Damiaan Denys

Deep Brain Stimulation of the Nucleus Accumbens for Treatment-Refractory Obsessive-Compulsive Disorder

CONTEXT Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Even when the best available treatments are applied, approximately 10% of patients remain severely afflicted and run a long-term deteriorating course of OCD. OBJECTIVE To determine whether bilateral deep brain stimulation of the nucleus accumbens is an effective and safe treatment for treatment-refractory OCD. DESIGN The study consisted of an open 8-month treatment phase, followed by a double-blind crossover phase with randomly assigned 2-week periods of active or sham stimulation, ending with an open 12-month maintenance phase. SETTING Academic research. Patients Sixteen patients (age range, 18-65 years) with OCD according to DSM-IV criteria meeting stringent criteria for refractoriness to treatment were included in the study. INTERVENTIONS Treatment with bilateral deep brain stimulation of the nucleus accumbens. MAIN OUTCOME MEASURES Primary efficacy was assessed by score change from baseline on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Responders were defined by a score decrease of at least 35% on the Y-BOCS. RESULTS In the open phase, the mean (SD) Y-BOCS score decreased by 46%, from 33.7 (3.6) at baseline to 18.0 (11.4) after 8 months (P < .001). Nine of 16 patients were responders, with a mean (SD) Y-BOCS score decrease of 23.7 (7.0), or 72%. In the double-blind, sham-controlled phase (n = 14), the mean (SD) Y-BOCS score difference between active and sham stimulation was 8.3 (2.3), or 25% (P = .004). Depression and anxiety decreased significantly. Except for mild forgetfulness and word-finding problems, no permanent adverse events were reported. CONCLUSION Bilateral deep brain stimulation of the nucleus accumbens may be an effective and safe treatment for treatment-refractory OCD. CLINICAL TRIAL REGISTRATION isrctn.org Identifier: ISRCTN23255677.

OBSESSIVE-COMPULSIVE DISORDER: A REVIEW OF THE DIAGNOSTIC CRITERIA AND POSSIBLE SUBTYPES AND DIMENSIONAL SPECIFIERS FOR DSM-V

Background: Since the publication of the DSM‐IV in 1994, research on obsessive–compulsive disorder (OCD) has continued to expand. It is timely to reconsider the nosology of this disorder, assessing whether changes to diagnostic criteria as well as subtypes and specifiers may improve diagnostic validity and clinical utility. Methods: The existing criteria were evaluated. Key issues were identified. Electronic databases of PubMed, ScienceDirect, and PsycINFO were searched for relevant studies. Results: This review presents a number of options and preliminary recommendations to be considered for DSM‐V. These include: (1) clarifying and simplifying the definition of obsessions and compulsions (criterion A); (2) possibly deleting the requirement that people recognize that their obsessions or compulsions are excessive or unreasonable (criterion B); (3) rethinking the clinical significance criterion (criterion C) and, in the interim, possibly adjusting what is considered “time‐consuming” for OCD; (4) listing additional disorders to help with the differential diagnosis (criterion D); (5) rethinking the medical exclusion criterion (criterion E) and clarifying what is meant by a “general medical condition”; (6) revising the specifiers (i.e., clarifying that OCD can involve a range of insight, in addition to “poor insight,” and adding “tic‐related OCD”); and (7) highlighting in the DSM‐V text important clinical features of OCD that are not currently mentioned in the criteria (e.g., the major symptom dimensions). Conclusions: A number of changes to the existing diagnostic criteria for OCD are proposed. These proposed criteria may change as the DSM‐V process progresses. Depression and Anxiety, 2010.

Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder

Little is known about the underlying neural mechanism of deep brain stimulation (DBS). We found that DBS targeted at the nucleus accumbens (NAc) normalized NAc activity, reduced excessive connectivity between the NAc and prefrontal cortex, and decreased frontal low-frequency oscillations during symptom provocation in patients with obsessive-compulsive disorder. Our findings suggest that DBS is able to reduce maladaptive activity and connectivity of the stimulated region.

