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Deep Brain Stimulation for Intractable Psychiatric Disorders

Wayne K. Goodman1 and Ron L. Alterman2
1

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Department of Psychiatry and 2 Department of Neurosurgery, Friedman Brain Institute of the Mount Sinai School of Medicine, New York, New York 10029; email: wayne.goodman@mssm.edu

Annu. Rev. Med. 2012. 63:51124 First published online as a Review in Advance on October 27, 2011 The Annual Review of Medicine is online at med.annualreviews.org This articles doi: doi: 10.1146/annurev-med-052209-100401 Copyright c 2012 by Annual Reviews. All rights reserved 0066-4219/12/0218-0511$20.00

Keywords
depression, obsessive-compulsive disorder (OCD), psychiatric disorders

Abstract
Deep brain stimulation (DBS) has virtually replaced ablative neurosurgery for use in medication-refractory movement disorders. DBS is now being studied in severe psychiatric conditions, such as treatmentresistant depression (TRD) and intractable obsessive-compulsive disorder (OCD). Effects of DBS have been reported in 100 cases of OCD and 50 cases of TRD for seven (ve common) anatomic targets. Although these published reports differ with respect to study design and methodology, the overall response rate appears to exceed 50% in OCD for some DBS targets. In TRD, >50% of patients responded during acute and long-term bilateral electrical stimulation in a different target. DBS was generally well tolerated in both OCD and TRD, but some unique, target- and stimulation-specic adverse effects were observed (e.g., hypomania). Further research is needed to test the efcacy and safety of DBS in psychiatric disorders, compare targets, and identify predictors of response.

Supplemental Material

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INTRODUCTION
OCD: obsessivecompulsive disorder MDD: major depressive disorder PG: pulse generator

This century marks the start of a new era of neurosurgical treatment for severe psychiatric disorders: the use of deep brain stimulation (DBS) devices. In 1999, the rst reports were published in Lancet on the use of DBS in intractable obsessive-compulsive disorder (OCD) (1) and Tourette syndrome (2). The rst report of DBS in refractory major depressive disorder (MDD) appeared in 2005 (3). The pace of research is accelerating, and DBS for one psychiatric indication, intractable OCD, is already clinically available on a humanitarian basis in the United States. This article reviews the current status of DBS for OCD and MDD. DBS forTourette syndrome, with its 10 potential anatomic targets, was excluded from the article owing to space considerations (4). The subject of neurosurgery for psychiatric disorders seems incomplete without some reminders about the lessons learned from the indiscriminant use of frontal leucotomies (severing white matter connections to the prefrontal cortex) (5). Between 1939 and 1951, >18,000 frontal leucotomies were performed in the United States alone (6). The problems of this rst period in psychiatric neurosurgery were not limited to the crudeness of the surgical procedures and cavalier behavior of its principal proponent, Walter Freeman (7, 8). Despite the call for rigorous clinical trials, none was performed that would approach our current methodological standards. The protection of human subjects was woefully inadequate and the specter of behavioral control haunted the era. Frontal lobotomy came to an abrupt end in the 1950s with the introduction of chlorpromazine, a safer and more effective alternative for managing psychosis (5). Other factors, including public outrage, contributed to its demise (6, 7). Although lobotomy vanished, the use of more modern neurosurgical approaches that produced more precise and much smaller lesions in patients with psychiatric illness was not entirely abandoned. With the introduction of the stereotactic frame and its later marriage
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to high-resolution structural imaging, surgical morbidity and collateral damage to personality were reduced dramatically (7, 8). A further renement came in the form of radiosurgical approaches (e.g., the gamma knife) that could produce precise deep brain lesions without a craniotomy (8). The main clinical advantages of DBS over lesioning procedures are reversibility and adjustability (5). Because of these features, DBS has become the standard of care for medicationrefractory Parkinsons disease, essential tremor, and dystonia (9, 10) (see Table 1 for FDA approval status). If DBS treatment is unsuccessful, the hardware can be explanted with little consequence for the patient. The available data from postmortem examination of brains from patients with implanted electrodes suggest that the pathological changes produced by chronic DBS are limited to minimal gliosis along the electrode tract (11). The main disadvantage of DBS compared to radiosurgery is the high cost ($80,000) of the operation and hardware.

DEEP BRAIN STIMULATION DEVICE AND PROCEDURES

A DBS device consists of four components: (a) the stimulating lead, which is implanted stereotactically within the desired brain target and is equipped with four electrode contacts for delivering therapeutic stimulation (Figure 1); (b) a locking device, which anchors the lead and covers the burr hole through which the lead is placed; (c) a programmable pulse generator (PG), which is placed under the skin of the chest wall or abdomen like a cardiac pacemaker and delivers the therapeutic current; and (d ) an extension cable, which is tunneled under the skin and connects the PG to the lead. DBS surgery is a two-stage procedure: rst, implantation of the leads in the brain; and second, implantation of the PG and extensions. The rst stage may be performed with the patient awake under local anesthesia because brain parenchyma does not contain pain receptors. This allows for the performance of brief stimulation trials prior to anchoring the leads in

