Deep brain stimulation (DBS) is a promising intervention for treatment-resistant depression (TRD). Effects on cognitive functioning are unclear since they have been studied in small samples. We aim ...to estimate the impact of DBS on cognitive functioning in TRD with a systematic review and meta-analyses. After systematically searching PubMed we included 10 studies which compared standardized neuropsychological tests before and after DBS or between active and sham DBS in TRD. Different random-effects meta-analyses were done for different cognitive (sub-)domains and for different follow-up time windows (<6 months, 6-18 months, and >18 months). We found no significant differences in cognitive functioning up to 6 months of DBS. After 6-18 months of DBS small to moderate improvements were found in verbal memory (Hedge's g = 0.22, 95% CI = 0.01-0.43, p = 0.04), visual memory (Hedge's g = 0.37, 95% CI = 0.03-0.71, p = 0.04), attention/psychomotor speed (Hedge's g = 0.26, 95% CI = 0.02-0.50, p = 0.04) and executive functioning (Hedge's g = 0.37, 95% CI = 0.15-0.59, p = 0.001). Not enough studies could be retrieved for a meta-analysis of effects after >18 months of DBS or for the comparison of active and sham DBS. Qualitatively, generally no differences in cognitive functioning between active and sham DBS were found. No cognitive decline was found in this meta-analysis up to 18 months of DBS in patients with TRD. Results even suggest small positive effects of DBS on cognitive functioning in TRD, although this should be interpreted with caution due to lack of controlled data.
Electroconvulsive therapy (ECT) is effective even in treatment-resistant patients with major depression. Currently, there are no markers available that can assist in identifying those patients most ...likely to benefit from ECT. In the present study, we investigated whether resting-state network connectivity can predict treatment outcome for individual patients. We included forty-five patients with severe and treatment-resistant unipolar depression and collected functional magnetic resonance imaging scans before the course of ECT. We extracted resting-state networks and used multivariate pattern analysis to discover networks that predicted recovery from depression. Cross-validation revealed two resting-state networks with significant classification accuracy after correction for multiple comparisons. A network centered in the dorsomedial prefrontal cortex (including the dorsolateral prefrontal cortex, orbitofrontal cortex and posterior cingulate cortex) showed a sensitivity of 84% and specificity of 85%. Another network centered in the anterior cingulate cortex (including the dorsolateral prefrontal cortex, sensorimotor cortex, parahippocampal gyrus and midbrain) showed a sensitivity of 80% and a specificity of 75%. These preliminary results demonstrate that resting-state networks may predict treatment outcome for individual patients and suggest that resting-state networks have the potential to serve as prognostic neuroimaging biomarkers to guide personalized treatment decisions.
It has been hypothesized that maladaptive habit formation contributes to compulsivity in psychiatric disorders such as obsessive-compulsive disorder (OCD). Here, we used an established animal model ...of OCD, Sapap3 knockout mice (SAPAP3−/−), to investigate the balance of goal-directed and habitual behavior in compulsive individuals and if altered habit formation is associated with compulsive-like behavior.
We subjected 24 SAPAP3−/− and 24 wildtype littermates (WT) to two different schedules of reinforcement in a within-subjects design: a random-ratio (RR) schedule to promote goal-directedness, and a random-interval (RI) schedule, known to facilitate habitual responding. SAPAP3−/− acquired responding under both schedules, but showed lower response rates and fewer attempts to collect food pellets than WT, indicative of altered reward processing. As expected, WT were sensitive to sensory-specific satiety (outcome devaluation) following RR training, but not RI training, demonstrating schedule-specific acquisition of goal-directed and habitual responding, respectively. In contrast, SAPAP3−/− were sensitive to outcome devaluation after both RR and RI training, suggesting decreased engagement of a habitual response strategy. No linear relation was observed between increased grooming and behavior during the outcome devaluation test in SAPAP3−/−.
Together, our findings demonstrate altered reward processing and impaired habit learning in SAPAP3−/−. We report a diminished propensity to form habits in these mice, which albeit inconsistent with the predominant idea of excessive habit formation in OCD, nonetheless points at dysregulation of behavioral automation in the context of compulsivity. Thus, the habit hypothesis of compulsivity should be updated to state that an imbalance of habitual and goal-directed responding in either direction can contribute to the development of compulsive behavior.
Neuroimaging studies suggest an association between apathy after deep brain stimulation (DBS) and stimulation of the ventral part of the subthalamic nucleus (STN) due to the associative fibers ...connected to the non-motor limbic circuits that are involved in emotion regulation and motivation. We have previously described three patients with severe apathy that could be fully treated after switching stimulation from a ventral electrode contact point to a more dorsal contact point.
