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Background: The aim of this study was to assess psychiatric and social outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinson's disease (PD).Methods: We randomly assigned patients to receive GPi DBS (n = 65) or STN DBS (n = 63). Standardized psychiatric and social questionnaires were assessed at baseline and after 12 months.Results: No differences were found between GPi DBS and STN DBS on psychiatric evaluation. Within-group comparisons showed small but statistically significant changes on several measures in both groups. Descriptive statistics indicated slight changes in social functioning. Marital satisfaction of patients and partners remained relatively stable after GPi and STN DBS.Conclusions: We found neither differences in psychiatric and social outcome between GPi DBS and STN DBS nor any relevant within-group differences. The decision for GPi DBS or STN DBS cannot be based on expected psychiatric or social effects. [ABSTRACT FROM AUTHOR]

Abstract: Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge. Changes in [11C]raclopride binding potential (BPND) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3mgkg−1) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D2/3 receptor BPND and change in BPND following amphetamine as a measure of dopamine release. Voxel-based analysis revealed significantly decreased baseline [11C]raclopride BPND in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BPND following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BPND changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BPND. This study provides evidence for decreased striatal D2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics. [Copyright &y& Elsevier]

Background: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate., Methods: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region., Results: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression., Conclusions: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson's disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value-akin to reward prediction errors-whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia's main output structures reflect distinct social context and value signals., (© 2024. The Author(s).)

Although neuroimaging has been widely applied in psychiatry, much of the exuberance in decades past has been tempered by failed replications and a lack of definitive evidence to support the utility of imaging to inform clinical decisions. There are multiple promising ways forward to demonstrate the relevance of neuroimaging for psychiatry at the individual patient level. Ultra-high field magnetic resonance imaging is developing as a sensitive measure of neurometabolic processes of particular relevance that holds promise as a new way to characterize patient abnormalities as well as variability in response to treatment. Neuroimaging may also be particularly suited to the science of brain stimulation interventions in psychiatry given that imaging can both inform brain targeting as well as measure changes in brain circuit communication as a function of how effectively interventions improve symptoms. We argue that a greater focus on individual patient imaging data will pave the way to stronger relevance to clinical care in psychiatry. We also stress the importance of using imaging in symptom-relevant experimental manipulations and how relevance will be best demonstrated by pairing imaging with differential treatment prediction and outcome measurement. The priorities for using brain imaging to inform psychiatry may be shifting, which compels the field to solidify clinical relevance for individual patients over exploratory associations and biomarkers that ultimately fail to replicate., (© 2024. The Author(s).)

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment., (© 2023. The Author(s).)

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD) 1 . However, achieving stable recovery is unpredictable 2 , typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting 3 . We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment., (© 2023. The Author(s).)

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson's disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection., Methods: The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 μsec for STN; 3.3 V and 90 μsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared., Results: VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex., Conclusions: On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

Objective . Deep brain stimulation is a treatment option for patients with refractory obsessive-compulsive disorder. A new generation of stimulators hold promise for closed loop stimulation, with adaptive stimulation in response to biologic signals. Here we aimed to discover a suitable biomarker in the ventral striatum in patients with obsessive compulsive disorder using local field potentials. Approach. We induced obsessions and compulsions in 11 patients undergoing deep brain stimulation treatment using a symptom provocation task. Then we trained machine learning models to predict symptoms using the recorded intracranial signal from the deep brain stimulation electrodes. Main results. Average areas under the receiver operating characteristics curve were 62.1% for obsessions and 78.2% for compulsions for patient specific models. For obsessions it reached over 85% in one patient, whereas performance was near chance level when the model was trained across patients. Optimal performances for obsessions and compulsions was obtained at different recording sites. Significance . The results from this study suggest that closed loop stimulation may be a viable option for obsessive-compulsive disorder, but that intracranial biomarkers are patient and not disorder specific. Clinical Trial: Netherlands trial registry NL7486., (Creative Commons Attribution license.)

