the cerebellar neurons (cerebellothalamic fibers). an upper limb in between the two. It also shows the There is some degree of overlap and interdigitation between somatotopy in the internal capsule. In this classic these two nuclei (230). figure, the GPi homunculus does not strictly repre- sent the GPi somatotopy, as has been suggested with DBS Surgical Technique more recent data. (From, Schaltenbrand G, Wahren In this section, we review the general principles and tech- W: Atlas for Stereotaxy of the Human Brain. Stuttgart, Thieme Medical Publishers, 1977. niques of DBS surgery, which is the most common surgical Reproduced with permission [313].) treatment for movement disorders today. Although there is

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general agreement about the efficacy of DBS for movement dis- orders, there is some variance in the protocols for placement of DBS leads (220, 272, 323, 358). The surgical technique has its foundation in stereotactic principles. It has evolved from strong reliance on stereotactic atlases and incorporates advances in imaging and neurophys- iological mapping techniques. At present, most neurosur- geons performing DBS use a variety of these approaches to localize the target of interest. These variations are a result of training patterns, surgeon preferences, and surgical practice FIGURE 7. Leksell stereotactic frame (Elekta, Stockholm, logistics. There is no single correct approach, as long as out- Sweden). The system is based on FIGURE 8. Method for place- comes are good and complications are kept to a minimum. the center-of-arc principle, and ment of the Leksell headframe. The lack of randomized prospective studies comparing one the basic components are the The frame placement is performed approach to another is also a major barrier to advancement Cartesian coordinate frame, which under local anesthesia with the and standardization in this field. is attached to the patient’s head patient sitting up. The frame The basic components of DBS implantation surgery involve using four pins, and the semicir- should be placed parallel to a line stereotactic anatomic targeting, physiological target verifica- cular arc. extending from the lateral can- tion, DBS lead implantation, and implantable pulse generator thus to the tragus (orbitomeatal (IPG) or power-source placement. The components of the sur- line depicted in red) to approxi- mate the plane of the anterior gery can all be done in one setting or in stages, depending on obtained preoperatively are the group’s preference. We review these components, high- commissure-posterior commissure then loaded into a surgical (AC-PC) line. lighting common practice patterns and acknowledging the navigation computer, and the variance of practices across centers. fiducials are registered. The Headframes and Acquisition of Stereotactic Coordinates frameless assembly is then used to plan a trajectory to the tar- get of interest. The reported advantages of the frameless sys- The least debated aspect of the surgery is the method chosen tems are related to arguments of increased efficiency of surgi- for acquisition of stereotactic coordinates. Currently, both cal planning and imaging acquisition before the day of surgery frame-based and frameless techniques are commercially avail- and enhancement of the patient’s comfort with less immobiliza- able for localization within the stereotactic space. tion of the head and neck (Fig. 10). Currently, there is no major advantage to using one system Frame-based Systems versus another; the surgeon’s preference guides the selection The frame-based approach is the “gold standard” that has process. Relatively few centers perform frameless DBS surger- been used for many years with proven precision and reliability. ies compared with the number that perform frame-based DBS. A variety of headframes can be used, such as the Leksell (Elekta, A randomized prospective study is necessary to determine the Stockholm, Sweden), Cosman-Roberts-Wells (Radionics, levels of patient comfort, precision, outcome, and efficiency Burlington, MA), Riechert-Mundinger (Fischer-Leibinger, inherent in one system versus another. Freiburg, Germany), and other commercially available systems. Based on a survey of North American centers that perform DBS Imaging surgeries, it appears that the Cosman-Roberts-Wells frame is the most commonly used, followed by the Leksell frame (Fig. 7) Ventriculography (271). The stereotactic accuracy of each frame has been well In the late 1960s, Guiot et al. (128, 129) defined the position established (233), and these frame-based approaches represent of various deep nuclei based on the distance between the AC the standard of care after decades of clinical use, consistency, and PC and the height of the thalamus, as obtained from ven- and dependability. Placement of the headframe is achieved triculography (Fig. 11). This method was the cornerstone of under local anesthesia. The frame should be placed parallel to a functional neurosurgery for decades and is still used in several line extending from the lateral canthus to the tragus, to approx- centers worldwide (30, 34, 177). However, the advent of mod- imately parallel the anterior commissure (AC)-posterior com- ern imaging has, for the most part, replaced ventriculography missure (PC) line (Fig. 8). with computed tomographic (CT) and MRI scans. Frameless Systems CT Scans The introduction of the frameless technique and device for A thin-cut stereotactic CT scan (approximately 2-mm slices, DBS lead placement (90, 150) has provided an alternative with no gap and no gantry tilt) can be easily obtained to localize approach that has been embraced by some groups. The frame- the AC and PC and subsequently be computationally fused with based fiducials have been replaced by small screws that are an MRI scan on a stereotactic planning station. CT scans are free visible on computed tomography, which are secured to the from the image distortions inherent to MRI and allow the stereo- patient’s cranium before the surgery (Fig. 9). The images tactic space to be defined with a high degree of accuracy.

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FIGURE 11. Schematic diagram showing the procedure of ventriculogra- FIGURE 9. Three-dimensional phy and location of the AC and PC. Usually radiopaque dye such as image showing fiducials placed iohexol is injected into the lateral ventricle through a frontal parasagittal for frameless registration using a burr hole, anterior to the coronal suture. Ventriculogram images are Nexframe (Medtronic, Minnea- obtained in lateral and anteroposterior views with standard magnification polis, MN) frameless stereotactic by using orthogonal x-ray imaging with a fixed distance. The stereotactic system. The fiducials are small coordinates of the AC, the PC, and the theoretical target points relative to FIGURE 10. Intraoperative image screws that are visible on com- the AC-PC line are then calculated. of Nexframe and Nexdrive puted tomography, which are (Medtronic) systems in use for secured to the patient’s cranium frameless stereotactic placement of before the surgery. The preopera- A B a DBS lead. Nexframe is a dispos- tively obtained images are loaded able device that fits over the into a surgical navigation com- puter and the fiducials are regis- Navigus stimloc base (Medtronic) tered. The frameless assembly is and allows DBS procedures to be then used to plan a trajectory to performed directly in the operating the target of interest. room or MRI environments with- out the use of a conventional stereotactic headframe. Once MRI Scans Nexframe is aligned with the MRI is the imaging modal- intended trajectory using image- ity of choice in stereotactic guidance software, it functions as a stable cranium-mounted guide for targeting and planning. the introduction of the DBS lead. C Various sequences can be On the top is a disposable micro- used. The most common are a drive that also acts as a simplified T1-weighted, volumetric interface for microelectrode record- FIGURE 12. T1-weighted MRI acquisition of the whole brain ing (MER) and is used for MER scans showing stereotactic location with gadolinium enhance- and final implantation of neu- of the AC and the PC on axial (A), ment, a T2-weighted axial and rostimulating electrodes. coronal (B), and sagittal (C) sec- tions. coronal acquisition, and inver- sion recovery (IR) sequences. The T2-weighted and IR sequences delineate the STN and GPi well. The thalamic nuclei, however, are not visualized well on MRI scans of 3 T or less. Anatomic Targeting Indirect Targeting Formulas and Brain Atlas Approaches Anatomic targeting is the initial method for localizing the Indirect targeting techniques use the stereotactic coordinates structures of interest. The goal is to achieve the most precise of the AC and the PC as determined by imaging (Fig. 12). The localization using multiple data sources. Different centers use locations of the STN, GPi, and VIM can be subsequently deter- various combinations of anatomic targeting strategies. In gen- mined based on their average anatomic distances with respect eral, one can target via an indirect method using reformatted to the AC, PC, and midcommissural point (MCP). Typical anatomic atlases and formulas of known distances, or via direct anatomic coordinates for the sensorimotor components of these targeting approaches. The STN and GPi can be directly visual- nuclei can be calculated. This includes the STN (11–13 mm lat- ized on T2-weighted and IR MRI scans. Currently, imaging res- eral to the midline, 4–5 mm ventral to the AC-PC plane, and olution is not sufficient to visualize the VIM. Emphasis here is 3–4 mm posterior to the MCP), the GPi (19–21 mm lateral to the placed on anatomic targeting of the STN, because it is the most midline, 2–3 mm anterior to the MCP, and 4–5 mm ventral to common target used for PD, but brief descriptions of GPi and AC-PC plane), and the VIM upper extremity target (11–12 mm VIM targeting are also included. lateral to the wall of the third ventricle, at the level of the AC-

