Pelle P. de Koning

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.

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.

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.

Surgery for psychiatric disorders.

Surgery in psychiatric disorders has a long history and has regained momentum in the past few decades with deep brain stimulation (DBS). DBS is an adjustable and reversible neurosurgical intervention using implanted electrodes to deliver controlled electrical pulses to targeted areas of the brain. It holds great promise for therapy-refractory obsessive-compulsive disorder. Several double-blind controlled and open trials have been conducted and the response rate is estimated around 54%. Open trials have shown encouraging results with DBS for therapy-refractory depression and case reports have shown potential effects of DBS on addiction. Another promising indication is Tourette syndrome, where potential efficacy of DBS is shown by several case series and a few controlled trials. Further research should focus on optimizing DBS with respect to target location and increasing the number of controlled double-blinded trials. In addition, new indications for DBS and new target options should be explored in preclinical research.

Subjective Effects of Cannabis Before the First Psychotic Episode

Objective: The aim of the present study was to gain more insight into the positive and negative effects of cannabis in the prodromal phase of schizophrenia and in the ultra-high-risk (UHR) state for psychosis. Method: A theory-driven questionnaire was used to examine subjective effects in the prodromal phase in male subjects with a recent onset of schizophrenia or related disorder (n = 52) and in the UHR state in help-seeking male subjects screened for being at UHR for psychosis (n = 17); both groups were compared to cannabis-using controls from the general population (n=52). Results: Recent-onset patients and UHR subjects reported feeling more anxious, depressed and suspicious immediately after cannabis use. Some patients also reported feeling less depressed after cannabis use. Recent-onset patients reported increased visual and acoustic hallucinations, and confusion after cannabis use. Of the recent-onset patients 37% reported that their very first psychotic symptoms occurred during cannabis intoxication. Long-term effects of cannabis reported more often by both patient groups were depression, less control over thoughts and social problems. Conclusions: These results suggest that schizophrenia patients in the prodromal phase and subjects at UHR for psychosis are more sensitive to some negative effects of cannabis, in particular psychotic effects, compared to cannabis users from the general population. Although limited by the retrospective design in the recent-onset patients, the present study adds qualitative evidence to longitudinal studies that suggest that cannabis is a component cause in the onset of the first psychotic episode. Further studies are needed on the objective and subjective effects of cannabis in UHR subjects.

Deep brain stimulation targeted at the nucleus accumbens decreases the potential for pathologic network communication.

D eep brain stimulation (DBS) entails electrode implantation and high-frequency electrical stimulation of a specific brain target. DBS targeted at the nucleus accumbens (NAc) is a promising treatment option for otherwise treatmentrefractory obsessive-compulsive disorder (OCD) (1). Recently, our group demonstrated that NAc DBS in OCD not only results in local activity changes but also in reduction of pathological overconnectivity throughout the frontostriatal network (2). This reduction in overconnectivity correlates with symptom improvements, empirically supporting the hypothesis that DBS overwrites pathologic network activity (3). The goal of our current endeavor was to determine mechanistically how DBS could modulate connectivity within the frontostriatal network. The electroencephalogram (EEG) is a noninvasive neuroimaging technique that provides a time window into the network activity of millions of neurons. Neuronal interactions in the EEG

Deep brain stimulation for obsessive–compulsive disorder is associated with cortisol changes

Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been linked to the hypothalamic-pituitary-adrenal (HPA) axis, we set out to study whether DBS affects the HPA axis in OCD patients. We compared a stimulation ON and OFF condition with a one-week interval in 16 therapy-refractory OCD patients, treated with DBS for at least one year, targeted at the nucleus accumbens (NAc). We measured changes in 24-h urinary excretion of free cortisol (UFC), adrenaline and noradrenaline and changes in obsessive-compulsive (Y-BOCS), depressive (HAM-D) and anxiety (HAM-A) symptom scores. Median UFC levels increased with 53% in the OFF condition (from 93 to 143nmol/24h, p=0.12). There were no changes in urinary adrenaline or noradrenaline excretion. The increase in Y-BOCS (39%), and HAM-D (78%) scores correlated strongly with increased UFC levels in the OFF condition. Our findings indicate that symptom changes following DBS for OCD patients are associated with changes in UFC levels.