Background: Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD), but patients typically require high stimulation voltages and DBS comes with a risk for adverse events (AE)., Objective: The aim of the present study was to advance DBS for OCD by optimizing energy efficiency and minimize adverse events using a cyclic form of stimulation METHODS: This double blind, randomized crossover trial compares 2 weeks of continuous versus cyclic DBS (0.1 s ON, 0.2 s OFF) in 16 patients with OCD. We compared OCD symptoms (Yale-Brown Obsessive-Compulsive Scale, Y-BOCS), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), AEs, battery life, cognitive performance and quality of life., Results: Average Y-BOCS scores at baseline increased significantly with 5.5 points (p = 0.006) in the cyclic condition. Average HAM-D and HAM-A scores increased with 2.2 (p = 0.088) and 2.8 points (p = 0.018). The overall health scale of quality of life worsened during cyclic DBS (p = 0.044). Patients reported on average 3.3 AEs during continuous stimulation and 4.4 AEs during cyclic stimulation (p = 0.175), though stimulation-related AEs such as headache and concentration problems reduced during cyclic DBS. Battery usage during continuous DBS was 0.021 V per hour compared to 0.008 V per hour during cyclic DBS., Conclusion: Though specific stimulation-related AEs improved, cyclic stimulation (0.1 s ON, 0.2 s OFF) comes with a high relapse risk in patients with DBS for OCD. Cyclic DBS is no alternative for standard DBS treatment, but applicable in case of debilitating AEs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: While a growing body of research highlights a bi-directional link between diabetes and mood disorders, little is known about the relationship between diabetes and obsessive-compulsive disorder (OCD). The aim of the present review is to investigate current evidence linking OCD, insulin-signaling and diabetes., Methods: A PubMed search was conducted to review all the available studies assessing diabetes, glucose metabolism and insulin-signaling in OCD patients and vice versa., Results: Some clinical and epidemiological studies show a higher prevalence of diabetes in OCD and vice versa compared to the general population. Animal and genetic studies suggest a possible role of insulin-signaling in the pathophysiology of OCD. Deep brain stimulation (DBS) studies suggest that abnormal dopaminergic transmission in the striatum may contribute to impaired insulin sensitivity in OCD. While DBS seems to increase insulin sensitivity, a possible protective role of serotonin reuptake-inhibitors on diabetic risk needs further studies., Conclusion: Despite their preliminary nature, these data highlight the importance of further investigations aimed at assessing metabolic features in OCD patients and OCD symptoms in diabetes patients to understand the impact of each condition on the pathophysiology and course of the other. Understanding the role of insulin in the obsessive-compulsive brain could open new treatment pathways for OCD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation has been extensively studied as a therapeutic option for treatment-resistant depression (TRD). DBS across different targets is associated with on average 60% response rates in previously refractory chronically depressed patients. However, response rates vary greatly between patients and between studies and often require extensive trial-and-error optimizations of stimulation parameters. Emerging evidence from tractography imaging suggests that targeting combinations of white matter tracts, rather than specific grey matter regions, is necessary for meaningful antidepressant response to DBS. In this article, we review efficacy of various DBS targets for TRD, which networks are involved in their therapeutic effects, and how we can use this information to improve targeting and programing of DBS for individual patients. We will also highlight how to integrate these DBS network findings into developing adaptive stimulation and optimal trial designs., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Background: Deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) is effective in half of patients, but also is invasive and labor-intensive., Objective: Selecting probable responders beforehand would more optimally allocate treatment resources and prevent patients' disappointment. Some centers use clinical and demographic predictors to exclude patients from DBS treatment, but the evidence base remains uncertain., Methods: This observational cohort study examined the association of baseline demographic and disease characteristics with a 1-year prospective course of OCD and depressive symptoms in a cohort of 70 consecutive patients who received DBS of the ventral anterior limb of the internal capsule (vALIC-DBS) for OCD according to DSM-IV or DSM-5 criteria between April 2005 and October 2017. Baseline characteristics and symptom decrease were analyzed using Fisher exact tests and binary logistic regression to examine whether they could predict individual response (> 35% reduction in Yale-Brown Obsessive Compulsive Scale score and 50% reduction in Hamilton Depression Rating Scale score, respectively)., Results: Insight into illness was the only significant predictor of individual response, with a positive predictive value of 84.4%, while the negative predictive value was 44.0% ( b  = 0.247, χ 2 1  = 5.259, P  = .022). Late-onset OCD was associated with more symptom decrease (β = -0.29; 95% CI, -0.53 to -0.04; P  = .023) and comorbid personality disorder with less symptom decrease over time (β = 0.88; 95% CI -0.29 to 1.47; P  = .004), but they could not significantly predict vALIC-DBS response. A later age at onset, comorbid personality disorder, and insight into illness were associated with clinical outcomes after vALIC-DBS, but predictive values were not large enough to facilitate clinical patient selection., Conclusions: Clinical and demographic factors cannot yet predict outcome and should not be used to exclude patients from treatment with vALIC-DBS. These first individual prediction analyses for vALIC-DBS response in OCD are important, given that some centers up until now still exclude patients based on clinical characteristics such as comorbid personality disorders., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Addressing treatment refractoriness in psychiatric diseases is an essential public health objective. The last two decades have seen an increasing interest for deep brain stimulation (DBS) of several brain targets. In this chapter, we have reviewed the main DBS clinical trials in psychiatric diseases, mainly obsessive compulsive disorders (OCD) and depression, but also emerging research in other psychiatric disorders. While its efficacy and safety are confirmed, DBS is still not considered as standard therapy in psychiatry. However, advances in neuroimaging research combined to behavioral and electrophysiological data uniquely provided by DBS studies improve knowledge on physiopathology in these brain diseases. This will help define the optimal brain targets according to specific phenotype dimensions. Revealing the mechanisms of action and effects of DBS will support that its impact goes beyond a loco-regional brain stimulation and confirms that electrical neuromodulation influences brain networks. Added to the progress in neuromodulation technology, these insights will hopefully facilitate a more widespread application of this promising treatment. Future development of a personalized multimodal assessment of underlying dysfunctional brain networks will open new circuit-specific treatment perspectives that may facilitate better patient outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This project aims to assess usability and acceptance of a customized Epic-based flowsheet designed to streamline the complex workflows associated with care of patients with implanted Deep Brain Stimulators (DBS). DBS patient care workflows are markedly fragmented, requiring providers to switch between multiple disparate systems. This is the first attempt to systematically evaluate usability of a unified solution built as a flowsheet in Epic. Iterative development processes were applied, collecting formal feedback throughout. Evaluation consisted of cognitive walkthroughs, heuristic analysis, and 'think-aloud' technique. Participants completed 3 tasks and multiple questionnaires with Likert-like questions and long-form written feedback. Results demonstrate that the strengths of the flowsheet are its consistency, mapping, and affordance. System Usability Scale scores place this first version of the flowsheet above the 70th percentile with an 'above average' usability rating. Most importantly, a copious amount of actionable feedback was captured to inform the next iteration of this build., (©2020 AMIA - All rights reserved.)