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PC plane, and anteroposterior location between two- and three- A B twelfths of the AC-PC distance anterior to the PC). A standardized brain atlas can be used to locate the x, y. and z coordinates of the STN, GPi, and VIM in relation to the MCP (Figs. 3 and 4). The stereotactic atlas can be stretched and mor- phed using surgical navigation software to better fit each patient’s anatomy. However, despite these technological advances, it is important to realize the limitations of the stereo- tactic atlases. The data in most atlases are based on a small number of brains. The Schaltenbrand and Wahren atlas (313) uses one brain for the frontal series and one brain for the axial and sagittal series. The Talairach and Tournoux atlas is based on one brain (339). The morphology and position of the STN is FIGURE 13. High resolution axial (A) and coronal (B) T2-weighted MRI scans showing the STN and structures in close proximity to it. STN, sub- different in each atlas (257, 301), and the actual size and the thalamic nucleus; SNR, substantia nigra reticulate; RN, red nucleus. position of the STN are highly variable among patients (136, 301) and within the stereotactic atlases. targeting the STN. In the authors’ experience, the interpedun- Direct Targeting cular distance can also serve as a good surrogate for the later- With the advances in neuroimaging technology, direct visu- ality of the STN target (unpublished data). alization of the various nuclei has become possible. Although The possibility of directly visualizing and targeting the STN computed tomography offers excellent stereotactic precision, it and GPi has brought forth innovative imaging application pos- can be difficult to visualize various targets and periventricular sibilities for DBS surgery. The use of intraoperative MRI to per- landmarks (375) when using it. MRI offers the advantage of form DBS surgery is being investigated by Martin et al. (235). excellent anatomic resolution in multiple planes. This allows Their preliminary results show that successful DBS implanta- for localization of the AC and the PC on T1-weighted images tion can be performed in patients under general anesthesia (Fig. 12), the visualization of the pallidum on IR and T2- with only anatomic targeting. This approach has multiple weighted sequences (Fig. 5), and identification of the STN on inherent advantages that will facilitate its acceptance and wide- axial, sagittal, and coronal T2-weighted images (Fig. 13) (32). spread use once additional studies demonstrate that the safety The advantage of directly visualizing deep targets is implicit; and efficacy are equivalent to the traditional techniques. one works with the patient’s individual anatomic variation Trajectory Planning rather than relying on a fixed brain that was sectioned several decades ago. Some centers rely entirely on MRI scans to calcu- Imaging is necessary for accurate targeting as well as for late anatomic targets (272, 330, 334). There are questions, how- planning of the surgical trajectory to the target. The strategy is ever, regarding the accuracy of the exact location of these tar- to avoid surface and subcortical vessels and to have an angle of gets within the stereotactic space because of distortion on MRI approach that passes through a large segment of the structure scans (311). To reduce the possibility of MRI-related inaccura- of interest. The precise entry point may be refined on the plan- cies, several centers use a protocol of merging the anatomically ning console, such that the trajectory passes through the crown superior MRI scans to stereotactically acquired CT scans (19, of a gyrus rather than into a sulcus, as well as away from the 220, 323, 375). vessels associated with the wall of the ventricle, thereby help- Several authors have described strategies to further refine ing to avoid hemorrhagic complications (Fig. 14). image-based targeting. Arguing that the relationship of the AC- PC line and the STN may be variable and inconsistent, they Neurophysiological Assessment and Verification propose the use of a landmark that is physically closer to the All surgeries for movement disorders are initially based target of interest (16, 24, 78, 330). In 2000, Bejjani et al. (24) on anatomic targeting techniques. However, physiological described using the anterior border of the red nucleus as a verification of these targets is a necessary step before final landmark for the AP coordinate of the STN. This approach has implantation of the DBS electrode can occur. This is crucial also been used by others (17, 78). Axial and coronal T2- because anatomic inaccuracies due to image distortion, brain weighted images are particularly important for adequate visu- shift, cerebrospinal fluid loss, and pneumocephalus can lead alization of the STN, as a sharp contrast can often be observed to final target deviation (124). A DBS lead that is misplaced between the nucleus and the surrounding white matter. The by as little as 2 mm can result in inaccuracy when locating red nucleus and the STN can be clearly visualized. The STN lies the final target. anterior and lateral to the red nucleus and, in this regard, the In a more practical sense, neurophysiological techniques are anterior border of the red nucleus can be used as a landmark necessary to refine lead positioning within a target and to opti- for the STN target (Figs. 3 and 13). Starr (330) later described mize clinical outcome and minimize stimulation-related side the relationship between the center of the red nucleus and the effects. In the lesioning era preceding DBS, physiological ver- middle of the electrode array as another internal landmark for ification was a major requirement before the creation of

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detailed physiological mapping of the borders of the nuclei. The hope is to improve treatment efficacy and limit postoper- ative side effects that are related to undesired stimulation of bordering structures (123, 373). In a survey of 36 DBS centers in North America, Ondo and Bronte-Stewart (269) found that 97% of centers use MER for assistance in lead placement. The average number of tracks was 2.3 per electrode, with a range of 1 to 18 tracks. They also reported that most centers use macrostimulation to assess the final clinical response. Although most centers advance one microelectrode at a time, several centers advance multiple microelectrodes simultane- ously and assess a larger area of the target (24, 31). Delivering stimulation through the microelectrode, when feasible, is per- formed at some centers to assess side effects resulting from proximity of the track to other structures such as the internal capsule (124, 372). MER allows for the delineation of the physiological signa- ture of various nuclei and white matter tracts. Single neu- rons, multiunit activities, and local field potentials can be dis- cerned with characteristic sound and visual expressions. The frequency and pattern of activity are observed, thus helping to confirm location based on characteristic physiological sig- natures. The boundaries between white matter and nuclei are important to distinguish, as are the length of the desired nucleus and an assessment of the surrounding structures. The FIGURE 14. Navigation view on Framelink (Medtronic) software using MER physiology of the STN, GPi, and VIM is discussed a contrast enhanced, T1-weighted MRI scan showing the enhancing ves- briefly below. sels in the periventricular region. The trajectory (blue arrows and lines) is carefully planned to avoid these deep vessels and more superficial corti- The STN cal vessels. The right upper panel demonstrates the images in a plane The information obtained in the track, such as the presence perpendicular to the planned trajectory (red point). or absence of thalamus or SNr, could also aid in determining the trajectory in relation to the nucleus, i.e., medial, lateral, anterior, or posterior. Figure 15 shows a sample MER trajectory lesions. Presently used physiological techniques include aimed at the STN. The thalamus is typically the initial structure microelectrode recording (MER), semi-MER, macrostimula- encountered by the MER. The specific thalamic nuclei recorded tion, and DBS lead stimulation. The degree of dependence on depend on the AP angle of approach, but typically include the these techniques varies widely. The exact detail of mapping for nucleus reticularis (Rt), the Voa, and the Vop. There are two each target is beyond the scope of this article; however, gener- typical cell activities: bursting units (interburst frequency, 15 Ϯ alities are provided and details can be obtained in the refer- 19 Hz) and irregular tonic firing (∼28 Hz) cells. The background ences provided. activity is substantially less dense than the background activity of the STN. After exiting the thalamus, a decrease of back- MER ground activity coupled with the resolution of, generally, fewer The MER technique uses microelectrodes with high imped- firing units indicate the zona incerta (ZI) and fields of Forel. ances (typically Ͼ0.4 mΩ) with a tip diameter in the range of 2 Activity in these areas has a similar bimodal distribution of to 4 μm (124, 158, 207). These microelectrodes are capable of bursting and tonic firing units, usually with low firing rates. A recording single units as well as delivering stimulation in the substantial increase in background neuronal activity signals microamp range (typically Ͻ100 mA). A hydraulic or electrical the entry into the STN. This increase in background activity, microdrive is used to advance a microelectrode in submilli- perhaps the most distinguishing characteristic of the STN com- metric steps. United States Food and Drug Administration- pared with the other structures encountered in this procedure, approved microelectrodes are commercially available and are can precede the resolution of single-unit activity indicative of made of tungsten or platinum/iridium. the STN by 1 to 2 mm. Mean firing rates have been reported in Some centers use a single MER penetration as confirmation the 34- to 47-Hz range, with standard deviations in the 25-Hz of the anatomic targets, whereas others rely on one or more range. Bursting units are common. The pattern of activity is tracks that reveal a set of acceptable criteria, such as an typically irregular. Cells that respond to passive movement of approximately 5-mm long area of STN (231). There are also the limbs are encountered in the dorsolateral part of the STN. centers that use a multiple-track penetration approach for very Within this motor area, lower extremity-related units tend to be