Dysfunctional Reward Circuitry in Obsessive-Compulsive Disorder

BACKGROUND Obsessive-compulsive disorder (OCD) is primarily conceived as an anxiety disorder but has features resembling addictive behavior. Patients with OCD may develop dependency upon compulsive behaviors because of the rewarding effects following reduction of obsession-induced anxiety. Reward processing is critically dependent on ventral striatal-orbitofrontal circuitry and brain imaging studies in OCD have consistently shown abnormal activation within this circuitry. This is the first functional imaging study to investigate explicitly reward circuitry in OCD. METHODS Brain activity during reward anticipation and receipt was compared between 18 OCD patients and 19 healthy control subjects, using a monetary incentive delay task and functional magnetic resonance imaging. Reward processing was compared between OCD patients with predominantly contamination fear and patients with predominantly high-risk assessment. RESULTS Obsessive-compulsive disorder patients showed attenuated reward anticipation activity in the nucleus accumbens compared with healthy control subjects. Reduced activity of the nucleus accumbens was more pronounced in OCD patients with contamination fear than in patients with high-risk assessment. Brain activity during reward receipt was similar between patients and control subjects. A hint toward more dysfunctional reward processing was found in treatment-resistant OCD patients who subsequently were successfully treated with deep brain stimulation of the nucleus accumbens. CONCLUSIONS Obsessive-compulsive disorder patients may be less able to make beneficial choices because of altered nucleus accumbens activation when anticipating rewards. This finding supports the conceptualization of OCD as a disorder of reward processing and behavioral addiction.

Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report.

OBJECTIVESmoking and overeating are compulsory habits that are difficult to stop. Several studies have shown involvement of the nucleus accumbens in these and other addictive behaviors. In this case report, we describe a patient who quit smoking and lost weight without any effort, and we review the underlying mechanisms of action. CLINICAL PRESENTATIONA 47-year-old woman presented with chronic treatment-refractory obsessive-compulsive disorder, nicotine dependence, and obesity. INTERVENTIONThe patient was treated with deep brain stimulation of the nucleus accumbens for obsessive-compulsive disorder. Unintended, effortless, and simultaneous smoking cessation and weight loss were observed. CONCLUSIONThis study supports the idea of compulsivity with common circuitry in the processing of diverse rewards and suggests that deep brain stimulation of the nucleus accumbens could be a possible treatment of patients with a dependency not responding to currently available treatments.

New developments in human neurocognition: clinical, genetic, and brain imaging correlates of impulsivity and compulsivity

Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.

Deep brain stimulation in addiction: a review of potential brain targets

Deep brain stimulation (DBS) is an adjustable, reversible, non-destructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS is currently investigated in psychiatry for the treatment of refractory obsessive–compulsive disorder, Tourette syndrome and depressive disorder. Although recent research in both animals and humans has indicated that DBS may be an effective intervention for patients with treatment-refractory addiction, it is not yet entirely clear which brain areas should be targeted. The objective of this review is to provide a systematic overview of the published literature on DBS and addiction and outline the most promising target areas using efficacy and adverse event data from both preclinical and clinical studies. We found 7 animal studies targeting six different brain areas: nucleus accumbens (NAc), subthalamic nucleus (STN), dorsal striatum, lateral habenula, medial prefrontal cortex (mPFC) and hypothalamus, and 11 human studies targeting two different target areas: NAc and STN. Our analysis of the literature suggests that the NAc is currently the most promising DBS target area for patients with treatment-refractory addiction. The mPFC is another promising target, but needs further exploration to establish its suitability for clinical purposes. We conclude the review with a discussion on translational issues in DBS research, medical ethical considerations and recommendations for clinical trials with DBS in patients with addiction.

Multicenter Voxel-Based Morphometry Mega-Analysis of Structural Brain Scans in Obsessive-Compulsive Disorder

OBJECTIVE Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables. METHOD A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects. RESULTS Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age). CONCLUSIONS These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

Current Status of Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Clinical Review of Different Targets

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Despite optimal cognitive-behavioral and pharmacologic therapy, approximately 10% of patients remain treatment resistant. Currently, deep brain stimulation (DBS) is being investigated as an experimental therapy for treatment-refractory OCD. This review focuses on the efficacy and adverse events of all published DBS targets for OCD: anterior limb of the internal capsule, ventral striatum/ventral capsule, nucleus accumbens, nucleus subthalamicus, and inferior thalamic peduncle. Small studies with various designs indicate an overall average Yale-Brown Obsessive Compulsive Scale score decrease ranging from 6.8 to 31 points. The average overall responder rate is ±50%. The frequency of adverse events seems to be limited. Larger prospective studies including neuroimaging are needed to estimate adequately the true potential of DBS in treatment of OCD and to elucidate its underlying mechanism of action and optimal brain target. We conclude that DBS may be a promising and safe therapy for treatment-resistant OCD.

Neurobiology of obsessive-compulsive disorder: serotonin and beyond.

The evidence for the involvement of the serotonergic system in the pathogenesis of obsessive-compulsive disorder (OCD) is circumstantial at best, despite being the focus for most pathophysiological research over the last 2 decades. This hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors (SSRIs) in alleviating OCD symptoms. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse. There is growing evidence, from both preclinical and clinical studies, that the dopamine system may also be involved in the pathogenesis of OCD, and that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both systems, the phenotypic heterogeneity of the disorder, and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Further studies with more selective pharmacologic agents and neurocognitive probes in humans, studies using deep brain stimulation in combination with neuroimaging, and the development of better animal models for OCD may further our understanding of this disabling condition