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Table 1 Partial list of brain stimulation devices for treatment of psychiatric disorders Description of procedure MDD that is severe, accompanied by psychosis or suicidality, or refractory to other treatments Other indications include catatonia and schizophrenia Treatment-resistant depression Used off-label in clinical practice for other psychiatric disorders Approved for narrow use in MDD patients who failed exactly one antidepressant medication in the current episode Noninvasive and safe Minor scalp discomfort and headaches possible; very rarely seizures Currently categorized as a Class III device. FDA is reviewing whether ECT devices should remain in Class III (highest risk) or be downgraded to Class II (intermediate risk) devices for certain uses Risks associated with general anesthesia Possible persistent autobiographical memory loss Uses: established or investigational FDA regulatory status Safety/tolerability of procedure References (43, 68)

Device

Electroconvulsive therapy (ECT)

Induction of generalized seizure with application of electricity to scalp Performed during anesthesia with cardiopulmonary support and use of muscle relaxants Typically 3 sessions per week for 24 weeks

Repetitive transcranial magnetic stimulation (rTMS)

Fluctuating magnetic eld from electromagnetic coil placed outside the skull induces an electrical current in the underlying cerebral cortex Typical course of treatment is ve 40-min sessions per week for 46 weeks Refractory epilepsy Treatment-resistant depression; benet seen only after prolonged (up to 12 months) use Approved as adjunctive therapy for refractory epilepsy Approved as adjunctive therapy for treatment-resistant depression (dened as 4 failed antidepressant treatments) Approved for essential tremor Approved for refractory Parkinsons disease Limited approval under HDE for dystonia and intractable OCD

(69, 70)

Vagus nerve stimulation (VNS)

Helical electrode is wrapped around left vagus nerve in the neck Connected to pulse generator under skin of chest that delivers 30 s of stimulation every 5 min Movement disorders Psychiatric disorders: Intractable OCD Treatment-resistant depression Tourette syndrome

Invasive: requires surgery to attach electrode in neck and device under skin of chest Risks of general anesthesia; rarely infection or injury to recurrent laryngeal nerve causing hoarseness

(71, 72)

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Deep brain stimulation (DBS)

See text

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Lead(s) implanted in brain anatomic target through burr hole(s) in cranium and locked in place Extension wires tunneled under skin and connected to pulse generator(s) implanted under skin of chest Programming of device settings performed wirelessly

Most invasive, highest risk: requires craniotomy and implantation of electrodes directly in brain parenchyma Risk of serious adverse events including intracerebral hemorrhage (2%) and infection (10%) More than 75,000 operations performed worldwide for movement disorders

Abbreviations: MDD, major depressive disorder; OCD, obsessive-compulsive disorder; FDA, U.S. Food & Drug Administration; HDE, humanitarian device exemption.

Medtronic 3391 DBS lead Caudate nucleus

Fibers of the anterior limb of the internal capsule

Putamen

2 1 GPi 0

GPe

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Nucleus accumbens Column of fornix Mammillothalamic tract

Figure 1 Three-dimensional (3D) illustration of bilaterally implanted deep brain stimulation (DBS) electrodes in the ventral capsule/ventral striatum. The 3D objects (leads and brain structures) are sitting on the axial plane 5 mm below the ACPC plane as viewed posterior to anterior. The trajectory of the leads is down the barrel of the anterior limb of the internal capsule. Each lead has four contacts, but only three are shown (contacts #0, #1, and #2); contact #3 is hidden by the caudate nucleus. The most ventral #0 contact is active, as represented by red radiating stimulation elds. Abbreviations: ACPC, anterior commissureposterior commissure; GPe, globus pallidus externus; GPi, globus pallidus internus. Image courtesy of Kirk Finnis, PhD (Medtronic Inc., USA).

ALIC: anterior limb of the internal capsule NAc: nucleus accumbens SCG: subcallosal cingulate gyrus STN: subthalamic nucleus

place. The second stage is conducted under general anesthesia either immediately or within days following completion of the rst stage. The surgical techniques employed to implant DBS devices for the treatment of psychiatric disorders are derived from the vast experience of performing both ablative and DBS surgery for movement disorders. In several respects, the therapeutic sites for treating psychiatric disorders are easier to target than those for movement disorders. First, the most common targetse.g., the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NAc), and the subcallosal cingulate gyrus (SCG; Brodmanns area 25)are larger and more readily visualized on T1-weighted magnetic resonance imaging (MRI) than are the sites that are stimulated to treat movement disorders, such as the
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subthalamic nucleus (STN). Second, these targets are located in brain regions where DBS is less likely to induce obvious adverse effects (e.g., muscular contractions, painful paresthesiae, eye deviations) that would limit the clinical efcacy of stimulation. One exception is hypomania, which has been observed with ALIC stimulation (see Complications of Surgery below). Third, the lack of an immediate positive clinical response to stimulation allows the surgery to be performed with the patient fully asleep or consciously sedatedalthough the smile reex (12) may prove to represent just such a positive clinical indicator (13). Of course, the lack of an immediate therapeutic response to stimulation also poses a disadvantage, as there is no intraoperative feedback to the surgeon that the therapeutic site has been

