Mariska Mantione

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.

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.

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.

Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation

The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep‐brain‐stimulation treatment for obsessive–compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate “top–down” (cortex → nucleus accumbens)‐ from “bottom–up” (nucleus accumbens → cortex)‐directed synchronization (functional connectivity). “Top–down”‐directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward‐related processing and may be relevant to understanding the mechanisms of deep‐brain stimulation and its beneficial effects on psychiatric conditions. Hum Brain Mapp, 2012.

Deep Brain Stimulation Induces Striatal Dopamine Release in Obsessive-Compulsive Disorder

BACKGROUND Obsessive-compulsive disorder is a chronic psychiatric disorder related to dysfunctional dopaminergic neurotransmission. Deep brain stimulation (DBS) targeted at the nucleus accumbens (NAc) has recently become an effective treatment for therapy-refractory obsessive-compulsive disorder, but its effect on dopaminergic transmission is unknown. METHODS We measured the effects of NAc DBS in 15 patients on the dopamine D2/3 receptor availability in the striatum with [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission computed tomography. We correlated changes in [(123)I]IBZM binding potential (BP) with plasma levels of homovanillic acid (HVA) and clinical symptoms. RESULTS Acute (1-hour) and chronic (1-year) DBS decreased striatal [(123)I]IBZM BP compared with the nonstimulated condition in the putamen. BP decreases were observed after 1 hour of stimulation, and chronic stimulation was related to concurrent HVA plasma elevations, implying DBS-induced dopamine release. BP decreases in the area directly surrounding the electrodes were significantly correlated with changes in clinical symptoms (45% symptom decrease). CONCLUSIONS NAc DBS induced striatal dopamine release, which was associated with increased HVA plasma levels and improved clinical symptoms, suggesting that DBS may compensate for a defective dopaminergic system.

Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.

IMPORTANCE Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. OBJECTIVE To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. DESIGN, SETTING, AND PARTICIPANTS Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. INTERVENTIONS Deep brain stimulation targeted to the vALIC. MAIN OUTCOMES AND MEASURES The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score). RESULTS Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology-Self-report scores from from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). CONCLUSIONS AND RELEVANCE Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham. TRIAL REGISTRATION trialregister.nl Identifier: NTR2118.

Deep brain stimulation for obsessive–compulsive disorders: long-term analysis of quality of life

Objective To evaluate the long-term effects of deep brain stimulation (DBS) on quality of life (QOL) in therapy-refractory obsessive–compulsive disorder (OCD) patients. Design 16 patients who met Diagnostic and Statistical Manual of Mental Disorders (4th ed) (DSM-IV) criteria for OCD and were considered therapy-refractory were treated with DBS. Patients were assessed 1 month before device implantation (T0), at 8 months of active stimulation (T1) and at 3–5 years of active stimulation (T2). QOL was measured with the WHO Quality of Life Scale-Brief Version (WHOQOL-BREF) that covers physical, psychological, social and environmental domains. The study was conducted between April 2005 and January 2011 at the Academic Medical Center, Amsterdam, The Netherlands. Results At T1 and T2, we found significant improvement (p<0.05) in the general score and in the physical, psychological and environmental domains of WHOQOL-BREF. Between T1 and T2, the physical and psychological domains improved further (p<0.05). At T2, the general score improved by a total of 90%, the physical and psychological domains both improved by 39.5% and the environmental domain improved by 16%. The social domain did not change between baseline and follow-up assessments. Conclusions In line with symptom improvement, patients QOL improved in the general score and in three of the four WHOQOL-BREF domains. This suggests that the improvement caused by DBS is not limited to symptom reduction alone, but also has a positive influence on patients’ perception of their physical, psychological, environmental and global QOL. Clinical trial registration http://isrctn.org identifier: ISRCTN23255677.

Deep brain stimulation increases impulsivity in two patients with obsessive-compulsive disorder.

Deep brain stimulation (DBS) is an adjustable, reversible, nondestructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS has recently shown promising results as an experimental treatment of refractory obsessive–compulsive disorder (OCD). The novelty of the treatment requires careful observation of symptoms and possible side effects in patients. This case report describes two patients with treatment-refractory OCD in whom increased voltage of deep brain stimulation targeted at the nucleus accumbens increased impulsivity. Voltage increase of stimulation resulted in an immediate inflation of self-confidence, irritability and impulsive behaviour and was reversed only after lowering the voltage. The mechanisms behind DBS are not yet fully understood. Possibly, stimulation in the area of the nucleus accumbens affects the corticostriatal circuitry, which plays an important role in impulsivity. Location and amplitude of stimulation might be critical in inducing these behaviours. These two cases underline the importance of a careful clinical assessment of impulsive behaviours during DBS for OCD.

Think twice: Impulsivity and decision making in obsessive-compulsive disorder

Background and Aims Recent studies have challenged the anxiety-avoidance model of obsessive–compulsive disorder (OCD), linking OCD to impulsivity, risky-decision-making and reward-system dysfunction, which can also be found in addiction and might support the conceptualization of OCD as a behavioral addiction. Here, we conducted an exploratory investigation of the behavioral addiction model of OCD by assessing whether OCD patients are more impulsive, have impaired decision-making, and biased probabilistic reasoning, three core dimensions of addiction, in a sample of OCD patients and healthy controls. Methods We assessed these dimensions on 38 OCD patients and 39 healthy controls with the Barratt Impulsiveness Scale (BIS-11), the Iowa Gambling Task (IGT) and the Beads Task. Results OCD patients had significantly higher BIS-11 scores than controls, in particular on the cognitive subscales. They performed significantly worse than controls on the IGT preferring immediate reward despite negative future consequences, and did not learn from losses. Finally, OCD patients demonstrated biased probabilistic reasoning as reflected by significantly fewer draws to decision than controls on the Beads Task. Conclusions OCD patients are more impulsive than controls and demonstrate risky decision-making and biased probabilistic reasoning. These results might suggest that other conceptualizations of OCD, such as the behavioral addiction model, may be more suitable than the anxiety-avoidance one. However, further studies directly comparing OCD and behavioral addiction patients are needed in order to scrutinize this model.

Deep brain stimulation in obsessive–compulsive disorder

The use of deep brain stimulation in psychiatric disorders has received great interest owing to the small risk of the operation, the reversible nature of the technique, and the possibility of optimizing treatment postoperatively. Currently, deep brain stimulation in psychiatry is investigated for obsessive-compulsive disorder, Gilles de la Tourettes syndrome, and major depression. This chapter reviews the application of deep brain stimulation in obsessive-compulsive disorder. Preliminary results suggest that deep brain stimulation in obsessive-compulsive disorder can effectuate a decrease of 40-60% in at least half of the patients. Although various side effects occur, most of these are transitory and linked to specific stimulation parameters which can be changed. Because only a few studies have been performed with a limited number of patients in accordance with varying research protocols, appliance of deep brain stimulation to obsessive-compulsive disorder is still at an experimental stage. The speed of the effect of deep brain stimulation causes fundamental assumptions on the pathophysiology of obsessive-compulsive disorder.