Objective: Obsessive-compulsive disorder (OCD) is associated with variable risk of suicide and prevalence of suicide attempt (SA). The present study aimed to assess the prevalence of SA and associated sociodemographic and clinical features in a large international sample of OCD patients., Methods: A total of 425 OCD outpatients, recruited through the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) network, were assessed and categorized in groups with or without a history of SA, and their sociodemographic and clinical features compared through Pearson's chi-squared and t tests. Logistic regression was performed to assess the impact of the collected data on the SA variable., Results: 14.6% of our sample reported at least one SA during their lifetime. Patients with an SA had significantly higher rates of comorbid psychiatric disorders (60 vs. 17%, p<0.001; particularly tic disorder), medical disorders (51 vs. 15%, p<0.001), and previous hospitalizations (62 vs. 11%, p<0.001) than patients with no history of SA. With respect to geographical differences, European and South African patients showed significantly higher rates of SA history (40 and 39%, respectively) compared to North American and Middle-Eastern individuals (13 and 8%, respectively) (χ2=11.4, p<0.001). The logistic regression did not show any statistically significant predictor of SA among selected independent variables., Conclusions: Our international study found a history of SA prevalence of ~15% in OCD patients, with higher rates of psychiatric and medical comorbidities and previous hospitalizations in patients with a previous SA. Along with potential geographical influences, the presence of the abovementioned features should recommend additional caution in the assessment of suicide risk in OCD patients.