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properly targeted. That the optimal therapeutic sites are less well dened than they are for movement disorders also leaves more room for error at present. In psychiatric conditions, device programming typically begins one or two weeks after surgery, allowing time for full return to the preoperative baseline state. The device is programmed telemetrically using a hand-held device. The following stimulation parameters can be adjusted: signal intensity, selection of active electrode contact(s), frequency of waveform, and pulse width. As the number of different possible permutations is enormous, programming algorithms built on prior clinical experience are followed to render this task more manageable. At this juncture, however, optimizing DBS settings to enhance benet and minimize side effects for psychiatric disorders is more art than science (14). The patient is given a similar hand-held device with limited functionality to take home. Because PGs can be inadvertently inactivated by strong magnetic elds (such as from a metal detector), the patient may need to check and restore operation of the PG. Conversely, if adverse events occur, the patients can turn off the PG. As a safeguard, the patient cannot change other parameters that alter the stimulation eld location or intensity. For example, it would be problematic if the patient could self-induce hypomania (15). To date, studies of DBS in neuropsychiatric disorders have employed continuous stimulation settings, although for some paroxysmal psychiatric disorders (e.g., Tourette syndrome and OCD), on demand or even cycled stimulation might be more desirable. Closed-loop devices are under development in which output to the target is responsive to input from the same or another brain region (16).

OBSESSIVE-COMPULSIVE DISORDER
Patients with OCD experience unwanted and disturbing intrusive thoughts (obsessions) and are driven to perform ritualized behaviors

(compulsions) aimed at reducing anxiety or discomfort. Even though patients generally acknowledge the senselessness of the obsessions and excessiveness of the compulsions, the symptoms of OCD are hard to control and, when severe, can consume more than eight hours of mental and physical activity each day. OCD is common, with a lifetime prevalence of 2.3% (17). Comorbidity with MDD is high (17), and a subset of patients with OCD also meets criteria for Tourette syndrome (18). Despite advances in pharmacological and behavioral therapies for OCD, some patients with severe symptoms fail to improve sufciently following many years of treatment (19). For such patients, an option of last resort has been the use of ablative neurosurgery, either cingulotomy (20) or anterior capsulotomy (21), in which small bilateral lesions (several millimeters in diameter) are produced in the white matter of either the cingulum bundle or ALIC, respectively. The available evidence suggests these ablative procedures may lead to long-term benets with acceptable levels of risk (22, 23). DBS at the ALIC was rst reported to be a promising intervention for OCD in a 1999 publication by Nuttin et al. (1). The roots of DBS stimulation for OCD can be traced to positive experiences with both gamma capsulotomy and thermolytic ablative surgery in this brain region (21). The gamma-knife studies at Brown University suggested that lesions in the most ventral region of the ALIC, extending inferiorly into the ventral striatum, improved outcome (5). DBS was proposed as a reversible alternative to ablation because it was generally believed that high-frequency electrical stimulation (on the order of 130 Hz) would produce functional ablation of the same target. [More recent mechanistic studies suggest that the net effects of DBS on neuronal function are more complex than signal disruption alone and can include axonal activation (24, 25).] The expected effect was to interrupt or modulate the pathways that mediate OCD behaviors. Functional brain imaging studies in patients with OCD provided an independent rationale for DBS therapy in the region of the ventral ALIC (52). Pathways
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Abbreviations: ALIC, anterior limb of the internal capsule; OCD, obsessive-compulsive disorder; TRD, treatment-resistant depression; SCG, subcallosal cingulate gyrus (Brodmanns area 25); VC/VS, ventral capsule/ventral striatum; ITP, inferior thalamic peduncle; STN, subthalamic nucleus; NAc, nucleus accumbens; HAB, lateral habenula. a Although the ALIC, VC/VS, and NAc are labeled as different targets, there is considerable overlap in these areas. Moreover, the actual position of the active electrode contact (or contacts), the specic stimulating lead used (which can differ in contact spacing), and the characteristics of the stimulation eld account for considerable variance within a given intended target. For the purpose of this review, the name of the target used in each publication is retained, but it should be understood these targets might not be as distinct as the different names imply. b Because counting the number of unique cases in the literature is challenging, these gures should be considered approximate. For example, some articles on long-term follow-up may not be clear as to how many cases are included from previous reports on acute response.