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strategy is then to identify the border between the sensory nucleus and the VIM where the cerebellar afferents are received. Once the border is identified and the somatotopic laterality is established, the DBS electrode can be placed approximately 3 to 4 mm anterior to the border of thalamic sensory relay nucleus to avoid current spread into the sensory nucleus and development of persistent paresthesias as a side effect of stimulation. Despite the widespread use of MER, whether the utility of MER approaches is superior to other methods is an area of debate and controversy. There are centers that still use only macrostimulation, and they report comparable results (137). There is a need for a prospective randomized study comparing MER to non-MER approaches to reconcile this issue. In addi- tion to MER, there are centers that use semi-microelectrodes to map the corresponding nuclei and white matter. Semi- microelectrodes have lower impedances and cannot discrimi- nate single neurons, but do provide good physiological data regarding the structures being traversed (108, 393). FIGURE 15. Representative samples of neuronal recordings in a typical tract while targeting the STN. All of the samples are 1 second in length and demon- Macroelectrode Mapping and Stimulation strate the typical firing pattern at each of those nuclei. Macrostimulation involves stimulation in the range of mil- (Reproduced with permission from Thieme). liamps to determine benefits and side effects. There are sev- eral different ways of delivering macrostimulation. Macro- stimulation can be performed with a lesioning probe or, most more medial than upper extremity-related units. An abrupt commonly in the United States, the DBS electrode itself can be decrease in background noise is indicative of exiting the STN used as the macroelectrode (269). This is advantageous as the and entering the SNr. The gap between the STN and the SNr results obtained during surgery are likely to be reproduced can vary from a few hundred microns to 3 mm. In general, the with chronic stimulation from the DBS. Still, macroelec- features that distinguish the SNr from the STN include higher trode/DBS stimulation is one of the important steps for DBS firing rates (50–70 Hz), a paucity of kinesthetic-responsive surgery as it provides insight into therapeutic efficacy and units, and a more regular firing pattern. stimulation-induced side effects. The GPi During MER, the general objectives of the mapping strate- DBS Electrode Implantation gies are to define a long segment of sensorimotor GPi, deter- In planning the implantation, it is important to understand mine the border regions between the GPi and the GPe, identify that the active site of chronic stimulation may not be the bot- the optic tract at the bottom of the trajectory by means of visual tom of the target at the bottom of the trajectory. In the STN evoked potentials, and distinguish the internal capsule, which implant, for example, the bottom contact of the quadripolar is medially and posteriorly located (124). Several authors advo- STN electrode is seldom used because the optimal site for cate use of more than one track to gather this information (10, stimulation is believed to be at the dorsolateral segment of the 23, 125, 130, 181, 372). Although some groups use only one or nucleus or immediately dorsal to it (146, 308). two tracks (15, 277), there are insufficient data to state which The two commercially available electrodes have four con- method of neurophysiology is superior for mapping the GPi tacts of 1.5 mm in height and 1.27 mm in diameter and differ and which mapping strategy has a better outcome. In their only in the spacing between contacts: 1.5 mm in the 3387 model review, Gross et al. (124) stated that, based on the existing neu- and 0.5 mm in the 3389 model (Medtronic, Minneapolis, MN) rophysiological data, it is unclear how much the final target (Fig. 16). Fluoroscopy is used at many centers to monitor the within the GPi is modified. DBS lead implantation and ascertain that it is assuming a straight trajectory that does not deviate from the intended tar- The VIM get. Once implanted, the electrode may cause a microlesional Historically, the VIM target has been localized between effect that is manifested by transient improvements in tremors two- and three-twelfths of the AC-PC distance anterior to the and, in the case of PD, rigidity and bradykinesia. Such an effect PC (128, 129). Most centers target the sensory nucleus because is seldom observed during GPi surgery for dystonia. of its consistent somatotopic arrangement, which can be eas- With DBS intraoperative test stimulation, the patients are ily identified during MER by eliciting evoked responses from assessed for clinical benefits and side effects. The typical tactile-stimulation-responding neurons (231). The general parameters mirror the settings used for chronic stimulation

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A B

C

FIGURE 16. A, the two commercially available electrodes each have four contacts of 1.5 mm in height and 1.27 mm in diameter and differ only in the spacing between contacts, as illustrated in B. C, the placement of the DBS lead, connectors, and implantable pulse generator (IPG) in a human. (A and C obtained from www.medtronic.com; B, printed with permission from Wiley-Liss).

and include 1 to 5 V, 90 μs pulse width, and 130 Hz fre- the burr hole device or placed along the path of tunneling to quency. The larger the difference between clinical improve- serve as strain relief. ment thresholds and side-effects thresholds, the better the therapeutic window of stimulation for the patient. During Implantation of the Pulse Generator macrostimulation, the patient is monitored for symptomatic The second stage of the DBS procedure is implantation of improvement such as tremor, rigidity, and bradykinesia. the implantable pulse generator (IPG), also referred to as the Dyskinesias may appear during stimulation and are gener- “neurostimulator,” and placement of the extension lead that ally a positive predictor of the efficacy of chronic stimulation connects the DBS lead to the IPG. Currently, there are two (157, 290). The importance of side-effect determination types of available IPGs: single channel (Medtronic Soletra) should be underscored, especially for patients in whom the for one DBS lead, and dual channel (Medtronic Kinetra) for therapeutic efficacy is unclear or situations in which the two leads. This is the last step of surgery, and it is performed patient’s cooperation is hampered (30, 31, 330). under general anesthesia. This step can be performed the Once the DBS electrode is implanted at the final location, it same day or in a delayed or staged fashion. must be secured to the burr hole at the cranium. Continuous The patient is placed in a supine position, with the head fluoroscopy is helpful to monitor the potential for electrode turned to the opposite side of the intended site of IPG implan- displacement. Anchoring and securing the lead can be achieved tation. In brief, an infraclavicular subcutaneous pocket is cre- by various techniques depending on the surgeon’s preference ated for the IPG, and the proximal end of the DBS electrode is and expertise. These include securing the lead to the cranium exposed in the parietal region. A subcutaneously implanted with ligature embedded in dental cement or using mini-plates extension wire is tunneled from the parietal region to the infr- and screws, DBS manufacturer-provided plastic burr hole ring aclavicular pocket, thus connecting the DBS electrode to the and cap, or the Medtronic Stim-Loc anchoring device IPG pocket in the chest. The most common location for the (Medtronic). Once secured, the distal end of the DBS lead is IPG placement is infraclavicular, and it is typically marked 1 attached to an extension wire or to a connector that will protect to 2 cm below the clavicle and 4 cm away from the midline or the contacts. The distal tip is tunneled subcutaneously to the 2 cm from the lateral manubrial border. However, certain parietal/occipital region. The excess lead can be coiled around patients may require placement in other locations due to body

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habitus (very thin patients), age (pediatric patients), activities STN (378). As discussed below (in Complications of DBS and hobbies, a history of previous surgery in the region, or Surgery), it is possible that STN stimulation is more prone to cosmetic reasons. cognitive and behavioral complications (see Cognitive and Neurobehavioral Outcome and Complications with DBS). Outcomes of DBS for Movement Disorders However, outcomes from upcoming randomized, prospective large studies are expected to provide more insights into the rel- The literature relevant to movement disorder surgery is ative efficacy and risks associated with STN versus GPi DBS extensive: There are more than 1000 published articles per- for the treatment of PD. taining to DBS for movement disorders. In addition to the The encouraging results of STN DBS originally reported by retrospective and case report format of much of the literature, Benabid and the pioneering Grenoble group (26, 31, 180, 181, the reversibility feature (turning DBS on and off) on-demand 214–216, 289) motivated a large number of studies in the past allows for controlled, blinded assessments, making it one of decade that have further validated the safety and efficacy of the better-studied neurosurgical interventions. In addition, this procedure (80, 67, 79, 93, 94, 102, 107, 134, 145, 160, 165, validated rating scales for movement disorders have been 208, 212, 225, 258, 271, 276, 281, 304, 307, 315, 318, 344, 359, 360, established and are used in most surgical trials. These stan- 362, 394). A meta-analysis of the literature published in 2006 dardized, disease-specific rating scales allow for outcomes to reviewed the literature from 1993 to 2004. The mean reduction be expressed in a more objective fashion that is specific to the in UPDRS Part III scores among the 34 articles included in the disease of interest. study was 52% (comparing the DBS-on, medication-off state to STN and GPi DBS for PD the medication-off, DBS-off state). There was a large variation in reported outcomes, ranging from 82 to 17%. The mean (see video at web site) reduction in UPDRS Part II scores was 49.9%, ranging from 72 DBS has become the surgical procedure of choice for move- to 29.5%. As noted above, the preoperative response to L-dopa ment disorders, replacing stereotactic ablative procedures, for is considered a good outcome predictor of response to sur- the most part, in countries where access to this technology is gery and is, therefore, a heavily considered determination available. Outcomes from DBS are expressed more frequently regarding a patient’s candidacy for surgery. The correlation as absolute or as percent score reductions in the Unified between L-dopa response and positive outcomes after STN Parkinson’s Disease Rating Scale (UPDRS) Part III (motor) dur- DBS was confirmed by this meta-analysis as well as other ing the medication-off state. Thus, UPDRS Part III is a standard studies (384). outcome scale indicating motor benefits from a therapy. Data A few prospective, controlled studies have provided funda- on the impact of DBS upon activities of daily living (ADLs), mental contributions to the DBS literature and merit more percent reduction in dyskinesias, or incremental “on time” peri- detailed discussion. In 2001, the DBS for PD Study Group ods without dyskinesias are inconsistently reported. reported on the outcomes of 96 patients undergoing STN and Reductions in dyskinesias can be considered as a direct effect of 38 patients undergoing GPi DBS. The improvements in UPDRS DBS or may be secondary to a reduction in medication require- Part III motor subscores at the time of the 3-month follow-up ments (183, 369). (assessed with double-blind evaluations after patients were Prospective studies have reported on the outcomes of GPi randomly assigned to stimulation-on or -off states) were 49 and STN DBS for the cardinal symptoms of PD. Both targets and 37% for these groups, respectively. A continuation of this are shown to be beneficial (177, 183), although a trend exists study was reported in 2005 with 3-year or longer follow-up among these studies to indicate that STN DBS is more effec- period for 69 patients from the initial study. The 3-year or tive. In addition, STN DBS tends to allow for a greater reduc- longer follow-up data demonstrated that the effects of DBS for tion in the postoperative medication burden with consequent PD are long-lasting. The long-term benefits of DBS were later reduction in dyskinesias (80, 86, 181, 183, 282, 303). Direct com- substantiated by Krack et al. (177). Forty-nine consecutive parisons of GPi versus STN stimulation have been performed patients treated with bilateral STN DBS were assessed at 1, 3, in small samples of patients. The outcome data from these and 5 years after implantation. The mean reductions in UPDRS studies were not conclusive enough to exclude the GPi as an Part III scores at these time points were 66, 59, and 54%, respec- accepted DBS target for PD (368) and generally corroborated tively. ADLs were also improved. A significant decrease in effi- the advantage of using the STN in improving UPDRS Part III cacy was observed when the first and fifth years after surgery scores and L-dopa intake (15, 59). In addition, a recent report were compared. Nevertheless, most of these patients were of long-term bilateral pallidal stimulation in 11 PD patients dependent upon others before surgery and continued to enjoy confirmed the therapy’s sustained efficacy in alleviating dysk- independence throughout the entire follow-up period. Similar inesias. However, motor scores that had been alleviated in the 5-year follow-up results were reported by Schüpbach et al. first year deteriorated during the 5-year follow-up to an extent (315), with 54% reductions in UPDRS Part III scores and a 40% greater than would be expected from disease progression maintained reduction in UPDRS Part II scores. Additional long- alone. The lost motor benefits were not regained with addi- term outcome studies with follow-up periods ranging from 2 to tional programming, but were successfully recaptured in four 4 years reported on mean UPDRS Part III reductions of 48% in patients by repositioning the electrodes from the GPi to the 25 patients (170), 43% in 20 patients (367), 55% in 22 patients

