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The timely article by Dunn and colleaegues (2011) raises several pertinent issues relevant to all health care teams treating and studying patients with resistant psychiatric disease. Importantly, t...

Psychiatric disorders are common and are responsible for significant human morbidity and mortality. Although current treatment approaches are effective for many patients, a substantial minority remains treatment-resistant. Advances in the understanding of how disturbances in brain networks lead to psychiatric manifestations and the observation of the effectiveness of deep brain stimulation (DBS) in disorders of motor circuitry such as Parkinson’s disease and dystonia has motivated its investigation in other circuit-based disorders. This chapter reviews the clinical experience of DBS in the major mood and anxiety disorders, namely major depression and obsessive–compulsive disorder. We review the circuitry of these conditions, as well as target selection for these and other emerging DBS indications in psychiatry. Neuromodulation is becoming an increasingly important component of the care of psychiatric patients, and DBS, in properly selected patients, and guided by an expert multi-disciplinary team, may offer promise for patients with few treatment alternatives.

Vulnerability is an important criterion to assess the ethical justification of the inclusion of participants in research trials. Currently, vulnerability is often understood as an attribute inherent to a participant by nature of a diagnosed condition. Accordingly, a common ethical concern relates to the participant's decisionmaking capacity and ability to provide free and informed consent. We propose an expanded view of vulnerability that moves beyond a focus on consent and the intrinsic attributes of participants. We offer specific suggestions for how relational aspects and the dynamic features of vulnerability could be more fully captured in current discussions and research practices.

The next several decades will see an exponential rise in the number of patients with disorders of memory and cognition, and of Alzheimer’s disease in particular. Impending demographic shifts, an absence of effective treatments, and the significant burden these conditions place on patients, caregivers, and society, mean there is an urgent need to develop novel therapies. Deep brain stimulation (DBS) is a neurosurgical procedure that is a standard-of-care for many patients with treatment-refractory Parkinson’s disease, dystonia, and essential tremor. DBS has proven to be an effective means of modulating activity in disrupted motor circuitry, and has shown promise as a modulator of other dysfunctional circuits, including for mood and anxiety disorders. The deficits in Alzheimer’s disease and other disorders of memory and cognition are also beginning to be thought of as arising from dysfunction in neural circuits. Such dysfunction may be amenable to modulation using focal brain stimulation. A global experience is now emerging for the use of DBS for these conditions, targeting key nodes in the memory circuit, including the fornix and nucleus basalis of Meynert. Such work holds promise as a novel therapeutic approach for one of medicine’s most urgent priorities.

After the tragic death of a young woman named Libby Zion in a New York Hospital, resident duty hour (RDH) restrictions were introduced in this state. An investigation ruled that lack of supervision, the resident's lack of familiarity with this woman's complex diagnosis and resident fatigue were contributing factors in the tragic outcome. In July 2003, the Accreditation Council for Graduate Medical Education (ACGME) mandated an 80-hour duty limit on residents, averaged over a 4-week period. In 2011, the ACGME mandated 16-hour duty periods for first year residents whereas the province of Quebec instituted 16-hour periods for all in-house residents in 2012. The stated goals of duty hour limitations were to improve patient safety, resident well-being, and education.1 Surgical disciplines have expressed concern with the contraction of duty hours stating that the impact on training time could have a negative effect on educational and patient outcomes.2 Specifically, the American College of Surgeons, Division of Education, has stated that mastery in surgery requires extensive and immersive experiences.3 A “one-size fits all” approach to RDHs may not be appropriate given the variation in training needs, diversity of practice patterns, and various competencies required among disciplines.4,5 In March 2012, the Royal College of Physicians and Surgeons of Canada undertook a project to develop a pan-Canadian consensus on issues related to RDH. A national steering committee was struck and this committee further created 6 expert working groups. Recognizing that surgical training is unique in many aspects and that there have been significant obstacles related to the implementation of RDH in surgery, a specific working group entitled Special Considerations for Procedural and Surgical Disciplines was created. The National Steering Committee's full report is published elsewhere (www.residentdutyhours.ca).5 As part of this process, the Procedural/Surgical discipline working group performed a systematic review and meta-analysis to evaluate the association between RDH and clinical and educational outcomes in surgery.