Deep brain stimulation for obsessive-compulsive disorder affects language: a case report.

BACKGROUND AND IMPORTANCE Deep brain stimulation (DBS) is an effective treatment for patients with refractory neuropsychiatric disorders. Along with symptom improvement, DBS may have concurrent behavioral effects that help to unravel the role of specific brain circuitries in complex human behavior. CLINICAL PRESENTATION This article reports on 2 patients with obsessive-compulsive disorder who received DBS targeted at the nucleus accumbens that resulted in a temporary change of accent and use of vocabulary. CONCLUSION Changes in accent and speaking manners are most likely related to direct DBS stimulation effects of the electrode targeted at the nucleus accumbens. The shift in accent, resembling foreign accent syndrome after injuries in brain language centers, has not been reported before in the course of DBS. Induction of aggressive vocabulary may be related to transient hypomanic behavior after DBS.

Virtual Reality Objectifies the Diagnosis of Psychiatric Disorders: A Literature Review

Background To date, a diagnosis in psychiatry is largely based on a clinical interview and questionnaires. The retrospective and subjective nature of these methods leads to recall and interviewer biases. Therefore, there is a clear need for more objective and standardized assessment methods to support the diagnostic process. The introduction of virtual reality (VR) creates the possibility to simultaneously provoke and measure psychiatric symptoms. Therefore, VR could contribute to the objectivity and reliability in the assessment of psychiatric disorders. Objective In this literature review, we will evaluate the assessment of psychiatric disorders by means of VR environments. First, we investigate if these VR environments are capable of simultaneously provoking and measuring psychiatric symptoms. Next, we compare these measures with traditional diagnostic measures. Methods We performed a systematic search using PubMed, Embase, and Psycinfo; references of selected articles were checked for eligibility. We identified studies from 1990 to 2016 on VR used in the assessment of psychiatric disorders. Studies were excluded if VR was used for therapeutic purposes, if a different technique was used, or in case of limitation to a non-clinical sample. Results A total of 39 studies were included for further analysis. The disorders most frequently studied included schizophrenia (n = 15), developmental disorders (n = 12), eating disorders (n = 3), and anxiety disorders (n = 6). In attention-deficit hyperactivity disorder, the most comprehensive measurement was used including several key symptoms of the disorder. Most of the studies, however, concerned the use of VR to assess a single aspect of a psychiatric disorder. Discussion In general, nearly all VR environments studied were able to simultaneously provoke and measure psychiatric symptoms. Furthermore, in 14 studies, significant correlations were found between VR measures and traditional diagnostic measures. Relatively small clinical sample sizes were used, impeding definite conclusions. Based on this review, the innovative technique of VR shows potential to contribute to objectivity and reliability in the psychiatric diagnostic process.

Deep brain stimulation in obsessive-compulsive disorder targeted at the nucleus accumbens.

The nucleus accumbens (NAc) was selected as a target for deep brain stimulation (DBS) in therapy-resistant obsessive–compulsive disorder (OCD) because of its predominant role in the corticostriatothalamocortical circuitry. To date, five efficacy studies have reported on NAc DBS for the treatment of OCD with a total of 34 subjects. These small studies (N = 2–16), with various designs, indicate an overall Yale–Brown Obsessive–Compulsive Scale score decrease ranging from 6.8 to 17.5 points. The average overall responder rate was ±50 %. The frequency of adverse events appears to be limited and generally reversible by readjusting the stimulation. Since our understanding of the mode of action of NAc DBS for the treatment of OCD is still limited, larger prospective studies including neuroimaging are needed to adequately estimate its true potential and to elucidate its underlying mechanism of action and optimal location of stimulation administration. We conclude that DBS targeted at the NAc is a promising and safe therapy for treatment-resistant OCD.