Nathan A. Shapira

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Brain activation by disgust-inducing pictures in obsessive-compulsive disorder

BACKGROUND There is growing interest in the role of disgust in the pathogenesis of obsessive-compulsive disorder (OCD). METHODS Eight OCD subjects with contamination preoccupations and eight gender- and age-matched healthy volunteers viewed pictures from the International Affective Picture System during functional magnetic resonance imaging scans. RESULTS A different distribution of brain activations was found during disgust-inducing visual stimulation in several areas, most notably the insula, compared with neutral stimulation in both OCD subjects and healthy volunteers. Furthermore, whereas activation during the threat-inducing task in OCD subjects showed a pattern similar to that in healthy volunteers, the pattern of activation during the disgust-inducing task was significantly different, including greater increases in the right insula, parahippocampal region, and inferior frontal sites. CONCLUSIONS This pilot study supports the relevance of disgust in the neurocircuitry of OCD with contamination-preoccupation symptoms; future studies looking at non-OCD individuals with high disgust ratings, non-contamination-preoccupied OCD individuals, and individuals with other anxiety disorders are needed.

Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming

Background: Recently, anterior limb of the internal capsule and nucleus accumbens deep brain stimulation (DBS) has been used in the treatment of medication-refractory obsessive–compulsive disorder (OCD). This region has been previously explored with lesion therapy, but with the advent of DBS there exists the possibility of monitoring the acute and chronic effects of electrical stimulation. The stimulation-induced benefits and side effects can be reversibly and blindly applied to a variety of locations in this region. Objective: To explore the acute effects of DBS in the anterior limb of the internal capsule and nucleus accumbens region. Methods: Ten total DBS leads in five patients with chronic and severe treatment-refractory OCD were tested. Patients were examined 30 days after DBS placement and received either “sham” testing or actual testing of the acute effects of DBS (the alternative condition tested 30 days later). Results: Pooled responses were reviewed for comparability of distribution using standard descriptive methods, and relationships between the variables of interest were sought using χ2 analysis. A total of 845 stimulation trials across the five patients were recorded and pooled. Of these 16% were elicited from sham stimulation and 17% from placebo (0 V stimulation). A comparison of active to sham trials showed that sham stimulation was not associated with significant side effects or responses from patients. Non-mood-related responses were found to be significantly associated with the ventral lead contacts (0 and 1) (p = 0.001). Responses such as taste, smell and smile were strongly associated with the most ventral lead positions. Similarly, physiological responses—for example, autonomic changes, increased breathing rate, sweating, nausea, cold sensation, heat sensation, fear, panic and panic episodes—were significantly associated with ventral stimulation (p = 0.001). Fear and panic responses appeared clustered around the most ventral electrode (0). Acute stimulation resulted in either improved or worsened mood responses in both the dorsal and ventral regions of the anterior limb of the internal capsule. Conclusion: The acute effects of DBS in the region of the anterior limb of the internal capsule and nucleus accumbens, particularly when obtained in a blinded fashion, provide a unique opportunity to localise brain regions and explore circuitry.

A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder

BACKGROUND One of the few combination approaches to the treatment of obsessive-compulsive disorder (OCD) with encouraging support is the addition of an antipsychotic to a serotonin reuptake inhibitor. METHODS The study consisted of a 6-week, placebo-controlled addition of olanzapine 5-10 mg (6.1 +/- 2.1 mg, mean +/- SD) to fluoxetine in OCD subjects who were partial or nonresponders to an 8-week, open-label fluoxetine trial (40 mg in 43 subjects, 20 mg in 1 subject). RESULTS Both the fluoxetine-plus-olanzapine (n = 22) and fluoxetine-plus-placebo (n = 22) groups improved significantly over 6 weeks [F(3,113) = 11.64, p <.0001] according to Yale-Brown Obsessive Compulsive Scale scores with repeated-measures analysis of variance; however, the treatment x time interaction was not significant for olanzapine versus placebo addition to fluoxetine. CONCLUSIONS These findings indicate no additional advantage of adding olanzapine for 6 weeks in OCD patients who have not had a satisfactory response to fluoxetine for 8 weeks, compared with extending the monotherapy trial.

Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics

BACKGROUND A subgroup of children with obsessive-compulsive and tic disorders are proposed to have an infectious trigger. The purpose of this study was to investigate the relationship between group A streptococcal titers and symptom fluctuations in children with a clinical course resembling that described for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. METHODS Twenty-five children with obsessive-compulsive disorder and/or tic disorder were evaluated for neuropsychiatric severity and group A streptococcal antibody titers (streptolysin O, deoxyribonuclease B, and carbohydrate A) at 6-week intervals for > or = six consecutive evaluations (total visits=277). RESULTS Children with large symptom fluctuations (n=15) were compared with children without dramatic fluctuations (n=10). Co-movements of obsessive-compulsive/tic severity and group A streptococcal antibodies were assessed. In subjects with large symptom changes, positive correlations were found between streptococcal titers and obsessive-compulsive severity rating changes (p=.0130). These subjects were also more likely to have elevated group A streptococcal titers during the majority of observations (p=.001). Tic symptom exacerbations occurred more often in the fall/winter months than spring/summer months (p=.03). CONCLUSIONS Patients with marked obsessive-compulsive/tic symptom changes may be characterized by streptococcal titer elevations and exhibit evidence of seasonal tic exacerbations.