Background For patients with psychiatric illnesses remaining refractory to ‘standard’ therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered ‘established’ in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient’s capacity and autonomy, multifaceted preoperative as well as postoperative long-term followup evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.

There is an urgent need to develop novel therapies for patients with anorexia nervosa (AN). A condition that is heterogeneous, highly resistant to treatment, and associated with striking rates of morbidity and mortality, few therapeutic advances specifically for AN have been made in the past 150 years. A re-orientation in the last two decades toward neuroscientific explanations for AN offers hope that an increased understanding of the illness' neural roots will lead to better treatments (Kaye et al, 2009). Deep brain stimulation (DBS) is a neurosurgical procedure that targets critical nodes in dysfunctional neural circuits driving pathological behaviors (Lozano and Lipsman, 2013; Mayberg et al, 2005). DBS' efficacy in disorders like Parkinson's Disease has driven its investigation in other circuit-based conditions, including major depression (Lozano and Lipsman, 2013). Several factors led us to consider DBS in refractory AN. First, the primarily limbic structures implicated in the disorder, largely by functional neuroimaging, are consistent with the clinical observations that AN is predominantly a disorder of emotional processing. Further, the ability of DBS to safely and effectively access limbic nodes in mood- and anxiety-related circuits suggested that it could be applied to AN, a disorder marked by high rates of depressed mood and affective dysregulation. The subcallosal cingulate (SCC) has a key role in modulating emotional states and projects cortically, to medial- and orbitofrontal cortex, as well as subcortically to nucleus accumbens. Our group has also shown that SCC neurons participate directly in emotion processing, responding preferentially to affective-laden stimuli and decisions (Lipsman et al, 2013a). The SCC is thus both structurally and functionally integrated into emotion pathways, and its activity linked to disorders of emotion. Our initial experience in a small group of treatment-refractory patients (N=6; average age: 38 years; average illness duration: 18 years) showed DBS to be reasonably safe in AN, and associated with improvements in comorbid mood and anxiety symptoms (Lipsman et al, 2013b). These results were maintained during 6 months of clinical follow-up, with significant reductions in depressed mood and anxiety translating, over time, into increases in BMI (Figure 1). Although time spent on eating- and weight-related preoccupations and rituals did decrease (Lipsman et al, 2013b), we believe the primary effect of DBS was an improved utilization of conventional AN treatment as a result of improved mood and affective regulation. Figure 1 Mean (N=6) percentage changes from baseline, of weight and depression ratings, at each study time point (1 month, 3 months, and 6 months). At 6 months post-DBS, the cohort experienced a mean 12% increase in BMI and a 40% reduction in depression ... The influence of focal stimulation on global cerebral metabolism can be investigated with functional imaging, such as positron emission tomography (PET; Figure 2). PET studies in both AN and depression patients have shown significant network-wide changes in glucose utilization with DBS of the SCC. For example, after 6 months of DBS, both patient groups see significant activity reductions in the SCC and insula, as well as significant activity increases in the parietal lobe (Lipsman et al, 2013b; Mayberg et al, 2005). In AN, this change in parietal activity constitutes an effective reversal of known baseline parietal hypometabolism seen in acutely ill AN patients (Delvenne et al, 1996). These results confirm that although DBS is a focal, targeted therapy, it can influence metabolism in remote regions, and that AN-relevant structures, such as those governing mood, emotion regulation, and body perception, can be modulated by SCC stimulation. Figure 2 Three-dimensional rendering of composite cerebral metabolic changes in six patients who underwent deep brain stimulation of subcallosal cingulum for anorexia nervosa. Red indicates areas of increased activity following 6 months of stimulation compared ... Determining the potential role of DBS in the AN treatment algorithm will await the results of larger, sham-stimulation trials. It is clear, however, that the condition's physical and emotional symptoms are inextricably linked, and novel treatment strategies will need to address both in equal measure, to offer patients hope for a meaningful and enduring recovery.