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(271), 57% in 29 patients (148), and 45% in 20 patients (365). The undergoing thalamic stimulation to the outcomes of 17 patients latter study also reported on complete withdrawal of medica- who had previously undergone thalamotomy. Although the tion (replaced by stimulation) in 10 out of 20 patients. Such a effects from tremor suppression were very similar in both dramatic and early reduction of medication intake may have groups, complications, particularly intracerebral hemorrhages, accounted for some of the complications observed by the were more common among patients with thalamotomies (35 authors, such as dysarthria and cognitive problems (200). versus 0%). Likewise, cognitive deterioration and hemiparesis occurred, respectively, in 29 and 12% of patients who had Thalamic (VIM) DBS for Tremor undergone thalamotomies but in none of those with thalamic stimulation. Although thalamic stimulation is chronically effec- (see video at web site) tive for most patients (37, 57, 186, 213, 222, 228, 293, 316), reduc- The standardized assessment of tremor can be achieved via tions in efficacy during longer-term follow-up periods have the Tremor Rating Scale (TRS) (151, 329). Stereotactic thalamo- been reported (32, 173). tomies targeted at the VIM nucleus are well-established proce- The vast majority of thalamic DBS procedures have been tar- dures for the management of tremors from PD or essential geted at the upper extremity function. However, lower extrem- tremor (8, 103, 115–117, 166, 167, 253–255, 343). In managing ity, head/neck, and axial tremor are also common problems patients with PD, thalamotomies alleviate tremors without sig- that negatively impact quality of life for patients with essential nificantly affecting the other cardinal symptoms of PD. Uni- tremor. Putzke et al. (293) reported on the outcomes of 22 lateral thalamotomies are considered relatively safe, but bilat- patients with head, voice, or trunk tremor undergoing bilateral, eral procedures carry an elevated risk of neurological deficits staged, DBS thalamic implants. Bilateral stimulation was more such as dysarthria and cognitive deterioration (237). Chronic effective than unilateral stimulation in alleviating axial tremors; stimulation was considered a potential alternative to thalamo- however, as for bilateral thalamotomies, the rate of neurologi- tomy, at least partly because the known tremor-alleviating cal complications was higher in patients who underwent bilat- effects of acute stimulation were used for physiological confir- eral stimulation. Dysarthria was observed in 27% of patients mation during ablative stereotactic interventions (116, 255). In with bilateral stimulation, whereas none of those undergoing addition, thalamic chronic stimulation had already been unilateral stimulation experienced the same problem. Likewise, demonstrated to be feasible and safe for patients undergoing disequilibrium was more common during bilateral stimulation. stereotactic interventions for chronic pain conditions (153, 154, Although unilateral stimulation was comparatively less effec- 192, 211, 298–300, 354). Benabid et al. (35, 36) initially applied tive, it still demonstrated a significant reduction in axial thalamic stimulation contralateral to thalamotomy in patients tremors when compared with the preoperative baseline and with PD. Their preliminary experiences revealed a greater effi- stimulation-off periods. These findings are supported by the cacy of thalamotomy over stimulation. In 1991, the results of work of Koller et al. (172) in a prospective assessment of 38 chronic VIM stimulation for tremor were reported in a series of patients with head tremor undergoing unilateral thalamic stim- 32 patients with essential tremor or PD who had undergone 43 ulation. In this study, 71% of patients presented with tremor thalamic stimulation implants (11 patients underwent bilateral alleviation at 3 months. The effects remained generally stable stimulation). At a mean follow-up period of 13 months, 88% of over the long-term (1 yr) follow-up period. Stimulation set- the implanted DBS electrodes resulted in major or complete tings varied minimally during this period, further corroborat- relief from tremors. DBS, initially considered an alternative to ing the stability of the effects. Although staged bilateral proce- stereotactic thalamotomy, gradually became the surgical proce- dures are often preferred for axial symptoms, they may not be dure of choice for the treatment of essential tremor, as it safer than simultaneous implantation procedures (337). demonstrated similar efficacy rates and lower risks (174, 275, 316, 343). A direct comparison between thalamotomy and thal- GPi DBS for Dystonia amic stimulation was reported by Schuurman et al. (316). Stereotactic ablative surgery of the GPi (pallidotomy) has Seventy patients with PD, essential tremor, or tremor from mul- been attempted in the past in patients with generalized dysto- tiple sclerosis were randomized to stimulation or ablative sur- nia. Encouraging results have been reported (91, 92, 150, 371) gery groups. Patients with unilateral symptoms underwent a but, unlike reports of thalamotomies for treating tremor, the single intervention contralateral to the symptoms. Patients with best results are not observed immediately, but rather, after sev- bilateral tremors underwent either bilateral thalamic stimula- eral weeks or months (218, 224). Unilateral and, in particular, tion or a unilateral thalamotomy with contralateral stimula- bilateral pallidotomies may carry a higher risk of neurological tion. Patients with PD and essential tremor who had undergone morbidity, including lethargy and hemiparesis (270, 345), even thalamic stimulation performed significantly better in ADLs in the absence of hemorrhagic complications. Excellent results than those undergoing ablation. Sixteen adverse effects from bilateral stimulation of the GPi were initially reported for occurred among the patients randomized to the thalamotomy an 8-year-old child with severe dystonia (75). In this age group, group. In comparison, only six patients with thalamic stimula- bilateral pallidotomies were considered by the authors to be tion experienced adverse effects, which were successfully particularly risky (74), and DBS was attempted as a compas- resolved with stimulation cessation. Pahwa et al. (275) reported sionate, last-resort alternative. The results encouraged formal similar results when comparing the outcomes of 17 patients assessment of this technique with prospective cohorts. In most