Background: Deep Brain Stimulation (DBS) is effective for obsessive-compulsive disorder (OCD), but requires expensive medical procedures. To date, no study has examined the cost-effectiveness of DBS for OCD., Objective: To perform the first economic evaluation of DBS for therapy refractory OCD., Methods: We conducted a 2-year prospective, open cost-effectiveness study, comparing DBS (n = 17) with treatment as usual (TAU) (n = 11), with cost per Quality-Adjusted-Life-Year (QALY) as outcome measure. Apart from the base-case, or primary analysis, we conducted two practice-based scenarios: (1) standard care scenario, without research and innovation costs, and (2) rechargeable scenario, in which we assume the use of a rechargeable battery. Base-case and both scenarios were extrapolated to four years to estimate long-term cost-effectiveness., Results: Compared to TAU, DBS provides an additional 0.26 QALY (SD = 0.16). Median cost per QALY gained is estimated at €141,446 for base-case, €115,916 for standard care and €65,394 for the rechargeable scenario. Extending the time-horizon to four years results in a median cost per QALY of €80,313 for base-case, €69,287 for standard care, and turned out to be cost-saving at €4678 per QALY for the rechargeable scenario. Assuming a willingness to pay threshold of €80,000/QALY, DBS, under base-case and standard care had 25% and 35% probability of being more cost-effective than TAU. With the rechargeable scenario and in all scenarios extrapolated to four years, the probability of cost-effectiveness was equal or higher than TAU., Conclusions: This study indicates DBS for OCD is cost-effective in the long-term, especially when rechargeable batteries are taken into account., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The brain is limited in its capacity to consciously process information, necessitating gating of information. While conscious perception is robustly associated with sustained, recurrent interactions between widespread cortical regions, subcortical regions, including the striatum, influence cortical activity. Here, we examined whether the ventral striatum, given its ability to modulate cortical information flow, contributes to conscious perception. Using intracranial EEG, we recorded ventral striatum activity while 7 patients performed an attentional blink task in which they had to detect two targets (T1 and T2) in a stream of distractors. Typically, when T2 follows T1 within 100-500 ms, it is often not perceived (i.e., the attentional blink). We found that conscious T2 perception was influenced and signaled by ventral striatal activity. Specifically, the failure to perceive T2 was foreshadowed by a T1-induced increase in α and low β oscillatory activity as early as 80 ms after T1, indicating that the attentional blink to T2 may be due to very early T1-driven attentional capture. Moreover, only consciously perceived targets were associated with an increase in θ activity between 200 and 400 ms. These unique findings shed new light on the mechanisms that give rise to the attentional blink by revealing that conscious target perception may be determined by T1 processing at a much earlier processing stage than traditionally believed. More generally, they indicate that ventral striatum activity may contribute to conscious perception, presumably by gating cortical information flow., Significance Statement: What determines whether we become aware of a piece of information or not? Conscious access has been robustly associated with activity within a distributed network of cortical regions. Using intracranial electrophysiological recordings during an attentional blink task, we tested the idea that the ventral striatum, because of its ability to modulate cortical information flow, may contribute to conscious perception. We find that conscious perception is influenced and signaled by ventral striatal activity. Short-latency (80-140 ms) striatal responses to a first target determined conscious perception of a second target. Moreover, conscious perception of the second target was signaled by longer-latency (200-400 ms) striatal activity. These results suggest that the ventral striatum may be part of a subcortical network that influences conscious experience., (Copyright © 2017 the authors 0270-6474/17/371081-09$15.00/0.)

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.

Compulsive behaviors are driven by repetitive urges and typically involve the experience of limited voluntary control over these urges, a diminished ability to delay or inhibit these behaviors, and a tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity is not only a central characteristic of obsessive-compulsive disorder (OCD) but is also crucial to addiction. Based on this analogy, OCD has been proposed to be part of the concept of behavioral addiction along with other non-drug-related disorders that share compulsivity, such as pathological gambling, skin-picking, trichotillomania and compulsive eating. In this review, we investigate the neurobiological overlap between compulsivity in substance-use disorders, OCD and behavioral addictions as a validation for the construct of compulsivity that could be adopted in the Research Domain Criteria (RDoC). The reviewed data suggest that compulsivity in OCD and addictions is related to impaired reward and punishment processing with attenuated dopamine release in the ventral striatum, negative reinforcement in limbic systems, cognitive and behavioral inflexibility with diminished serotonergic prefrontal control, and habitual responding with imbalances between ventral and dorsal frontostriatal recruitment. Frontostriatal abnormalities of compulsivity are promising targets for neuromodulation and other interventions for OCD and addictions. We conclude that compulsivity encompasses many of the RDoC constructs in a trans-diagnostic fashion with a common brain circuit dysfunction that can help identifying appropriate prevention and treatment targets., (Copyright © 2016. Published by Elsevier B.V.)