Anorexia nervosa is a chronic and debilitating psychiatric disorder associated with one of the highest mortality rates of any psychiatric condition. Despite advances in neuroimaging, genetics, pharmacology, and psychosocial interventions in the last half-century, little progress has been made in altering the natural history of the condition or its outcomes. Evidence is now emerging that the condition is, at least in part, maintained by dysfunctional activity in key neuroanatomic circuits subserving illness-maintaining symptoms. Abnormal reward processing, compulsive hyperactivity, chronic anxiety, and depression, all suggest that anorexia nervosa shares much in common with other conditions, such as major depression and obsessive-compulsive disorder, for which surgical therapy with deep brain stimulation (DBS) has been tried, with promising results. As a result, the use of DBS in treatment-resistant anorexia nervosa should be evaluated in carefully designed, early-phase feasibility trials.

Disorders of cognition are a major societal burden. As the population grows and ages, these conditions demand urgent attention, as healthcare resources stretch to accommodate the growing number of patients. Although much is known about the neurobiology of dementia and Alzheimer's disease (AD), few treatments are available to arrest or slow down the illness. By targeting specific structures within known circuits, deep brain stimulation (DBS) can have effects across memory and cognitive networks, and is therefore a potentially promising avenue for novel dementia treatments. This chapter reviews the literature on DBS for AD and dementia associated with Parkinson's disease, and highlight some of the neuroanatomical targets that offer the most promise in modulating the underlying pathological activity in brain circuitry.

The last decade has seen a significant rise in interest in the use of deep brain stimulation (DBS) for the management of obsessive-compulsive disorder (OCD), one of psychiatry's most challenging conditions. The prominent role of both thought (obsessions) and motor (compulsions) dysfunction in OCD place the condition at the border between the neurological and the psychiatric. This is supported by a growing body of literature that implicates structures in decision-making, reward, and action-selection circuits in the disorder. Here, we provide an overview of the neurocircuitry of OCD while reviewing the DBS literature to date for the condition. Results of DBS trials in treatment- resistant OCD have been remarkably similar, with clinical response rates in the range of 40-60%, despite the use of a diverse range of targets. These results imply that a common underlying circuit is being modulated, and moreover that there is room for improvement, and debate, in the development of an evidence-driven DBS treatment for this chronic, debilitating illness.

Anorexia Nervosa (AN) is a serious psychiatric condition marked by firmly entrenched and maladaptive behaviors and beliefs about body, weight and food, as well as high rates of psychiatric comorbidity. The neural roots of AN are now beginning to emerge, and appear to be related to dysfunctional, primarily limbic, circuits driving pathological thoughts and behaviors. As a result, the significant physical symptoms of AN are increasingly being understood at least partially as a result of abnormal or dysregulated emotional processing. This paper reviews the nature of limbic dysfunction in AN, and how structural and functional imaging has implicated distinct emotional and perceptual neural circuits driving AN symptoms. We propose that top-down and bottom-up influences converge on key limbic modulatory structures, such as the subcallosal cingulate and insula, whose normal functioning is critical to affective regulation and emotional homeostasis. Dysfunctional activity in these structures, as is seen in AN, may lead to emotional processing deficits and psychiatric symptoms, which then drive maladaptive behaviors. Modulating limbic dysregulation may therefore be a potential treatment strategy in some AN patients.

Major depressive disorder is among the most prevalent psychiatric disorders and is a leading cause of morbidity and lost productivity.[1][1] The 1-year prevalence of major depressive disorder in the Canadian population is 3.2%–4.6%.[2][2] A large, multisite prospective trial showed that only 28%

Summary Background Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor. Methods Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. Findings Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. Interpretation MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated. Funding Focused Ultrasound Foundation.

Disorders of cognition are a major societal burden. As the population grows and ages, these conditions demand urgent attention, as healthcare resources stretch to accommodate the growing number of patients. Although much is known about the neurobiology of dementia and Alzheimer's disease (AD), few treatments are available to arrest or slow down the illness. By targeting specific structures within known circuits, deep brain stimulation (DBS) can have effects across memory and cognitive networks, and is therefore a potentially promising avenue for novel dementia treatments. This chapter reviews the literature on DBS for AD and dementia associated with Parkinson's disease, and highlight some of the neuroanatomical targets that offer the most promise in modulating the underlying pathological activity in brain circuitry.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. METHODS: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). RESULTS: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. CONCLUSION: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.