Table 2 Published reports on deep brain stimulation for obsessive-compulsive disorder (OCD) and treatment-resistant depression (TRD) showing

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N = 6 (29); N = 21 (32); N = 1 (77)

VC/VS

N = 15 (45)

coursing through the ALIC have been implicated in neurocircuitry models of OCD (26). Following the initial report of Nuttin et al. (1), several other groups have reported on their experience in intractable OCD with DBS of the ALIC (31) or neighboring brain regions, including the ventral capsule/ventral striatum (VC/VS; 39, 40) and NAc (36) (Table 2). Many of the ndings are from uncontrolled, open-label studies or case reports. Several studies included a double-blind period with an on/off phase (27, 28) or staggered-onset design (29). The two most rigorous studies employed a double-blind sham-controlled design with three-month treatment arms (30, 31). The largest long-term open-label follow-up study included 26 patients who were followed for a mean of 31.4 months (32). Using stringent criteria, >60% of these patients showed a response (22). A review by de Koning et al. concluded that the overall response rate was >50% across all published papers on the various DBS targets (33). Lower response rates were seen with STN stimulation (31) and unilateral stimulation to the NAc (30).

N = 1 (48) N = 1 (47) N = 20 (46); N = 1 (81)

HAB

N = 16 (31)

STN

N = 16

N = 5 (78)

ITP

N = 5

SCG

N = 28

N = 15

N = 21

N = 1

N = 1

MAJOR DEPRESSIVE DISORDER

MDD is a complex, multisystem illness characterized by persistently depressed mood or decreased interest in usual activities accompanied by difculty concentrating, insomnia or hypersomnia, psychomotor retardation or agitation, weight gain or loss, increased or decreased appetite, or feelings of worthlessness or guilt. Patients with depression may present with predominantly somatic complaints, such as pain or fatigue (34). Research studies have revealed putative biomarkers of depression, including altered neuroendocrine function (35) and distinctive patterns of brain activity (3). However, in the individual case, the diagnosis of MDD is based on clinical examination and exclusion of known medical causes such as hypothyroidism. Episodes of MDD last months or even years and are often recurrent. MDD has a lifetime prevalence of 16.2% in the United States and is associated with substantial suffering and

N = 2 (74); N = 2 (75); N = 5 (76); N = 16 (28); N = 1 (49); N = 10 (30)

NAc

anatomic targeta and numberb of cases treated

N = 3 (79); N = 10 (80) TRD

N = 36

N = 4 (1); N = 4 (27); N = 1 (49); N = 1 (73); N = 1 (15); N = 1 (51)

ALIC

OCD

Totals

N = 12

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Totals

N = 13

role impairment (36). According to the Global Burden of Disease 2000 study, depression is the fourth leading cause of disease burden worldwide (37). Psychological autopsy studies of suicides reveal a diagnosis of mood disorders in the majority of cases (38). Depression is also a risk factor for other medical illnesses, including cardiovascular disease (39) and stroke (40). Available treatment modalities can be broadly categorized as antidepressant medications, empirically based psychotherapies (e.g., cognitive therapy), or nonpharmacological somatic therapies, chiey brain stimulation devices (Table 1). About two-thirds of adult outpatients with MDD experience remission using conventional pharmacological or cognitive therapies (41). This remission rate is based on data from a large (N = 3,671) prospective study in which participants could receive up to four different sequential treatments (41). Those patients who failed the rst three steps had only a 13% chance of remitting during step four (41). In clinical practice, additional trials of other psychotropic agents (e.g., combinations of antidepressant and antipsychotic medication) might be considered for the patient with treatment-resistant depression (TRD) (42). Another option is electroconvulsive therapy (43) (Table 1). In fact, failure to respond to (or tolerate) electroconvulsive therapy is required in stringent denitions of TRD. Unfortunately, once patients reach advanced levels of treatment resistance, the number of viable treatment options is small. This treatment gap has spurred interest in developing novel therapeutic approaches to intractable MDD. One approach has been to identify new molecular targets for drug development (44); another has been to identify anatomic targets that can be modulated by DBS. Thus far, two competing DBS targets have emerged for the treatment of MDD: the VC/VS (45) and the SCG (46) (Table 2). [Two other potential targets that are still at the singlecase-report level are the inferior thalamic peduncle (47) and lateral habenula (48) (Table 2).] These two targets were advanced on the basis of different lines of reasoning. The VC/VS

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target was selected based on the observation of improved mood in studies of VC/VS DBS in OCD (32). In contrast, a role for SCG in modulating negative mood states was suggested by a series of functional neuroimaging studies (3), and it was hypothesized that suppressing hyperactivity in Brodmanns area 25 by direct stimulation of this brain region would confer antidepressant effects (3). The rationale for stimulation of the lateral habenula was based on animal models of depression that characterized this area as a node in the brains disappointment circuit (49). Mayberg and colleagues published openlabel outcome data on 20 patients with TRD who underwent DBS to the SCG (46). During extended follow-up (36 years), the response rate was 55% for the last available study visit in the intent-to-treat sample (42). Three patients were explanted at their request due to lack of efcacy. The high rate of mortality associated with TRD is underscored by the death of two patients by suicide. Neither of these deaths was attributed to device malfunction or effects of stimulation (2). Malone et al. (45) reported outcome and safety data from an open-label multicenter study of VC/VS stimulation in 15 patients with severe TRD. The criteria for treatment resistance were stringent and included failure to respond to an adequate trial of electroconvulsive therapy. After six months of continuous stimulation, 40% of the patients were classied as responders. The procedures were generally well tolerated.