To determine whether more dorsal stimulation of the STN decreases apathy compared to standard care in a multicenter randomized controlled trial with a crossover design.
We will include 26 patients with a Starkstein Apathy Scale (SAS) score of 14 or more after subthalamic nucleus (STN) deep brain stimulation (DBS) for refractory Parkinson's disease. This is a multicenter trial conducted in two teaching hospitals and one university medical center in the Netherlands after at least 3 months of STN DBS. Our intervention will consist of 1 month of unilateral dorsal STN stimulation compared to treatment as usual. The primary outcome is a change in SAS score following 1 month of DBS on the original contact compared to the SAS score following 1 month of DBS on the more dorsal contact. Secondary outcomes are symptom changes on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor part III, Montgomery-Åsberg Depression Rating Scale, 39-item Parkinson's disease questionnaire, Parkinson's disease impulsive-compulsive disorders questionnaire, changes in levodopa-equivalent daily dosage, apathy rated by the caregiver, and burden and quality of life of the caregiver.
ClinicalTrials.gov NL8279. Registered on January 10, 2020.
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.
Deep brain stimulation (DBS) is a promising new treatment for patients with treatment-refractory obsessive-compulsive disorder (OCD). However, since most DBS patients only show a partial response, ...the treatment still needs to be improved. In this study we hypothesized that cognitive-behavioural therapy (CBT) could optimize the post-operative management in DBS and we evaluated the efficacy of CBT as augmentation to DBS targeted at the nucleus accumbens.
A total of 16 patients with treatment-refractory OCD were treated with DBS targeted at the nucleus accumbens. After stabilization of decline in OCD symptoms, a standardized 24-week CBT treatment programme was added to DBS in an open-phase trial of 8 months. Changes in obsessive-compulsive, anxiety and depressive symptoms were evaluated using the Yale-Brown Obsessive Compulsive Scale, Hamilton Anxiety Scale and Hamilton Rating Scale for Depression.
Following the addition of CBT to DBS, a significant decrease in obsessive-compulsive symptoms was observed, but not in anxiety and depressive symptoms. In a subsequent double-blind phase, in which stimulation was discontinued, OCD symptoms returned to baseline (relapse) and anxiety and depressive symptoms worsened (rebound) compared with baseline.
The results of this explorative study suggest that a combined treatment of accumbens DBS and CBT may be optimal for improving obsessive-compulsive symptoms in treatment-refractory OCD. However, a subsequent randomized controlled trial is necessary to draw firm conclusions. It seems that DBS results in affective changes that may be required to enable response prevention in CBT. This may indicate that DBS and CBT act as two complementary treatments.
Neurobiological models of obsessive-compulsive disorder (OCD) posit that its clinical symptoms such as repetitive thoughts and behaviors are related to hyperactivity in the ...cortico-striato-thalamo-cortical (CSTC) circuit. Small scale neuroimaging studies have shown that treatment of OCD is associated with reduced activity across different brain structures within this circuitry. We performed the first meta-analysis of positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigated cerebral blood flow or glucose metabolism in patients with OCD before and after pharmacological or psychological treatment. We calculated standardized mean differences for the regions-of-interest most often reported. The meta-analysis revealed small reductions in activity in the caudate nucleus and orbitofrontal cortex after treatment with a serotonin reuptake inhibitor or cognitive behavioral therapy. Small reductions were also observed in the thalamus when one SPECT study with a large opposite effect was excluded from the analysis. Meta-regression analyses for the caudate nucleus showed no significant effect of the type of treatment, decrease in symptom severity, mean duration until the follow-up scan, or year of publication. These results show that pharmacological and psychological treatments reduce resting CSTC circuit activity, and provide further support for the CSTC circuit model in OCD.
Empirical evidence and clinical observations suggest a strong -yet under acknowledged-link between anorexia nervosa (AN) and non-suicidal self-injurious behavior (NSSI). By reviewing the literature ...on the psychopathology and neurobiology of AN and NSSI, we shed light on their relationship. Both AN and NSSI are characterized by disturbances in affect regulation, dysregulation of the reward circuitry and the opioid system. By formulating a reward-centered hypothesis, we explain the overlap between AN and NSSI. We propose three approaches understanding the relationship between AN and NSSI, which integrate psychopathology and neurobiology from the perspective of self-destructiveness: (1) a nosographical approach, (2) a research domain (RDoC) approach and (3) a network analysis approach. These approaches will enhance our knowledge of the underlying neurobiological substrates and may provide groundwork for the development of new treatment options for disorders of self-destructiveness, like AN and NSSI. In conclusion, we hypothesize that self-destructiveness is a new, DSM-5-transcending concept or psychopathological entity that is reward-driven, and that both AN and NSSI could be conceptualized as disorders of self-destructiveness.
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