The last decade has seen a significant rise in interest in the use of deep brain stimulation (DBS) for the management of obsessive–compulsive disorder (OCD), one of psychiatry’s most challenging conditions. The prominent role of both thought (obsessions) and motor (compulsions) dysfunction in OCD place the condition at the border between the neurological and the psychiatric. This is supported by a growing body of literature that implicates structures in decision-making, reward, and action-selection circuits in the disorder. Here, we provide an overview of the neurocircuitry of OCD while reviewing the DBS literature to date for the condition. Results of DBS trials in treatment- resistant OCD have been remarkably similar, with clinical response rates in the range of 40–60%, despite the use of a diverse range of targets. These results imply that a common underlying circuit is being modulated, and moreover that there is room for improvement, and debate, in the development of an evidence-driven DBS treatment for this chronic, debilitating illness.

Anorexia nervosa is a chronic and debilitating psychiatric disorder associated with one of the highest mortality rates of any psychiatric condition. Despite advances in neuroimaging, genetics, pharmacology, and psychosocial interventions in the last half-century, little progress has been made in altering the natural history of the condition or its outcomes. Evidence is now emerging that the condition is, at least in part, maintained by dysfunctional activity in key neuroanatomic circuits subserving illness-maintaining symptoms. Abnormal reward processing, compulsive hyperactivity, chronic anxiety, and depression, all suggest that anorexia nervosa shares much in common with other conditions, such as major depression and obsessive-compulsive disorder, for which surgical therapy with deep brain stimulation (DBS) has been tried, with promising results. As a result, the use of DBS in treatment-resistant anorexia nervosa should be evaluated in carefully designed, early-phase feasibility trials.

Brain implants, such as Deep Brain Stimulation (DBS), which are designed to improve motor, mood and behavioural pathology, present unique challenges to our understanding of identity, agency and free will. This is because these devices can have visible effects on persons' physical and psychological properties yet are essentially undetectable when operating correctly. They can supplement and compensate for one's inherent abilities and faculties when they are compromised by neuropsychiatric disorders. Further, unlike talk therapy or pharmacological treatments, patients need not 'do' anything for the treatment to take effect. If one accepts, as we argue here, that brain implants are unique among implantable types of devices, then this can have significant implications for what it means to persist as the same person and be the source of one's thoughts and actions. By examining two of the most common indications for DBS in current use, namely in the motor (Parkinson's Disease) and psychiatric (Major Depression) domains, we further argue that although DBS, as it is currently applied, does not necessarily represent a unique threat to personal identity and agency per se, it introduces an unprecedented 'third party' into the debate on these concepts. In this way, DBS can be used as a tool to begin probing, both conceptually and empirically, some of philosophy's most perennial metaphysical questions.

With the growing interdependence between medicine and technology, the prospect of connecting machines to the human brain is rapidly being realized. The field of neuroprosthetics is transitioning from the proof of concept stage to the development of advanced clinical treatments. In one area of brain-machine interfaces (BMIs) related to the motor system, also termed ‘motor neuroprosthetics’, research successes with implanted microelectrodes in animals have demonstrated immense potential for restoring motor deficits. Early human trials have also begun, with some success but also highlighting several technical challenges. Here we review the concepts and anatomy underlying motor BMI designs, review their early use in clinical applications, and offer a framework to evaluate these technologies in order to predict their eventual clinical utility. Ultimately, we hope to help neuroscience clinicians understand and participate in this burgeoning field.