VC/VS: ventral capsule/ventral striatum TRD: treatmentresistant depression

ADVERSE EFFECTS OF DEEP BRAIN STIMULATION

Potential complications of DBS can be categorized as related to surgical implantation, device failure, and stimulation. The rst two categories are well known from the >75,000 DBS implants that have been performed worldwide, mostly to treat movement disorders. In contrast, adverse effects induced by stimulation (or its interruption) at the targets employed to treat psychiatric disorders are just being described (see Discussion).
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Complications of Surgery
The most daunting risk of DBS therapy is that of stroke and/or hemorrhage during implantation of the DBS leads. Hemorrhage rates of 0%10% are reported in the literature (50), although larger series report rates of 2% (49, 51). Depending on the size and location, these hemorrhages may be inconsequential or may cause a variety of neurological decits or death. The risk of hemorrhage may be correlated to larger numbers of microelectrode recording trajectories (employed to electrophysiologically identify the therapeutic target) (49, 52) and implantation trajectories that traverse the sulci and/or the lateral ventricles (53, 54). At present, too few procedures have been performed to determine reliably the risk of hemorrhage for psychiatric disorders, but we expect the incidence will be no greater than that documented for DBS in movement disorders (1%4%). It may be even lower because the ventricles are easy to avoid when approaching these targets, and target localization is not dependent on microelectrode recording. Nevertheless, so long as the brain parenchyma is penetrated, hemorrhage and its potentially disastrous sequelae will remain a risk of these procedures. The second most feared complication of DBS surgery is postoperative confusion, which is commonly transient but may persist in a small percentage of cases. The risk of confusion is increased in elderly patients (55), particularly those with Parkinsons disease (of which dementia may be a component), and in patients undergoing bilateral contemporaneous implants. We expect that this also will be a rare complication in patients with refractory OCD and MDD because (a) these patients will be younger, on average, than Parkinsons patients; (b) they are unlikely to be suffering with an early, preclinical dementia; and (c) again, target localization is not dependent on microelectrode recording. The most common complication of DBS surgery is device-related infection, which is reported to occur in 0%15% of cases (50). In the vast majority of cases, these infections are
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not life-threatening and are readily treated by device removal and tailored antibiotic therapy. In theory, spread of an infection along the implanted brain lead could result in meningitis, cerebritis, or brain abscess, but in reality these are extremely rare occurrences. It is likely that infection rates will be reduced with greater experience and the development of smaller implants.

Complications Related to Chronic Hardware Implantation

The Medtronic Activa R DBS system has been commercially available in the United States and European Union for almost 15 years, so the long-term risks associated with implanting these devices are quite evident. Overall, chronic implantation of these devices is well tolerated. Although hardware-related complications are reported to occur in as many as 25% of patients at some point in time, the annualized risk is approximately 4%, and most of the complications are not life-threatening and are readily managed (5558). In our experience and that reported by others, erosion of the scalp tissue overlying the burr hole cap is the most significant long-term complication of the implanted device. This is most commonly observed in balding men and the elderly, whose scalps are more atrophic. These devices are battery powered and must therefore be replaced periodically. The effective life of a device depends on the amount of current that is required to achieve optimal clinical effect. This effective life may be as long as seven or eight years in patients with essential tremor, who turn their devices off at night, or as short as 12 months in some patients receiving VC/VS stimulation for OCD, where very high amplitudes and constant stimulation may be required. Battery replacement surgery is a short, simple, ambulatory procedure during which only the PG pocket is accessed, but it is expensive, and frequent battery-change surgeries impose both health and nancial burdens. The advent of PGs with rechargeable batteries will remedy this problem while introducing a

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Alterman

new burden: recharging the devices. This can be performed at home wirelessly, but may require several hours each day. Advances in our understanding of how DBS works may lead to improved stimulation paradigms that both improve clinical outcomes and decrease electrical energy requirements. In four patients who were implanted under the humanitarian device exemption (HDE) for OCD, we have been able to conserve battery life by having the patients turn off their PGs during sleep (W.G. Goodman, R. Alterman, unpublished data).

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DISCUSSION
The therapeutic effects of DBS have been reported in 100 cases of OCD (33) and 50 cases of TRD for seven (ve common) anatomic targets (Table 2). The actual numbers might be higher because DBS administered for OCD under the HDE (<50 patients since its inception in February 2009) is not included, and selective reporting of positive cases is possible (60). Although published reports differ with respect to study design, sample size, subject characteristics, and outcome measurement, the overall response rate appears to exceed 50% in OCD for DBS targets in the VS and NAc (33). In TRD, >50% of patients (N = 20) responded during acute and long-term (36 years) bilateral electrical stimulation of the SCG (46). The response rate of TRD to VC/VS stimulation appears lower (45). Despite the drawbacks of open-label follow-up data, the maintenance of response several years after implantation is encouraging for several DBS targets in OCD (33) and SCG stimulation in MDD (46). The literature on DBS for psychiatric disorders reports a low rate of serious adverse events related to surgery or hardware malfunction. An exception was an intracerebral brain hemorrhage that produced a permanent nger palsy in one patient undergoing STN DBS for OCD (31). Ongoing brain stimulation was generally well tolerated across multiple targets for both OCD and TRD. Some unique, target- and stimulation-specic adverse effects