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of the literature, treatment outcomes for generalized dystonia for PD because both STN and GPi DBS significantly improve are measured using the Burke-Fahn-Marsden Dystonia Rating tremor as well as other manifestations of PD. Patients with Scale (BFMDRS), whereas treatment outcomes for torticollis axial tremors tend to benefit from bilateral stimulation, which are assessed using the Toronto West Spasmodic Torticollis carries a higher risk of adverse neurological effects. Rating Scale. The former has a total of 120 points (higher is Bilateral pallidal (GPi) DBS is safe and effective for alleviat- worse) and takes into account the severity at each segment as ing primary generalized and segmental dystonia, but the well as the provoking factors. The latter scale, which is specific results may not be evident until after several weeks or months for torticollis, takes into account severity, disability, and pain. of stimulation. Patients who are positive for the DYT-1 muta- In 2004, Coubes et al. (74) reported on the long-term results tion and those with disease of early onset may experience of 31 patients with primary generalized dystonia, 14 of whom greater benefits. were positive for the DYT-1 gene mutation. There was an over- In reviewing the outcomes of movement-disorder surgery, it all mean improvement of 50% in the BFMDRS at 3 months, is important to emphasize that there should be more random- with additional gains observed at the 2-year follow-up evalua- ized, prospective, and controlled studies in the future. In addi- tion, reaching a mean improvement of 65%. DYT-1-positive tion, systematic and standardized assessment, reporting, and patients had improved more (74%) than patients with DYT-1- publication of outcome and complications are necessary. This negative disease (58%). Subsequent series also found better includes the use of published and accepted standardized rating outcomes among primary dystonia patients (92), with most scales for tremor, PD, and dystonia, with evaluations per- dramatic improvements observed in patients with disease of formed by a blinded observer who is unaware of the stimula- early onset (184). Gradual improvement (or maintenance) of tion status (on versus off). The implementation and publication results after 3 years has been demonstrated (364), further vali- of standard and rigorous study designs and outcome reporting dating DBS for treatment of generalized dystonia. Significant will facilitate the acceptance and development of DBS surgery and sustained long-term improvements have been reported in as a standard therapeutic modality for movement disorders. patients with spasmodic torticollis (49). Pallidal stimulation for dystonia has been formally assessed Cognitive and Neurobehavioral Outcome and in prospective, controlled, multicenter studies. Results from a Complications with DBS series of 22 patients with primary generalized dystonia (seven The vast majority of data documenting neurobehavioral out- of whom were DYT-1 positive) were described by Vidailhet comes after DBS involve patients who underwent surgery in and the French Stimulation du Pallidum Interne dans la the STN. The most common neuropsychiatric side effect in the Dystonie Study Group (363). At the 3-month follow-up, inves- immediate postoperative period after STN DBS is transient tigators who were blind to the status of stimulation assessed confusion, with an incidence that ranges between 1 and 36% dystonia severity through video recordings. At 12 months, the (5, 18, 61, 72, 95, 107, 131, 138, 177, 244, 250, 281, 285, 286, 303, dystonia-movement scores had decreased to a mean of 21, com- 352, 380, 389, 390). Evidence of greater neuropsychological pared with a baseline preoperative mean score of 46.3. Similar deficits before surgery is significantly associated with blinding methodologies were used by Kupsch and the DBS for increased confusion after surgery (284). In general, the data Dystonia Study Group (194) to assess patients with primary suggest that the most frequently observed long-term neu- generalized or segmental dystonia. Greater reductions in the ropsychological change after STN DBS is a decline in word flu- dystonia-movement scores were evident in the stimulation ency. A recent meta-analysis of the available data confirmed group (15.8 points, 39.3%) than in the sham stimulation group this finding (281). The meta-analysis revealed much smaller, (1.4 points, 4.9%). Surprisingly, there were no significant differ- yet significant, declines on measures assessing executive func- ences in the degree of amelioration of patients who were posi- tion, verbal learning, and memory. These findings are consis- tive for the DYT-1 mutation versus those who were negative for tent with those reviewed elsewhere in the literature (380, 390). the mutation. Significant differences were also not apparent However, it is critical to recall that the majority of available when the outcomes of patients with generalized dystonia were neuropsychological outcome studies have not included control compared with those with segmental dystonia. groups, did not statistically control for potential practice In summary, GPi or STN DBS has been demonstrated to be effects, and generally consisted of small groups, resulting in effective in alleviating the symptoms of medically refractory reduced power; this makes it very difficult to ascertain signif- PD in multiple reports in the literature. These results were con- icant cognitive effects unless the related effect sizes were very firmed by prospective series with double-blinded assessments large. Virtually no studies have clearly identified potential risk and were largely sustained at 5-year follow-up evaluations. A factors for increased cognitive decline after STN DBS. Aybek trend exists in favor of STN versus GPi DBS that must be ver- et al. (18) recently reported that the incidence of conversion to ified once the outcome of additional studies comparing GPi dementia in PD patients who underwent STN DBS over a and STN is available. 3-year follow-up period was similar to the incidence reported Chronic stimulation of the VIM thalamus has become the for medically treated patients. Furthermore, risk factors for procedure of choice for the treatment of tremors because of its the development of dementia in surgical patients were similar associated high efficacy rates and low risks. VIM DBS is also to those identified in non-surgical PD patients and included highly effective for PD tremor, but it is rarely performed today increased age, presence of hallucinations, and reduced scores

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on measures of executive cognitive function. The preliminary declines in word fluency were documented after left-sided data suggest that DBS in the STN may result in greater cogni- VIM stimulation in one study (380). tive and neurobehavioral changes than GPi DBS in patients In summary, the neurobehavioral outcome literature suggest with PD (15, 303, 378). This observation might reflect the rela- that the cognitive effects associated with DBS in the STN, GPi, tively smaller size of the STN with the increased proximity of and VIM are relatively minor in well-selected patients. The associative (cognitive), limbic, and motor circuits, and the sub- neuropsychiatric outcome data are more limited, and surgeons sequent increased likelihood of misplaced electrodes and/or should be alert to the possibility of neuropsychiatric symptoms current spread to non-motor circuits. More detailed, prospec- after surgery, particularly STN DBS, but it is still unknown tive studies are necessary to ascertain the relative neurobe- whether these symptoms reflect neurosurgical/neurostimula- havioral risks associated with STN versus GPi DBS for the tion effects or ongoing disease progression. treatment of PD. Despite the methodological concerns and rel- atively limited data, it appears that STN DBS is a relatively Complications of DBS Surgery safe procedure from a neuropsychological perspective in well- selected patients. Understanding the complications of any surgical procedure Neuropsychiatric symptoms have also been reported after helps in anticipating, preventing, recognizing, and promptly STN DBS, and several studies have reported hypomania, intervening on such occasions. The complications of DBS sur- depression, apathy, and suicidality (380). Postoperative hypo- gery can be mainly classified into four categories. These include mania was reported in 4 to 15% of STN patients in four studies intracranial hemorrhages, infections, hardware-related issues, (79, 147, 177, 306), and postoperative depression has been and stimulation-related complications. The incidence of reported to occur in up to 1.5 to 25% of patients (147, 156, 177, reported complications is variable among centers and has been 236, 245, 272, 302, 306, 348, 358, 379). The extent to which med- changing over the past few years as a result of the increased ication changes after surgery contributed to the reported experience of the surgical team, advancement in techniques, changes in mood state is not well known. Overall group and improvement in devices. Another factor contributing to depression scores have been reported to improve at 3 and 12 the observed variability in complication reporting is the lack of months after surgery in multiple studies (79, 89, 285, 379); how- a systemic and consistent process for complication definition, ever, most studies relied on reporting group mean depression recording, and assessment. For example, not all centers report- scores, which may be misleading. A more accurate indication of ing outcomes obtain postoperative imaging to evaluate for a the number of patients who met criteria for depression before hemorrhage that is nonsymptomatic. Instead, imaging is only and after surgery is a more clinically relevant variable. Some performed if there is clinical change in the patients. Similarly, uncontrolled series have documented suicide attempts and/or the reporting of infections is inconsistent because the definition suicides after placement of DBS electrodes in the STN (45, 177), of “infection” varies (i.e., an infection that requires hardware but, once again, there are no data to indicate a clear relationship explantation versus a superficial wound infection). to stimulation. Within the first 3 postoperative months, apathy, which can respond to administration of dopaminergic medica- Intracranial Hemorrhage tion, can occur, although the incidence is unknown. In con- Intracranial hemorrhage is one of the most important compli- trast, more permanent apathy was identified in 12% of patients, cations of movement-disorder surgery. Intraoperative hemor- in whom 80% had associated decreases on executive cognitive rhages are reported to occur in 0.2 to 12.5% of all STN DBS measures (177). It is important to recognize that all of the neu- cases (43, 46, 47, 50, 84, 121, 139, 161, 171, 173, 175, 177, 211, 212, ropsychiatric symptoms previously described are evident in 229, 347, 356, 361). The correlation of hemorrhage with the type medically managed nonsurgical patients with PD. Conse- of procedure is an area of controversy. According to Blomstedt quently, it is very difficult to ascertain, on the basis of the cur- and Hariz (50), there is no significant difference between the rent literature, the extent to which STN DBS is truly associated hemorrhage risk in lesioning (1.6%) versus DBS surgeries. with increased neuropsychiatric symptoms versus the role of Terao et al. (347), however, reported a lesion surgery bleeding underlying ongoing disease progression. rate of 15.8% (thalamotomy, 21.7%; pallidotomy, 11.8%) versus The neurobehavioral outcome literature after DBS in the a hemorrhage rate in DBS operations of 3.4% (347). Hemor- GPi and VIM is much more limited than that pertaining to rhages can be extradural, subdural, and intraparenchymal. STN DBS. Many studies examining cognitive and neuropsy- Intraparenchymal hemorrhages are the most common and typ- chiatric outcomes after GPi DBS documented no significant ically occur in the tract of the electrode or in the periventricu- declines. Isolated studies identified mild declines on measures lar region in close proximity to vessels associated with the ven- of word fluency and visuoconstructional skills (380). There tricles (Fig. 17). The size of the hemorrhages is generally small. are very few studies examining neurobehavioral outcomes There is little agreement on the predictors of intraoperative after VIM stimulation, and interpretation of the available data hemorrhages in patients who undergo DBS. The common fac- is confounded by small samples of patients with mixed diag- tors identified include: noses. In general, most of the data revealed no significant 1) High blood pressure: the practices of carefully controlling cognitive or neuropsychiatric declines. Improvements in ver- blood pressure and painstakingly planning the trajectory, bal memory were documented in two studies, whereas avoiding vasculature seen on the contrast-enhanced preop-