The recent emergence at the clinical level of minimally-invasive focal therapy such as laser-induced thermal therapy (LITT) has demonstrated promise in the management of brain metastasis [1], although control over the spatial pattern of heating is limited. Delivery of HIFU from minimally-invasive applicators enables high spatial control of the heat deposition in biological tissues, large treatment volumes and high treatment rate in well chosen conditions [2,3]. In this study, the feasibility of MRI-guided interstitial ultrasound therapy in brain was studies in-vivo in a porcine model. A prototype system originally developed for transurethral ultrasound therapy [4,5,6] was used in this study. Two burr holes of 12 mm in diameter were created in the animal's skull to allow the insertion of the therapeutic ultrasound applicator (probe) into the brain at two locations (right and left frontal lobe). A 4-element linear ultrasound transducer (f = 8 MHz) was mounted at the tip of a 25-cm linear probe (6 mm in diameter). The target boundary was traced to cover in 2D a surface compatible with the treatment of a 2 cm brain tumor. Acoustic power of each element and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary [2,4,5]. Two MRT-controlled ultrasound brain treatments per animal have been performed using a maximal surface acoustic power of 10W.cm-2. In all cases, it was possible to increase accurately the temperature of the brain tissues in the targeted region over the 55°C threshold necessary for the creation of irreversible thermal lesion. Tissue changes were visible on T1w contrast-enhanced images immediately after treatment. These changes were also evident on T2w FSE images taken 2 hours after the 1st treatment and correlated well with the temperature image. On average, the targeted volume was 4.7 ± 2.3 cm3 and the 55°C treated volume was 6.7 ± 4.4 cm3. The volumetric undertreatment and overtreatment were respectively 0.1 ± 0.1 cm3 and 0.7 ± 0.6 cm3. The radial targeting accuracy was on average 1 ± 3 mm. Treatments were completed within 7 ± 3 min, that is an treatment rate of 0.9 ± 0.7 cm3/min. MRI-controlled interstitial ultrasound therapy of brain tissue is feasible. This minimally-invasive approach avoids the need to propagate ultrasound through the skull and allows spatially controlled heating which could be used for tissue ablation or drug delivery.

Advances in neuromodulation and an improved understanding of the anatomy and circuitry of psychopathology have led to a resurgence of interest in surgery for psychiatric disease. Clinical trials exploring deep brain stimulation (DBS), a focally targeted, adjustable and reversible form of neurosurgery, are being developed to address the use of this technology in highly selected patient populations. Psychiatric patients deemed eligible for surgical intervention, such as DBS, typically meet stringent inclusion criteria, including demonstrated severity, chronicity and a failure of conventional therapy. Although a humanitarian device exemption by the US Food and Drug Administration exists for its use in obsessive-compulsive disorder, DBS remains a largely experimental treatment in the psychiatric context, with its use currently limited to clinical trials and investigative studies. The combination of a patient population at the limits of conventional therapy and a novel technology in a new indication poses interesting challenges to the informed consent process as it relates to clinical trial enrollment. These challenges can be divided into those that relate to the patient, their disease and the technology, with each illustrating how traditional conceptualisations of research consent may be inadequate in the surgical psychiatry context. With specific reference to risk analysis, patient autonomy, voluntariness and the duty of the clinician-researcher, this paper will discuss the unique challenges that clinical trials of surgery for refractory psychiatric disease present to the consent process. Recommendations are also made for an ethical approach to clinical trial consent acquisition in this unique patient population.

Background The biomedical literature is growing exponentially, with thousands of articles published each day. While the majority of published papers are of incremental value, every field also has a select, relatively small number of works that have presented important conceptual advances and have had a profound influence. We were interested in identifying such papers in the field of Major Depression. Objective To determine which and what type of articles in the field of Major Depression are citation classics, defined as having received equal to or exceeding 400 citations in the biomedical literature, as a surrogate marker for their impact in the field. Methods An online database of research publications was searched using a free, publicly accessible, and downloadable software. The terms “Depression” or “Depressive” were queried in the title of publications with no date restrictions. Out of scope publications not dealing with Major Depression or mood disorders were not considered. Results 243 citation classics representing the top cited manuscripts (approximately 0.1% of 240,000) in the field of Major Depression were identified. These highly cited works fell into six categories: scales/measures, medical psychiatry, clinical trials/management, mechanisms/translational studies, imaging investigations and epidemiological/population health studies. The journals in which citation classics are published are diverse, but typically are general psychiatric or medical publications. Conclusions Despite the size of the field, there is a relatively parsimonious collection of citation classics in the field of Major Depression. These deal primarily with the mechanisms and epidemiology of the disease, with papers dealing with depression management accounting for the fastest growing group of citation classics.