have been observed. In particular, stimulation of the VC/VS-NAc region has been associated with acute induction of elevated mood, with intensity that ranges from a smile to laughter to hypomania depending on the stimulation parameters (12, 15, 29, 32). Unpleasant adverse behavioral effects such as panic attacks have also been observed with DBS in the VC/VSNAc region at the most ventral contacts (61). In all reported cases, undesirable effects of DBS on mood, including hypomania, were reversible with changes in device settings. Apart from mild forgetfulness (33) reported in some cases, DBS has not been associated with clinically signicant changes in cognitive function during treatment of either OCD (22) or MDD (62). Accidental device cessation or battery depletion can result in depressed mood or worsening of OCD (32). There were two suicides in one study of TRD, but these were attributed to the underlying disorder, not to DBS device failure (46). Limitations of the published data on DBS in OCD and MDD include the small sample sizes (many are single case reports) and open-label design of most studies. Only a few studies all of them in OCDused a blinded on/off phase (30, 37, 39, 40, 44), and only two included a blinded treatment arm lasting as long as three months (38, 57). Randomized shamcontrolled studies (all hardware implanted but PG settings inactive in the sham group) with sufciently long blinded phases (preferably at least three months) are warranted in both OCD and MDD. Specically, in order to select the most appropriate patients, further research is needed to (a) test the efcacy and safety of DBS, (b) compare targets, (c) optimize device settings, and (d ) identify predictors of response. Equally important is achieving a better understanding of the mechanisms of action of DBS in psychiatric disorders so that less invasive interventions can be developed (5). One possibility is the development of extracranial neuromodulation devices (63) that can selectively stimulate deeper brain structures than is currently possible with commercially available transcranial magnetic stimulation (16).
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Many questions remain regarding the optimal DBS targets for psychiatric disorders. The eld is making the transition from following the lesion (learning from ablation) to following the science in identifying potential targets for DBS in psychiatric disorders. The work of Mayberg (see Reference 5) and of Henn and colleagues (48) provides good examples of translational research strategies. Having a nonhuman primate model of Parkinsons disease that mimics the pathology has aided the identication of potential targets for neurosurgical intervention (64). In contrast, the pathophysiology of major psychiatric disorders remains elusive. And although promising rodent models for depression exist (65, 66), extrapolating to human neurocircuitry is challenging [but not impossible (66)]. For now, the kind of brain imaging studies undertaken by Mayberg to dene the neurocircuitry of depression might be the most fruitful approach to identifying new targets (3). Other anatomic targets for psychiatric disorders might continue to be proposed based on the responses of comorbid psychiatric symptoms in patients receiving DBS for other indications. This was the rationale for investigating STN stimulation in OCD (31) and VC/VS stimulation in MDD (45). Finally, it should be noted that more than one anatomic structure might modulate the symptoms of MDD. Different nodes of the same circuit that subserve emotional regulation could be potential targets for DBS (46). Given the checkered history of psychosurgery and the fact that DBS is an invasive and high-risk procedure, the public needs reassurance that the clinical use of DBS

in [psychiatric disorders] will not overstep the bounds of empirical evidence (5). Questions have already been raised about whether the FDA should have approved an HDE for DBS in OCD (67). Indeed, the efcacy of VC/VS DBS for intractable OCD has not been established. Unfortunately, adequately powered randomized clinical trials of DBS in OCD may not be feasible because of the difculty of recruiting subjects and the high cost to the sponsor for a limited market. (In contrast, two device manufacturers are currently conducting multicenter sham-controlled trials of DBS in TRD, a potential indication with a sizeable market.) Even if the results are positive, the sample size of the current NIH-sponsored trial of VC/VS DBS in OCD is not large enough to meet criteria for a premarket approval by the FDA. In the meantime, the HDE for DBS in OCD needs to be buttressed by stringent patient selection and a robust informed-consent process that acknowledges efcacy is uncertain, spells out the potentially grave risks, and indicates alternative treatments. In our practice, we no longer refer to neurosurgery as the treatment of last resort (6). There may be other treatment options for OCD or MDD if DBS fails. One of the advantages of DBS over ablative surgery is the possibility of explanting the devices and returning the brain to its preoperative functioning. Patients with severe and refractory psychiatric disorders need to know that their physicians are not ready to give up on restoring them to health. As long as there is translational research, there is the prospect of new and better treatment modalities for patients with otherwise intractable major psychiatric disorders.