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A B 87, 112, 118, 124, 168, 171, 175, 194, 212, 229, 259, 265, 346, 349, 356, 361, 374, 376). This is probably because different clinical definitions are used for identifying infection. The criteria for diagnosing infec- tions are not well defined in the reported literature. DBS- FIGURE 18. Intraoperative image related infections have a vari- obtained during removal of an able presentation in terms of infected IPG showing the time and location. Typically, infected IPG with subsequent the infection presents within wound breakdown. 3 months after surgery, and FIGURE 17. Axial non-contrast computed tomographic (CT) scans show- ing intraparenchymal hemorrhage during the placement of a DBS elec- the most common site was at trode. A, hemorrhage at the thalamus (target site). B, hemorrhage at the the IPG (Fig. 18) (51, 80, 168, 194, 229, 349, 356, 374, 376). periventricular region with a small intraventricular extension. Infections of the IPG tend to present soon after surgery, as do infections at the burr hole. Infections at the connector may be related to erosions. This scenario was more common in the erative images, help reduce the incidence of hemorrhages. past, when the extension connectors were larger. The introduc- There is a statistically significant association of hemorrhagic tion of the lower-profile extension connector has significantly complications with hypertension (118). Bleeding occurs in reduced the incidence of erosions. 10.71% of hypertensive patients and 0.91% of those who Clinically, the infections presented as cellulitis, erythema, were normotensive (P ϭ 0.0111). The same study also docu- drainage, dehiscence, or stitch abscess. The common bacterial ments that the combination of MER and hypertension pathogens isolated are Staphylococcus aureus, S. epidermidis, increases the risk of hemorrhage to 16.67% (118). Serratia sp., Klebsiella sp., and sometimes, Escherichia coli and 2) MER: an increased incidence of bleeding in hypertensive mixed flora. Most of the published data fail to address any spe- patients who underwent MER (P ϭ 0.034) was observed by cific predictors for the infections. The risk of brain abscess from Gorgulho et al. (118). There are reports that strongly impli- DBS infection is extremely low, with only one case reported cate MER as a risk factor for hemorrhage (137), and there are (240). studies that state otherwise (46, 47, 372). It is difficult to The important management decision is whether to remove or draw any conclusion from the available literature pertaining keep the hardware. Very superficial infections can be treated to increased risk of hemorrhage with MER. with oral or intravenous antibiotics. Deep-tracking infections 3) Target: some studies have documented that the GPi is more require surgical intervention. However, if there is no purulent prone to hemorrhagic complication compared with the STN or necrotic material in direct contact with the hardware, or the thalamus. Binder et al. (47) have shown a 7% risk of debridement, irrigation, and a hardware-sparing approach can GPi hemorrhage compared with 2.2% risk of STN hemor- work. If the pus is in direct contact with the hardware or if the rhage. In 2001, the DBS study group reported similar results hardware is exposed, it should be promptly removed. In most (GPi, 9.8%; STN, 2.9%) (80). It has been suggested that cases with localized infection, partial hardware-removal strate- anatomic peculiarity of the vasculature in the GPi region gies can be successfully used, such as removal of the infected may be responsible for the increased incidence of hemor- IPG and retaining of the DBS lead that is not infected. After sev- rhage (47). The GPi is supplied by the lenticulostriate arter- eral weeks of antibiotic therapy, the removed hardware can be ies that come from the anterior circulation. These arteries safely replaced. are more prone to the effects of hypertension and may also be developmentally different (47). Hardware-related Complications 4) Trajectory planning: the use of image fusion of CT and MRI Hardware-related complications are the most common, with scans helps in performing accurate targeting. The images a varying incidence that ranges from 2.7 to 50% (27, 71, 138, that help most in avoiding hemorrhagic complications are 140, 175, 229, 232, 279). These include DBS electrode fracture, the postcontrast T1-weighted MRI scans. These images extension wire failure, lead migration, skin erosion, IPG mal- reveal small paraventricular, sulcal, intraventricular, and function, and pain over the pulse generator (11, 43, 46, 47, 50, ependymal vessels (Fig. 14) and assist with the planning of 76, 84, 87, 112, 118, 124, 168, 171, 175, 212, 265, 347, 356, 361). a vessel-free trajectory. They can be subdivided into complications associated with the lead, those associated with the extension wires, and the IPG (51, Infections 71, 132, 175, 229, 265, 278, 321, 376). Reported infection rates for DBS surgery vary widely, from Because the brain lead is the most delicate part of the hard- less than 1% to as high as 15% (11, 43, 46, 47, 51, 50, 76, 80, 84, ware, it can malfunction or get damaged due to a variety of

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causes. These include lead ized on the side contralateral to the stimulation. The treatment fracture, lead erosion, and for this is steering the current away from the capsule by adjust- lead malfunction. The frac- ing the stimulation-field parameters (87). Stimulation can also tures are most often the result induce side effects in ocular movements causing either monoc- of a fall or trauma (Fig. 19). ular deviation (spread to oculomotor nucleus), conjugate gaze However, fractures can occur deviation (spread to capsule) or eyelid apraxia (87, 179). secondary to migration of the Overall, the stimulation-induced complications must be moni- connector to the neck (296) or tored with the neurologist and the programming team. even with unusual condi- In summary, as the number of DBS surgeries increases, there tions, such as compulsive will be more complications. The hypervigilance of the team is FIGURE 19. Lateral cranial x- twisting (232). Lead erosion is necessary to avoid, recognize, and manage complications asso- ray showing two DBS leads, one not commonly observed and ciated with DBS implants. of which is broken with a curved is usually caused by superfi- end (arrow). This patient pre- cial placement of the lead. Neurorestorative Surgical Approaches for PD sented with loss of efficacy and Lead malfunctions are gener- DBS is currently the best surgical approach for movement local pain due to the hook-like part ally related to connector mi- disorders with respect to safety, efficacy, and proven track of the electrode pressing on the gration in the cervical region record. However, DBS is an implantable device, with its asso- scalp. that causes stress on the lead ciated complications, and it treats the symptoms of the patient and results in multiple open and not the underlying disease. In this context, restorative or short circuits. Complications associated with extension strategies aimed at treating the underlying disease pathophys- wires are more uncommon than of the DBS lead because the iology are important. extension material is more robust. Extension wire complica- A variety of surgical neurorestorative approaches have been tions include erosions (if placed superficially), fractures, and developed in an attempt to prevent the loss of nigral neurons pain and/or tightness that result from superficial placement and stimulate the regeneration of nigrostriatal projections. (51, 71, 132, 175, 229, 265, 278, 321, 376). Complications asso- These include the delivery of protein trophic factors, the deliv- ciated with the IPG include erosion, caudal migration of IPGs, ery of therapeutic genes, and the transplantation of a variety of and shocking sensations at the IPG site (51, 71, 87, 132, 175, potentially restorative cell types. 265, 278, 321, 376). Subfascial implantation of the IPG is an alternative to subcutaneous implantation and may be advan- Delivery of Therapeutic Growth Factors tageous in very thin patients. Translational research on growth factors for PD has focused on the glial-derived neurotrophic factor (GDNF), family lig- Stimulation-related Complications ands, and neurturin. Much of the literature supports the ability These are complications associated with programming of the of these proteins to protect dopaminergic neurons from a vari- DBS system after surgery. For the most part, these complica- ety of toxic insults in cell culture and rodent and primate mod- tions are reversible and require vigilance of the programmer. els (3). These observations led to two separate open-label stud- However, if a DBS lead is placed suboptimally, even the most ies of GDNF infusions into the human parkinsonian putamen expert programming cannot help, and the patient may require (114, 324). Both open-label studies demonstrated significant revision surgery. improvements in UPDRS scores in the recipients. The second The most common stimulation-induced complications are study demonstrated a gradual return to baseline in the first dyskinesias, worsening of axial symptoms, speech dysfunc- year after cessation of GDNF delivery. Enthusiasm generated tion, capsular stimulation, and ocular symptoms. Stimulation- by these open-label trials led to an international, multicenter, induced dyskinesias can be a good sign of accurate placement randomized placebo-controlled trial sponsored by Amgen and are generally self-limiting (179, 217). They are observed (Thousand Oaks, CA) and Medtronic. In this study, patients after STN DBS and may require adjustment in stimulation were randomized to receive either GDNF or vehicle through parameters or change of dosage of dopaminergic medications bilateral putamenal catheters. The approach was abandoned (87, 217). Worsening of axial symptoms such as freezing and by the sponsors after the safety and efficacy data were balance and gait disturbance have been reported in some stud- reviewed, including the development of anti-GDNF antibodies ies (59, 87, 104, 127, 170, 271, 394). It has been suggested that in some of the patients, and the observation that some monkeys changing the active contact and adjusting the stimulation had developed cerebellar lesions attributed to putamenal parameters are generally helpful (87, 127). Dysarthria or hypo- GDNF therapy. Results of the study at the time of termination phonia as a side effect of STN stimulation is observed in 4 to revealed no significant difference between the placebo and 17% of patients (59, 87, 104, 127, 170, 271, 394). The etiology is treatment groups, although positron-emission tomographic considered to be the spread of current to the capsule. Moving imaging revealed increased dopamine production in the treat- the active contact away from the capsule or reducing the ampli- ment group in the region immediately adjacent to the cannula tude may help reduce this side effect (87). Capsular stimulation tip (199). Proponents of intraparenchymal GDNF infusion ther- can also cause muscle contraction that can be focal or general- apy cite potential problems with catheter design and drug dis-