Bipolar disorder (BD) is a complex psychiatric disorder that is often underrecognized, misdiagnosed, and challenging to detect. During the past decade, substantial progress has been made in the development of pharmacotherapeutic and psychosocial interventions for various phases of BD. Notwithstanding these developments, the majority of BD individuals, and particularly patients with bipolar depression, receiving guideline concordant care do not experience syndromal or functional recovery, underscoring the need for novel treatments. Early success with deep brain stimulation (DBS) in the treatment of major depressive episodes as part of major depressive disorder (MDD) has provided the impetus to explore its application in other treatment-resistant psychiatric disorders, notably BD. Herein, we provide the rationale for employing DBS as an alternative treatment avenue in individuals with bipolar depression.We conducted a PubMed literature search, focusing on English language articles beginning in 1950 to the present day, and employed the following search terms: bipolar disorder, neurosurgery, deep brain stimulation, neuroimaging, and circuitry. Search results were then manually reviewed and relevant articles selected for analysis. Relevance was determined by author consensus and overall manuscript quality. We also reviewed articles on currently available treatment options for BD in order to develop a coherent and practical definition of treatment resistance with a focus on surgical intervention.Several lines of evidence indicate that although mania is the defining feature of bipolar I disorder, depressive symptoms and episodes dominate the longitudinal course, account for most of the illness burden including premature mortality, and are least responsive to contemporary treatments. Disease models in bipolar depression implicate abnormalities in the structure and function of discrete neural circuits that subserve affective processing and cognitive function with the subgenual cingulate cortex occupying a central role. Modulation of the cingulate cortex with DBS in treatment-resistant MDD populations has proven to offer acute and sustained antidepressant effects, suggesting possible benefits for other mood disorder populations.A surgical intervention for bipolar depression would not only be a proof of concept regarding disease modeling but also an important and novel treatment avenue for individuals affected by bipolar depression.

Obsessive-compulsive disorder (OCD) is a common psychiatric disease that is marked by recurring, anxiety-provoking thoughts (obsessions) accompanied by repetitive and time-consuming behaviors (compulsions). Among the controversies in the OCD literature is the issue of the origin of the disease and whether brain changes observed with modern imaging techniques are the causes or results of OCD behaviors and thoughts. These issues remain unresolved; however, significant strides have been made in understanding the illness from both phenomenological and pathophysiological perspectives. The current staple of OCD management remains pharmacological in nature and often occurs in conjunction with cognitive behavioral therapy. Refractory cases, however, are occasionally referred for neurosurgical consultation, and several procedures have been examined. Success in the treatment of Parkinson's disease, the reversibility of the therapy, and a relatively safe side-effect profile have allowed deep brain stimulation (DBS) to be examined as an alternative treatment for some psychiatric conditions. Here we assess the possibility of applying DBS to the treatment of OCD. Morphological, functional metabolic, and volumetric data point to several brain regions that are important to the etiology and maintenance of OCD. Converging evidence from the genetics and neurocircuitry literature suggests that several subcortical structures play prominent roles in the disease. The functional modification of these structures could potentially provide symptom relief. Here, we review the ablative and DBS procedures for refractory OCD, and provide a research-driven hypothesis that highlights the ventromedial head of the caudate nucleus, and structures up- and downstream from it, as potential DBS targets for treatment-resistant disease. We hope that a research-driven approach, premised on converging evidence and previous experience, will lead to a safe and effective DBS procedure that will benefit patients who remain disabled despite presently available therapies.

Spontaneous cerebral hemorrhage (ICH) is a major cause of mortality and morbidity worldwide. Although the mechanisms leading to ICH are relatively well known, little improvement in outcomes has occurred over the years, in spite of significant advances in surgical techniques and medical management options. Evidence is available to suggest that liquefying and/or removing the clot after ICH might be beneficial. The objective of this work is to test the feasibility of use of MRI guided focused ultrasound (MRgFUS) in the treatment of ICH. Our hypotheses are that MRgFUS can be used safely to effectively cause clot lysis and it will provide good radiological resolution of ICH.