Clinical outcome of deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) shows robust effects in terms of a mean Yale-Brown Obsessive-Compulsive Scale (YBOCS) reduction of 47.7 % and a mean response percentage (minimum 35 % YBOCS reduction) of 58.2 %. It appears that most patients regain a normal quality of life (QoL) after DBS. Reviewing the literature of the last 4 years, we argue that the mechanisms of action of DBS are a combination of excitatory and inhibitory as well as local and distal effects. Evidence from DBS animal models converges with human DBS EEG and imaging findings, in that DBS may be effective for OCD by reduction of hyperconnectivity between frontal and striatal areas. This is achieved through reduction of top-down-directed synchrony and reduction of frontal low-frequency oscillations. DBS appears to counteract striatal dysfunction through an increase in striatal dopamine and through improvement of reward processing. DBS affects anxiety levels through reduction of stress hormones and improvement of fear extinction.

Background: Deep brain stimulation (DBS) is regarded as an effective way to treat refractory obsessive-compulsive disorder (OCD). Little is known about the effects of DBS cessation following a longer period of stimulation., Objective: To determine the relapse and rebound effects of psychiatric symptoms, and their impact on Quality of Life (QoL) following acute cessation of DBS in OCD patients., Methods: We included 16 out of 32 patients who were treated with DBS between April 2005 and January 2011 at the Academic Medical Center, Amsterdam. After treatment for at least one year, patients entered a 1-week phase in which DBS was switched off. We evaluated psychiatric symptoms and QoL at three time points: before DBS surgery (pre-DBS), following at least one year of DBS treatment (DBS-on) and following 1 week of DBS off (DBS-off). Psychiatric symptoms were assessed with the Yale-Brown obsessive-compulsive disorder scale (Y-BOCS), the Hamilton anxiety rating scale (HAM-A) and the Hamilton depression rating scale (HAM-D). QoL was assessed using the World Health Organization QOL scale (WHOQOL-Bref)., Results: Switching from DBS-on to DBS-off, Y-BOCS scores increased with 50%, HAM-A scores with 80% and HAM-D scores with 83%. In the DBS-off period, HAM-A and HAM-D scores exceeded pre-surgery levels with approximately 40%, suggesting a rebound phenomenon. Furthermore, a deterioration of physical and psychological QoL to levels comparable with pre-surgery was found during DBS-off., Conclusion: Acute DBS cessation causes a relapse of obsessions and compulsions and a rebound of anxiety and depression. Additionally, improvements on QoL disappear., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder characterized by persistent thoughts and repetitive ritualistic behaviours. Despite optimal cognitive-behavioral and pharmacological therapy, approximately 10 % of patients remain treatment-resistant. Deep brain stimulation (DBS) is being investigated as experimental therapy for treatment-refractory OCD. In the current study, we determined the relationship between anatomical location of active electrode contacts and clinical outcome in 16 OCD patients undergoing bilateral nucleus accumbens (NAc) DBS. We found that most patients actually do not receive active stimulation in the NAc but in the more laterally, anteriorly and dorsally located ventral part of the anterior limb of the internal capsule, ventral ALIC (vALIC). Our nine patients receiving bilateral vALIC DBS improved on average 73 % on their Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, whereas the six patients with their centers of stimulation located otherwise improved on average only 42 %. We therefore propose bilateral vALIC as a promising new DBS target for patients with treatment-refractory OCD. Future studies employing a direct vALIC targeting approach in larger patient numbers are needed to test whether this proposal holds true.

Reward related behaviour is linked to dopaminergic neurotransmission. Our aim was to gain insight into dopaminergic involvement in the human reward system. Combining functional magnetic resonance imaging with dopaminergic depletion by α-methylparatyrosine we measured dopamine-related brain activity in 10 healthy volunteers. In addition to blood-oxygen-level-dependent (BOLD) contrast we assessed the effect of dopaminergic depletion on prolactin response, peripheral markers for dopamine and norepinephrine. In the placebo condition we found increased activation in the left caudate and left cingulate gyrus during anticipation of reward. In the α-methylparatyrosine condition there was no significant brain activation during anticipation of reward or loss. In α-methylparatyrosine, anticipation of reward vs. loss increased activation in the right insula, left frontal, right parietal cortices and right cingulate gyrus. Comparing placebo versus α-methylparatyrosine showed increased activation in the left cingulate gyrus during anticipation of reward and the left medial frontal gyrus during anticipation of loss. α-methylparatyrosine reduced levels of dopamine in urine and homovanillic acid in plasma and increased prolactin. No significant effect of α-methylparatyrosine was found on norepinephrine markers. Our findings implicate distinct patterns of BOLD underlying reward processing following dopamine depletion, suggesting a role of dopaminergic neurotransmission for anticipation of monetary reward.