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tribution as possible reasons for the trial’s failure (317). A second trial has been pursued by Oxford Biomedica Ongoing research with a naturally-occurring structural and (Oxford, England) for stereotactic injection of a lentiviral vector functional analog of GDNF, neurturin, suggest that this growth carrying three separate transgenes: tyrosine hydroxylase, factor may also offer a potential means of dopamine neuron AADC, and guanosine triphosphate cyclohydrolase I. Together, protection via intraparenchymal delivery. these gene products are capable of driving autonomous pro- duction of L-dopa with subsequent dopamine production. Delivery of Therapeutic Genes Thus, unlike the Genzyme strategy, the Biomedica vector, Two separate restorative gene-therapy strategies have entered named Prosavin, will drive dopamine production independent clinical trials: trophic factor gene delivery and dopamine of L-dopa administration (388). The company plans a Prosavin replacement. Ceregene (San Diego, CA) has taken the lead on trial in either England or France. stereotactic growth factor gene therapy with its product CERE- A third gene-therapy approach has been advanced by 120, an adeno-associated viral vector for the delivery of the Neurologix (Fort Lee, NJ). This approach induces subthalamic gene for neurturin. The basis for the Ceregene trial can be and pallidal inhibition through the expression of glutamate found in the primate studies of striatal GDNF gene delivery decarboxylase in the STN. Glutamate decarboxylase is the with viral vectors, which demonstrated protection of striatal enzyme that changes glutamate to GABA. Thus, inhibition is dopamine delivery with tyrosine hydroxylase staining, affected by the production of GABA in the STN, and a reduction positron-emission tomography, and behavior studies in two in efferent glutamate. Twelve patients received unilateral STN different monkey models. Preclinical studies by Ceregene injection at three escalating doses (n ϭ 4 patients per group) to demonstrated that CERE-120 could similarly protect dopamine minimize risk. Investigators reported sustained improvements neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in UPDRS motor scores at 12 months (24% off state and 27% on monkey model (176), as well as enhance dopamine markers state), with no serious adverse events related to gene therapy. and activity in aged primates. The Phase I CERE-120 trial tested Positron-emission tomographic studies confirmed reduction in the safety and tolerability of putamenal CERE-120 injection in thalamic metabolism (163). As the Neurologix project was the 12 patients. Surgery consisted of four injections targeting the first PD gene therapy trial to pass through regulation, particu- putamen on each side, with two deposits at each injection site. lar care was required in addressing safety over efficacy (as Open-label follow-up of this initial cohort for 6 months has reflected in the decision to inject unilaterally). The authors note revealed no serious adverse events or decline in neurological that effects were proportionally larger on the side contralateral condition. UPDRS off scores were reported to improve by to infusion, which lends weight to the hypothesis that gene- roughly 40% in these Phase I patients at 12 months postdosing based STN inhibition can provide a benefit beyond placebo. compared with each patient’s own baseline (P Ͻ 0.001) (333). On the basis of these results, a Phase II sham-surgery, con- Cell Transplantation Delivery trolled, multicenter trial was initated in December 2006. The approach of cell transplantation has the longest history, The next strategy, alteration of neurotransmitter production, and perhaps, the most complex landscape. A wide variety of has been pursued by three groups. The first trial (Genzyme, cells have been studied as potential means to provide neuro- Westborough, MA) uses an adeno-associated viral vector to protection and potentially replace lost dopamine neurons. deliver the gene for aromatic amino acid L-dopa decarboxylase Initial efforts used autografts of adrenal medullary cells as a (AADC). Initial experiments demonstrated that AADC expres- potential source of dopamine but failed to show consistent sion in the putamen could restore striatal dopamine when L- improvements (97). Subsequent efforts involved the transplan- dopa was administered in animal models of PD (21). This strat- tation of fetal mesencephalic tissue containing nigral dopamine egy provides a potential means to control the amount of cells transplanted into the putamen. Results in this study dopamine produced through the amount of L-dopa adminis- proved inconsistent as well, with some patients showing tered. The investigators hypothesized that this approach would improvements. However, a subset of patients developed an prevent the development of runaway dyskinesias such as those exacerbation of dyskinesias thought to be a result of heteroge- that complicated fetal mesencephalic transplants. This team neous and uncontrolled production of dopamine throughout (21) conducted extensive preclinical studies, including an the putamen (106, 305). Contemporary efforts at neural trans- examination of the role of convection-enhanced delivery in plantation have involved putamenal implantation of retinal viral injection as well as testing of a silicon tubing injection pigment epithelial cells grown in a bead matrix called cannula. The issue of ideal cannula design has emerged as Spheramine (Titan, San Francisco, CA). Retinal pigment epithe- important to prevent vector-cannula binding with a resulting lial cells can produce L-dopa, but also appear to have decrease in the titer delivered. The ongoing Phase I trial has trophic/protective effects on adjoining neurons (305, 335). An included patients at the University of California, San Francisco ongoing Phase II, controlled, multicenter trial is under way to with bilateral intrastriatal adeno-associated viral-AADC injec- assess the safety and efficacy of Spheramine implants. tions. To date, there have been no serious adverse events. Advances in stem cell technology have made it possible to Positron-emission tomography studies in initial patients manufacture dopaminergic neurons. A wide variety of proto- demonstrated a 15% increase in striatal AADC activity 6 cols have been developed for the production of dopamine cells months after injection. from embryonic stem cells, fetal-derived uncommitted and