Obsessive-compulsive disorder (OCD) is among the most common anxiety disorders and one of the most challenging psychiatric conditions to treat. Despite several classes of medications and multiple schools of psychotherapy, a significant proportion of patients remain symptomatic and disabled by their illness. There is therefore an important need to examine alternative approaches to management, a need that has been recognized for well over half a century, since the first published reports of surgery for “obsessional neurosis.”1 In this study, Sheth et al.3 review their institution’s experience with ablative limbic system surgery in an openlabel trial in 64 consecutive cases of treatment-resistant OCD. They report that all 64 patients underwent cingulotomy, with 30 of those requiring at least one additional procedure: either another cingulotomy or conversion to subcaudate tractotomy. At longest follow-up of more than 5 years, the authors report that 47% of patients met the criteria for full response (defined as a ≥ 35% decrease in the Yale-Brown Obsessive Compulsive Scale score), with an additional 22% of patients reaching partial response criteria (decrease of ≥ 25% in the Yale-Brown Obsessive Compulsive Scale score). These are encouraging and positive results, especially given the extent of previous treatment failure and the degree of treatment resistance that the authors carefully established in these patients. Although no treatment can claim a complete response in all patients, this is especially true in OCD, for which both the condition and its treatments are equally diverse and heterogeneous. It is therefore not entirely surprising that just under half of the patients required 2 and sometimes 3 procedures to achieve symptom control. This underscores the importance of close follow-up, judicious assessments, and careful weighing of additional therapeutic options. Additional procedures, however, increase risk, and although the authors do demonstrate the relative safety of their procedure, the occurrence of intraoperative generalized seizures and postoperative abulia in some of their patients is a reminder that limbic surgery is not without its potential pitfalls. Most published series and trials studying surgery for OCD, be it ablation or stimulation, report relatively similar rates of remission and response. This is a little perplexing given the diverse array of targets, including the anterior limb of the internal capsule, the ventral caudate and striatum, inferior thalamic peduncle, and subthalamic nucleus. Perhaps common underlying circuits are influenced by these various procedures. Independent of target and treatment modality, other critical factors contribute to patient outcomes, including treatment expectations, social support, and possibly genetic interactions. Inevitably, the results of ablative surgery in OCD will be compared to those in the deep brain stimulation (DBS) literature, with proponents of the latter touting the reversibility and measurability of that procedure, and its suitability for blinded assessments. The authors rightly point out that DBS is a resource-intensive procedure that in its current, largely investigative applications necessitates heavy involvement of a dedicated research team that can unintentionally and indirectly influence patient expectations and outcomes. It is important to note, however, that this is a feature of all major clinical trials, surgical or otherwise, and is not specific to DBS or OCD. Furthermore, it may be that DBS and ablative procedures are not mutually exclusive, and as has been shown in depression, perhaps there is room for both in the treatment algorithm, even within the same patient.2 Sheth et al. should be commended not only for their large series and encouraging results, but also for their emphasis on judicious record keeping, careful longitudinal assessments, and individualization of care in patients who remain symptomatic. This may well be the optimal approach for a condition as heterogeneous as OCD, whose treatment remains as complex as ever. (http://thejns.org/doi/abs/10.3171/2012.7.JNS12841)

Purpose: The recent clinical emergence of minimally invasive image-guided therapy has demonstrated promise in the management of brain metastasis, although control over the spatial pattern of heating currently remains limited. Based on experience in other organs, the delivery of high-intensity contact ultrasound energy from minimally invasive applicators can enable accurate spatial control of energy deposition, large treatment volumes, and high treatment rate. In this acute study, the feasibility of active MR-Temperature feedback control of dynamic ultrasound heat deposition for interstitial thermal ablation in brain was evaluatedin vivo. Methods: A four-element linear ultrasound transducer (f = 8.2 MHz) originally developed for transurethral ultrasound therapy was used in a porcine model for generating thermal ablations in brain interstitially. First, the feasibility of treating and retreating preciselyin vivo brain tissues using stationary (non-rotating device) ultrasound exposures was studied in two pigs. Experimental results were compared to numerical simulations for maximum surface acoustic intensities ranging from 5 to 20 W cm−2. Second, active MRT feedback-controlled ultrasound treatments were performed in three pigs with a rotating device to coagulate target volumes of various shapes. The acoustic power and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary. Modeling of in vivo treatments were performed and compared to observed experimental results. Results: Overall, the time-space evolution of the temperature profiles observedin vivo could be well estimated from numerical simulations for both stationary and dynamic interstitial ultrasound exposures. Dynamic exposures performed under closed-loop temperature control enabled accurate elevation of the brain tissues within the targeted region above the 55 °C threshold necessary for the creation of irreversible thermal damage. Treatment volumes ranging from 1 to 9 cm3 were completed within 8 ± 3 min with a radial targeting error