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DISCLOSURE STATEMENT
R.L.A. receives occasional honoraria and consulting fees from Medtronic. He is a member of the Clinical Event Committee, which evaluates adverse events related to Medtronics pivotal trial of deep brain stimulation for depression. W.K.G. received an honorarium from Medtronic in 2009 for teaching about obsessive-compulsive disorder in a course sponsored by Medtronic. LITERATURE CITED
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53. Gologorsky Y, Ben-Haim S, Moshier EL, et al. 2011. Transgressing the ventricular wall during subthalamic deep brain stimulation surgery for Parkinsons disease increases the risk of adverse neurological sequelae. Neurosurgery 69:29499 54. Sansur CA, Frysinger RC, Pouratian N, et al. 2007. Incidence of symptomatic hemorrhage after stereotactic electrode placement. J. Neurosurg. 107:9981003 55. Doshi PK. 2011. Long-term surgical and hardware-related complications of deep brain stimulation. Stereotact. Funct. Neurosurg. 89:8995 56. Boviatsis EJ, Stavrinou LC, Themistocleous M, et al. 2010. Surgical and hardware complications of deep brain stimulation. A seven-year experience and review of the literature. Acta Neurochir. (Wien) 152:205362 57. Paluzzi A, Belli A, Bain P, et al. 2006. Operative and hardware complications of deep brain stimulation for movement disorders. Br. J. Neurosurg. 20:29095 58. Oh MY, Abosch A, Kim SH, et al. 2002. Long-term hardware-related complications of deep brain stimulation. Neurosurgery 50:126874; discussion 7476 59. Deleted in proof 60. Schlaepfer TE, Fins JJ. 2010. Deep brain stimulation and the neuroethics of responsible publishing: when one is not enough. JAMA 303:77576 61. Shapira NA, Okun MS, Wint D, et al. 2006. Panic and fear induced by deep brain stimulation. J. Neurol. Neurosurg. Psychiatry 77:41012 62. McNeely HE, Mayberg HS, Lozano AM, et al. 2008. Neuropsychological impact of Cg25 deep brain stimulation for treatment-resistant depression: preliminary results over 12 months. J. Nerv. Ment. Dis. 196:40510 63. Levkovitz Y, Roth Y, Harel EV, et al. 2007. A randomized controlled feasibility and safety study of deep transcranial magnetic stimulation. Clin. Neurophysiol. 118:273044 64. Langston JW, Forno LS, Rebert CS, et al. 1984. Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res. 292:39094 65. Krishnan V, Nestler EJ. 2011. Animal models of depression: molecular perspectives. Curr. Top. Behav. Neurosci. 7:12147 66. Li B, Piriz J, Mirrione M, et al. 2011. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470:53539 67. Fins JJ, Mayberg HS, Nuttin B, et al. 2011. Misuse of the FDAs humanitarian device exemption in deep brain stimulation for obsessive-compulsive disorder. Health Aff. (Millwood ) 30:30211 68. Goodman W. 2011. Electroconvulsive therapy in the spotlight. N. Engl. J. Med. 364:178587 69. George MS. 2010. Transcranial magnetic stimulation for the treatment of depression. Exp. Rev. Neurother. 10:176172 70. OReardon JP, Solvason HB, Janicak PG, et al. 2007. Efcacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol. Psychiatry 62:120816 71. Rush AJ, Marangell LB, Sackeim HA, et al. 2005. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol. Psychiatry 58:34754 72. Rush AJ, Sackeim HA, Marangell LB, et al. 2005. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol. Psychiatry 58:35563 73. Anderson D, Ahmed A. 2003. Treatment of patients with intractable obsessive-compulsive disorder with anterior capsular stimulation. Case report. J. Neurosurg. 98:11048 74. Aouizerate B, Cuny E, Bardinet E, et al. 2009. Distinct striatal targets in treating obsessive-compulsive disorder and major depression. J. Neurosurg. 111:77579 75. Franzini A, Messina G, Gambini O, et al. 2010. Deep-brain stimulation of the nucleus accumbens in obsessive compulsive disorder: clinical, surgical and electrophysiological considerations in two consecutive patients. Neurol. Sci. 31:35359 76. Sturm V, Lenartz D, Koulousakis A, et al. 2003. The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders. J. Chem. Neuroanat. 26:29399 77. Bikson M, Bulow P, Stiller JW, et al. 2008. Transcranial direct current stimulation for major depression: a general system for quantifying transcranial electrotherapy dosage. Curr. Treat. Options Neurol. 10:37785
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78. Jimenez-Ponce F, Velasco-Campos F, Castro-Farfan G, et al. 2009. Preliminary study in patients with obsessive-compulsive disorder treated with electrical stimulation in the inferior thalamic peduncle. Neurosurgery 65:2039; discussion 209 79. Schlaepfer TE, Cohen MX, Frick C, et al. 2008. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 33:36877 80. Bewernick BH, Hurlemann R, Matusch A, et al. 2010. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol. Psychiatry 67:11016 81. Neimat JS, Hamani C, Giacobbe P, et al. 2008. Neural stimulation successfully treats depression in patients with prior ablative cingulotomy. Am. J. Psychiatry 165:68793

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Contents
Huntingtons Disease: Advocacy Driving Science Nancy S. Wexler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
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Annual Review of Medicine Volume 63, 2012