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committed progenitors, and even adult progenitors harvested 2. Agid Y: Parkinson’s disease: Pathophysiology. Lancet 337:1321–1324, 1991. from the subventricular zone. Parallel strategies have been 3. Airaksinen MS, Saarma M: The GDNF family: Signalling, biological func- developed to purify the dopaminergic cells from nondopamin- tions and therapeutic value. Nat Rev Neurosci 3:383–394, 2002. 4. Akert K, Koella WP, Hess R Jr: Sleep produced by electrical stimulation of ergic cells in these preparations with the hope of creating a the thalamus. Am J Physiol 168:260–267, 1952. sustainable, practical source for pure, differentiated, human 5. Alegret M, Junque C, Valldeoriola F, Vendrell P, Pilleri M, Rumia J, Tolosa E: dopaminergic cells. Finally, a fusion of gene-delivery technol- Effects of bilateral subthalamic stimulation on cognitive function in ogy with transplantation (ex vivo gene transfer) provides a Parkinson disease. 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Alterman RL, Shils JL, Miravite J, Tagliati M: Lower stimulation frequency cal technical advancements, therapeutic device developments, can enhance tolerability and efficacy of pallidal deep brain stimulation for dystonia. Mov Disord 22:366–368, 2007. and innovative approaches. The growth in our understanding 10. Alterman RL, Sterio D, Beric A, Kelly PJ: Microelectrode recording during of the neural circuitry of the disease has determined and posteroventral pallidotomy: Impact on target selection and complications. refined our surgical targets. This increased understanding of Neurosurgery 44:315–323, 1999. the neurobiology of movement disorders will guide the discov- 11. Amirnovin R, Williams ZM, Cosgrove GR, Eskandar EN: Experience with ery of additional targets for surgical exploration and transla- microelectrode guided subthalamic nucleus deep brain stimulation. Neurosurgery 58 [Suppl]:ONS96–ONS102, 2006. tional clinical research. 12. 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Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP: Pallidal vs At present, DBS is the standard therapy of choice for subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 62:554–560, 2005. movement-disorder patients who are medication intractable 16. Andrade-Souza YM, Schwalb JM, Hamani C, Eltahawy H, Hoque T, Saint- and who meet the surgical selection criteria. DBS has a proven Cyr J, Lozano AM: Comparison of three methods of targeting the subthala- safety and efficacy profile and long-term outcomes have been mic nucleus for chronic stimulation in Parkinson’s disease. Neurosurgery demonstrated by prospective, randomized studies. Technologi- 56:360–368, 2005. cal advances in DBS systems have already resulted in improve- 17. Andrade-Souza YM, Schwalb JM, Hamani C, Hoque T, Saint-Cyr J, Lozano AM: Comparison of 2-dimensional magnetic resonance imaging and 3-pla- ments and will continue to do so. 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377. Volkmann J: Deep brain stimulation for the treatment of Parkinson’s disease. technical approaches are rapidly evolving, and it represents a coming J Clin Neurophysiol 21:6–17, 2004. era where elective neurosurgery can greatly enhance quality of life for 378. Volkmann J, Allert N, Voges J, Sturm V, Schnitzler A, Freund HJ: Long-term a prolonged period in serious neurological diseases. results of bilateral pallidal stimulation in Parkinson’s disease. Ann Neurol 55:871–875, 2004. Philip A. Starr 379. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V: Safety and San Francisco, California efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 56:548–551, 2001. eep brain stimulation for movement disorders joined the main- 380. Voon V, Kubu C, Krack P, Houeto JL, Troster AI: Deep brain stimulation: stream of neurosurgical practice only in the last 10 years, yet as Neuropsychological and neuropsychiatric issues. Mov Disord 21 [Suppl D noted by Rezai et al. (who have played no small role in increasing 14]:S305–S327, 2006. 381. Walker AE: Cerebral pedunculotomy for the relief of involuntary move- access to this procedure for patients with movement disorders as well ments; hemiballismus. Acta Psychiatr Neurol 24:723–729, 1949. as other more novel indications), more than 1000 articles have been 382. Walker AE: Cerebral pedunculotomy for the relief of involuntary move- published on this topic. A detailed, comprehensive review of this com- ments. II. Parkinsonian tremor. J Nerv Ment Dis 116:766–775, 1952. plex field would require a whole supplement (1), but the authors pro- 383. Weetman J, Anderson IM, Gregory RP, Gill SS: Bilateral posteroventral pal- vide a review that nevertheless addresses all of the major issues and is lidotomy for severe antipsychotic induced tardive dyskinesia and dystonia. in a very readable form. J Neurol Neurosurg Psychiatry 63:554–556, 1997. Certain aspects of surgical technique tend to inspire extensive debate 384. Welter ML, Houeto JL, Tezenas du Montcel S, Mesnage V, Bonnet AM, among functional neurosurgeons, such as the use of framed vs. frame- Pillon B, Arnulf I, Pidoux B, Dormont D, Cornu P, Agid Y: Clinical predic- less devices, or the use of microelectrode recording techniques. Rezai et tive factors of subthalamic stimulation in Parkinson’s disease. Brain al. provide balanced views of these areas, correctly pointing out that 125:575–583, 2002. 385. Wichmann T, DeLong MR: Pathophysiology of Parkinson’s disease: The these and other issues can only be resolved with prospective, random- MPTP primate model of the human disorder. Ann N Y Acad Sci 991:199– ized, blinded trials. However, it is not feasible to subject every nuance 213, 2003. of functional neurosurgical procedures to such a metric. Ten years later, 386. Wichmann T, Delong MR: Deep brain stimulation for neurologic and neu- we still do not know from prospective randomized trials (Class 1 evi- ropsychiatric disorders. Neuron 52:197–204, 2006. dence) whether the subthalamic nucleus (STN) truly is a “superior” tar- 387. Wills AJ, Jenkins IH, Thompson PD, Findley LJ, Brooks DJ: A positron emis- get to the globus pallidus internus, and what the relative risks and sion tomography study of cerebral activation associated with essential and benefits are (although two such trials will be arriving soon, one from writing tremor. Arch Neurol 52:299–305, 1995. Emory and the Cleveland Clinic, and the other from the multicenter 388. Wong LF, Goodhead L, Prat C, Mitrophanous KA, Kingsman SM, Mazarakis National Institutes of Health/Veteran’s Administration trial). Ten years ND: Lentivirus-mediated gene transfer to the central nervous system: Therapeutic and research applications. Hum Gene Ther 17:1–9, 2006. later, we must still suffer the endless debate about the utility of micro- 389. Woods SP, Fields JA, Lyons KE, Koller WC, Wilkinson SB, Pahwa R, Troster electrode recording, now obfuscating the pioneering work on new AI: Neuropsychological and quality of life changes following unilateral thal- potential targets for Parkinson’s disease (2, 3). As new indications, e.g., amic deep brain stimulation in Parkinson’s disease: A one-year follow-up. depression (7), and new targets, e.g., pedunculopontine nucleus (PPN), Acta Neurochir (Wien) 143:1273–1278, 2001. arrive on the landscape, new and old issues will arise, providing more 390. Woods SP, Fields JA, Troster AI: Neuropsychological sequelae of subthalamic fodder for prospective, randomized, clinical trials: Which is better, STN, nucleus deep brain stimulation in Parkinson’s disease: A critical review. PPN, STN + PPN, or STN then PPN (4, 5)? Which is better, gene ther- Neuropsychol Rev 12:111–126, 2002. apy or cell therapy or deep brain stimulation? If gene therapy is better, 391. Wooten GF: Progress in understanding the pathophysiology of treatment- then which gene therapy? Anterior internal capsule or Area 25 for related fluctuations in Parkinson’s disease. Ann Neurol 24:363–365, 1988. 392. Wycis HT, Baird HW, Spiegel EA: Pallidotomy and pallido-amygdalotomy depression? Medtronic (Minneapolis, MN) or Advanced Neuromodu- in certain types of convulsive disorders. Confin Neurol 17:67–68, 1957. lation Systems (Plano, TX)? Which method is better: yours, or mine, or 393. Yokoyama T, Sugiyama K, Nishizawa S, Yokota N, Ohta S, Uemura K: both, or neither? And has anyone yet subjected prospective, random- Subthalamic nucleus stimulation for gait disturbance in Parkinson’s dis- ized, double-blind, sham/placebo-controlled trials to a prospective, ease. Neurosurgery 45:41–49, 1999. randomized, clinical trial? Two such trials seemingly eliminated fetal 394. Zhang JG, Zhang K, Ma Y, Hu WH, Yang AC, Chu JS, Wu ST, Ge M, Zhang cell transplantation for Parkinson’s disease, but were the trials fair? Y, Wang ZC: Follow-up of bilateral subthalamic deep brain stimulation for Perhaps we will even see this subject revisited in the years to come (6). Parkinson’s disease. Acta Neurochir Suppl 99:43–47, 2006. If Rezai et al. reflects the state of the art for movement disorders alone 395. Zhang JG, Zhang K, Wang ZC: Deep brain stimulation in the treatment of 10 years later and approximately a century after surgery for move- tardive dystonia. Chin Med J (Engl) 119:789–792, 2006. 396. Zhang JG, Zhang K, Wang ZC, Ge M, Ma Y: Deep brain stimulation in the ment disorders began, I suspect functional neurosurgeons will be well treatment of secondary dystonia. Chin Med J (Engl) 119:2069–2074, 2006. occupied for the next century too. Robert E. Gross Acknowledgments Atlanta, Georgia We thank Charles Steiner, M.E., Martha Tobin, M.A., and Christine Moore, A.A., for their expert technical assistance in the preparation of this manuscript. 1. Benabid AL, Deuschl G, Lang AE, Rezai AR: Deep brain stimulation for COMMENTS Parkinson’s disease. Mov Disord 21 [Suppl 14]:S168–S170, 2006. 2. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant his ambitious article shows what a privilege it is to participate in the depression. Neuron 45:651–660, 2005. Textraordinary world of movement disorder surgery. This narrow 3. Mazzone P, Stanzione P, Lozano A, Scarnati E, Peppe A, Galati S, Stefani A: subspecialty is paradigmatic of the “golden age” of neurosurgery, com- Reply: The peripeduncular and pedunculopontine nuclei: A putative dispute bining so many of the elements that fascinate and inspire us: Its rise has not discouraging the effort to define a clinically relevant target. Brain 130:E74, been fueled by seminal discoveries in basal ganglia physiology, the 2007 (comment).

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4. Plaha P, Gill SS: Bilateral deep brain stimulation of the pedunculopontine ezai et al. provide an outstanding review of the history, present nucleus for Parkinson’s disease. Neuroreport 16:1883–1887, 2005. Rstatus, and possible future of movement disorder surgery that has 5. Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi progressed from gross ablations to precise lesioning to neuroaugmen- M, Brusa L, Scarnati E, Mazzone P: Bilateral deep brain stimulation of the tation and neuromodulation. Initially based on empiricism and a crude pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain understanding of the neural circuitry of the motor system, functional 130:1596–1607, 2007. neurosurgery has been ever more refined by better understanding of 6. Tuszynski M: Rebuilding the brain: Resurgence of fetal grafting. Nat Neurosci 10:1229–1230, 2007. extrapyramidal neurophysiology and cellular neurochemistry. As a 7. Zrinzo L, Zrinzo LV, Hariz M: The pedunculopontine and peripeduncular result of modern advances in basic science, future procedures may go nuclei: A tale of two structures. Brain 130:E73, 2007. beyond simple manipulation of large cellular populations for the con- trol of symptoms (as we do now with deep brain stimulation neu- n this article, Rezai et al. provide an excellent overview of the current roaugmentation) to neurochemically target-specific cellular groups Istatus of movement disorder neurosurgery. The information is pro- within these populations. In addition, genetically programmed stem vided in a well-organized manner and the literature review is exten- cells may be used to repopulate central nervous system regions whose sive. The conclusions presented are based on the available literature, cells have been decimated by the underlying disease process. However, gray areas in our knowledge are appropriately highlighted, and profes- the ultimate therapy may focus on identifying and reversing the neu- sional biases are minimized. This is a comprehensive first read for any- rotoxic triggers that result in selective loss of neuromelanin-containing one interested in participating in this exciting field of neurosurgery. dopaminergic neurons in the substantia nigra.

Ron L. Alterman Patrick J. Kelly Bronx, New York New York, New York

Dissection of the brain, (engraving, after A. Vesalius, Fabrica, 1543), T. Geminus, Compendiosa totius anatomie delineatio. London, J. Herford, 1545. (From: Roberts KB, Tomlinson JDW: The Fabric of the Body: European Traditions of Anatomical Illustration. Oxford, Clarendon Press, 1992).

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