There is an urgent need for an effective therapy for treatment-refractory mental illness. Trials ongoing globally that explore surgical treatment, such as deep brain stimulation, for refractory psychiatric disease have produced some promising early results. However, diverse inclusion criteria and variable methodological and ethical standards, combined with the sordid past of neuromodulation, confound trial interpretation and threaten the integrity of a new and emerging science. What is required is a standard of ethical practice, globally applied, for neurosurgical trials in psychiatry that protects patients and maintains a high ethical benchmark for clinicians and researchers to meet. With mental illness, as well as treatment resistance, reaching epidemic proportions, ethically and scientifically sound clinical trials will lead to effective and safe surgical treatments that will become vital components of the clinicians' armamentarium. Ethical criteria, such as the ones proposed here, need to be established now and applied in earnest if the field is to move forward and if patients with no other therapeutic options are to receive much-needed treatment.

Deep brain stimulation (DBS) has proven to be an effective and safe treatment option in patients with various advanced and treatment-refractory conditions. Thus far, most of the experience with DBS has been in the movement disorder literature, and more specifically in the adult population, where its use in conditions such as Parkinson disease has revolutionized management strategies. The pediatric population, however, can also be afflicted by functionally incapacitating neurological conditions that remain refractory despite the clinicians' best efforts. In such cases, DBS offers an additional treatment alternative. In this paper, the authors review their institution's experience with DBS in the pediatric population, and provide an overview of the literature on DBS in children. The authors conclude that DBS in children can and should be considered a valid and effective treatment option, albeit in highly specific and carefully selected cases.

Adjacent to every intensive care unit, operating room and emergency department is arguably the most important room in the hospital — the Family Room. This is where the normally parallel emotional lives of patients and physicians intersect, where feelings and vulnerabilities are exposed, and where

Background Anorexia nervosa is characterized by extreme low body weight and alterations in affective processing. The subcallosal cingulate regulates affect through wide-spread white matter connections and is implicated in the pathophysiology of anorexia nervosa. Objectives We examined whether those with treatment refractory anorexia nervosa undergoing deep brain stimulation (DBS) of the subcallosal white matter (SCC) show: 1) altered anatomical SCC connectivity compared to healthy controls, 2) white matter microstructural changes, and 3) microstructural changes associated with clinically-measured affect. Methods Diffusion magnetic resonance imaging (dMRI) and deterministic multi-tensor tractography were used to compare anatomical connectivity and microstructure in SCC-associated white matter tracts. Eight women with treatment-refractory anorexia nervosa were compared to 8 age- and sex-matched healthy controls. Anorexia nervosa patients also completed affect-related clinical assessments presurgically and 12 months post-surgery. Results 1) Higher (e.g. left parieto-occipital cortices) and lower (e.g. thalamus) connectivity in those with anorexia nervosa compared to controls. 2) Decreases in fractional anisotropy, and alterations in axial and radial diffusivities, in the left fornix crus, anterior limb of the internal capsule (ALIC), right anterior cingulum and left inferior fronto-occipital fasciculus. 3) Correlations between dMRI metrics and clinical assessments, such as low pre-surgical left fornix and right ALIC fractional anisotropy being related to post-DBS improvements in quality-of-life and depressive symptoms, respectively. Conclusions We identified widely-distributed differences in SCC connectivity in anorexia nervosa patients consistent with heterogenous clinical disruptions, although these results should be considered with caution given the low number of subjects. Future studies should further explore the use of affect-related connectivity and behavioral assessments to assist with DBS target selection and treatment outcome.