Direct-to-Consumer Genetic Testing: Perceptions, Problems, and Policy Responses Timothy Cauleld and Amy L. McGuire p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23 Human Genome Sequencing in Health and Disease Claudia Gonzaga-Jauregui, James R. Lupski, and Richard A. Gibbs p p p p p p p p p p p p p p p p p p p p p35 The Genetic Architecture of Schizophrenia: New Mutations and Emerging Paradigms Laura Rodriguez-Murillo, Joseph A. Gogos, and Maria Karayiorgou p p p p p p p p p p p p p p p p p p p p63 CCR5 Antagonism in HIV Infection: Current Concepts and Future Opportunities Timothy J. Wilkin and Roy M. Gulick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81 New Paradigms for HIV/AIDS Vaccine Development Louis J. Picker, Scott G. Hansen, and Jeffrey D. Lifson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95 Emerging Concepts on the Role of Innate Immunity in the Prevention and Control of HIV Infection Margaret E. Ackerman, Anne-Sophie Dugast, and Galit Alter p p p p p p p p p p p p p p p p p p p p p p p p p 113 Immunogenetics of Spontaneous Control of HIV Mary Carrington and Bruce D. Walker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131 Recent Progress in HIV-Associated Nephropathy Christina M. Wyatt, Kristin Meliambro, and Paul E. Klotman p p p p p p p p p p p p p p p p p p p p p p p p 147 Screening for Prostate Cancer: Early Detection or Overdetection? Andrew J. Vickers, Monique J. Roobol, and Hans Lilja p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161 Targeting Metastatic Melanoma Keith T. Flaherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171 Nanoparticle Delivery of Cancer Drugs Andrew Z. Wang, Robert Langer, and Omid C. Farokhzad p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185

Circulating Tumor Cells and Circulating Tumor DNA Catherine Alix-Panabi` res, Heidi Schwarzenbach, and Klaus Pantel p p p p p p p p p p p p p p p p p p p 199 e Translation of Near-Infrared Fluorescence Imaging Technologies: Emerging Clinical Applications E.M. Sevick-Muraca p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217 Familial and Acquired Hemophagocytic Lymphohistiocytosis G.E. Janka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233 The Management of Gastrointestinal Stromal Tumors: A Model for Targeted and Multidisciplinary Therapy of Malignancy Heikki Joensuu and Ronald P. DeMatteo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
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Carotid Stenting Versus Endarterectomy David Doig and Martin M. Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259 Mitral Valve Prolapse T. Sloane Guy and Arthur C. Hill p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277 Telomeres, Atherosclerosis, and the Hemothelium: The Longer View Abraham Aviv and Daniel Levy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293 Aquaporins in Clinical Medicine A.S. Verkman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303 Role of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders Lale Ozcan and Ira Tabas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Role of Fructose-Containing Sugars in the Epidemics of Obesity and Metabolic Syndrome Kimber L. Stanhope p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 329 Vaccines for Malaria: How Close Are We? Mahamadou A. Thera and Christopher V. Plowe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345 Crisis in Hospital-Acquired, Healthcare-Associated Infections David P. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359 Novel Therapies for Hepatitis C: Insights from the Structure of the Virus Dahlene N. Fusco and Raymond T. Chung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 373 Multiple Sclerosis: New Insights in Pathogenesis and Novel Therapeutics Daniel Ontaneda, Megan Hyland, and Jeffrey A. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 389 Traumatic Brain Injury and Its Neuropsychiatric Sequelae in War Veterans Nina A. Sayer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405

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Eosinophilic Esophagitis: Rapidly Advancing Insights J. Pablo Abonia and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 421 Physician Workforce Projections in an Era of Health Care Reform Darrell G. Kirch, Mackenzie K. Henderson, and Michael J. Dill p p p p p p p p p p p p p p p p p p p p p p p 435 Reducing Medical Errors and Adverse Events Julius Cuong Pham, Monica S. Aswani, Michael Rosen, HeeWon Lee, Matthew Huddle, Kristina Weeks, and Peter J. Pronovost p p p p p p p p p p p p p p p p p p p p p p p p p p p p 447 Relationships Between Medicine and Industry: Approaches to the Problem of Conicts of Interest Raymond Raad and Paul S. Appelbaum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
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Wireless Technology in Disease Management and Medicine Gari D. Clifford and David Clifton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479 Geographic Variation in Health Care Tom Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 493 Deep Brain Stimulation for Intractable Psychiatric Disorders Wayne K. Goodman and Ron L. Alterman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511 Contemporary Management of Male Infertility Peter J. Stahl, Doron S. Stember, and Marc Goldstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 525 Indexes Cumulative Index of Contributing Authors, Volumes 5963 p p p p p p p p p p p p p p p p p p p p p p p p p p p 541 Cumulative Index of Chapter Titles, Volumes 5963 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 545 Errata An online log of corrections to Annual Review of Medicine articles may be found at http://med.annualreviews.org/errata.shtml

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