Satiety dysfunction in Prader-Willi syndrome demonstrated by fMRI.

The neurobiology relating to the insatiable appetite observed in Prader-Willi syndrome (PWS) has not been fully characterised. Two functional magnetic resonance imaging (fMRI) scans were performed on each of three adults with PWS. The scans were carried out pre- and post-treatment with the antiepileptic topiramate, which had little effect on body weight and appetite in these subjects. Subjects fasted overnight and drank a 75 g dextrose solution prior to fMRI scans for measurement of brain activation levels during/after glucose ingestion. Following glucose administration, there was a significant delay in activation at the hypothalamus and other brain regions associated with satiety compared with previous data on obese volunteers. These regions include the insula, ventromedial prefrontal cortex, and nucleus accumbens. Individuals with PWS showed a mean latency of 24 min while in a previous study obese volunteers had shown a latency of 15 min and lean volunteers a latency of 10 min in the hypothalamus. Our results provide evidence towards a satiety dysfunction in the central nervous system of PWS patients.

What's in a "smile?" intra-operative observations of contralateral smiles induced by deep brain stimulation

Abstract Objective: To descirbe smiling and euphoria induced by deep brain stimulation (DBS). Background and Significance: The brain systems inducing emotional experiences and displays are not entirely known, but the ventral striatum including the nucleus accumbens have been posited to play a critical role in mediating emotions with positive valence. DBS has been successfully employed for the treatment of movement disorders, and most recently obsessive compulsive disorder (OCD). The purpose of this report is to describe the emotional changes associated with stimulation of the ventral striatum. Methods: A single patient with intractable OCD had electrode arrays placed in the right and left anterior limbs of the internal capsule and region of the nucleus accumbens. Changes in facial movement during stimulation were quantified by video recording. Ten video segments, time locked to the onset of stimulation, were digitized and changes in pixel intensity that occurred over both sides of the lower face, on a frame by frame basis, following stimulation onset were computed. These summed changes in pixel intensity represented the dependent variable of “entropy” and directly corresponded to changes in light reflectance that occur during facial movement. Results: During stimulation on both the right and left side, the patient consistently developed a half smile on the side of the face contralateral to the stimulating electrode, and also became euphoric. The effect ceased when DBS was discontinued. Conclusions: DBS in the region of the nucleus accumbens produced smile and euphoria suggesting that alterations in the ventral striatum may result in emotional experience and displays. We hypothesize the existence of a limbic-motor network responsible for such changes. This observation suggests that DBS may be useful as a therapy for mood disorders.

Case series on the use of aripiprazole for Tourette syndrome

Characterized by multiple motor and phonic tics, Tourette syndrome (TS) is also associated with a constellation of comorbid disorders, including obsessive–compulsive symptoms that occur in 40–60% of patients. The pathophysiology of tics has been linked by many studies to specific cortical and basal ganglia changes and hypothesized to relate to dysregulation of dopamine responsive/dependent circuits (Jordan et al., 2004). Aripiprazole, a recently released atypical antipsychotic noted for its partial D2 agonist activity along with a low propensity for extrapyramidal effects, has been shown to be efficacious in reducing symptoms of schizophrenia in adults. The value of aripiprazole for treating neuropsychiatric disorders in children has not previously been reported. We present results of a retrospective chart review of six youth with TS and comorbid obsessive–compulsive disorder (OCD) who were treated for 12 wk with aripiprazole.

Effects of Topiramate in Adults With Prader-Willi Syndrome

Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with behavioral manifestations, including hyperphagia, compulsive behavior, self-injury, and mild to moderate mental retardation. In an 8-week open-label study, we evaluated adjunctive therapy with the anticonvulsant topiramate in 8 adults with Prader-Willi syndrome. Appetite was measured by a 1-hour access to food four times throughout the study and quantified with a visual analogue scale. Topiramate did not significantly change calories consumed, Body Mass Index, or increase self-reported appetite. In addition, there were no significant changes in compulsions. Surprisingly, topiramate treatment resulted in a clinically significant improvement in the self-injury (i.e., skin-picking) that is characteristic of this syndrome. Potential benefits of topiramate for self-injury should be evaluated further in controlled trials.

A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation.

This article provides an overview of the etiology, epidemiology, and first-line treatment options for obsessive-compulsive disorder (OCD). The subject of treatment-resistant and treatment-refractory OCD is then discussed, including a definition of these often-debated terms, and the latest treatment options delineated. This includes a review of the latest research concerning the pharmacological agents that have been studied as monotherapy or augmenting agents for the treatment of OCD, the use of experimental medications and procedures, treatment with reversible, minimally invasive procedures, such as vagal nerve stimulation and transcranial magnetic stimulation, invasive but the potentially reversible deep brain stimulation, and irreversible lesioning with ablative psychosurgery. A discussion of the role of psychotherapy in the treatment of OCD is also included.