A multicenter double-blind randomized crossover study comparing the impact of dorsal subthalamic nucleus deep brain stimulation versus standard care on apathy in Parkinson's disease: a study protocol.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. TRIAL REGISTRATION: ClinicalTrials.gov NL8279. Registered on January 10, 2020.

Mental illness and cardiovascular health: observational and polygenic score analyses in a population-based cohort study.

BACKGROUND: Individuals with serious mental illness have a markedly shorter life expectancy. A major contributor to premature death is cardiovascular disease (CVD). We investigated associations of (genetic liability for) depressive disorder, bipolar disorder and schizophrenia with a range of CVD traits and examined to what degree these were driven by important confounders. METHODS: We included participants of the Dutch Lifelines cohort (N = 147 337) with information on self-reported lifetime diagnosis of depressive disorder, bipolar disorder, or schizophrenia and CVD traits. Employing linear mixed-effects models, we examined associations between mental illness diagnoses and CVD, correcting for psychotropic medication, demographic and lifestyle factors. In a subsample (N = 73 965), we repeated these analyses using polygenic scores (PGSs) for the three mental illnesses. RESULTS: There was strong evidence that depressive disorder diagnosis is associated with increased arrhythmia and atherosclerosis risk and lower heart rate variability, even after confounder adjustment. Positive associations were also found for the depression PGSs with arrhythmia and atherosclerosis. Bipolar disorder was associated with a higher risk of nearly all CVD traits, though most diminished after adjustment. The bipolar disorder PGSs did not show any associations. While the schizophrenia PGSs was associated with increased arrhythmia risk and lower heart rate variability, schizophrenia diagnosis was not. All mental illness diagnoses were associated with lower blood pressure and a lower risk of hypertension. CONCLUSIONS: Our study shows widespread associations of (genetic liability to) mental illness (primarily depressive disorder) with CVD, even after confounder adjustment. Future research should focus on clarifying potential causal pathways between mental illness and CVD.

Effects of deep brain stimulation on cognitive functioning in treatment-resistant depression: a systematic review and meta-analysis.

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.

Apathy following deep brain stimulation in Parkinson's disease visualized by 7-Tesla MRI subthalamic network analysis.

BACKGROUND: Apathy is reported after subthalamic nucleus deep brain stimulation (STN DBS) and associated with a decreased quality of life in Parkinson's disease (PD) patients. Recent studies hypothesized that the location of active DBS contact point relative to the STN subdivisions (motor, associative and limbic) could be related to an increase of apathy. METHODS: 22 PD-patients that underwent STN DBS between January 2019 and February 2020 were divided in an apathy and non-apathy group using the change in the Starkstein Apathy Scale (SAS) after six months of DBS. For both groups the location of DBS electrodes was determined based on 7T MRI subthalamic network analysis, enabling visualization of the subdivisions and their projections relative to the active contact point. MDS-UPDRS III scores were included to evaluate DBS effect. RESULTS: In six patients a post-DBS increase in apathy score was assessed, versus 16 non-apathy patients. Network analysis showed that active contacts in apathy patients were more often positioned in or close to the area within the STN with high density of surrounding projections to associative cortex areas than in non-apathy patients; 63% apathy versus 42% (P = 0.02). The density of surrounding motor projections was lower in the group with increased apathy (18%) than in the group without increased apathy (38%, P = 0.01). Motor UPDRS improvement for the apathy group was 39% and for the non-apathy group 58% (n.s.) CONCLUSION: This new approach in patient-specific subthalamic 7T MRI network analysis visualized an anatomical connectivity substrate for apathy in DBS, with active electrode contacts predominantly in the associative STN.

Neural effects of deep brain stimulation on reward and loss anticipation and food viewing in anorexia nervosa: a pilot study.

BACKGROUND: Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN. METHODS: We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only. RESULTS: At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group. CONCLUSION: The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( https://www.trialregister.nl/trial/3322 ): NL3322 (NTR3469).

Anorexia Nervosa (An) is a severe eating disorder with many, sometimes life-threatening, complications. A substantial number of AN patients do not respond to the available treatment options and remain chronically ill or even die as a consequence of the AN. Because part of the causes of AN may reside in the brain, we studied the efficacy and safety of a potential new treatment option for AN, namely deep brain stimulation (DBS). DBS has proven to be an effective treatment option for movements disorders like Parkinson's Disease and other psychiatric disorders such as obsessive compulsive disorder. Our previous pilot study and other research have shown that DBS leads to improvements in weight, mood, anxiety, and eating disorder symptoms. In this substudy, we examined the effects of DBS on specific brain circuitries that are implicated in AN. We conducted brain scans (fMRI) to measure brain activity while patients performed tasks. We observed a difference in brain response when we compared scans taken before and after the DBS, which supports our thoughts on the involvement of specific parts of the brain in AN.

Psychological distress modulates dorsal anterior cingulate cortex responses to salient stimuli in obsessive-compulsive disorder.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) experience an exacerbation of symptoms under psychological distress. The neurobiological underpinnings of this effect of stress remain elusive. Here, we induced psychological distress to explore its effect on neural reactivity of the salience network during a symptom provocation task. METHODS: Twenty-three patients with OCD and twenty-three healthy volunteers underwent functional magnetic resonance imaging scanning after stress induction and a control condition in a cross-over design. Psychological distress was induced using the socially evaluated cold pressor test (SECPT) and neural responses were measured during a symptom provocation task. RESULTS: OCD participants showed a blunted cortisol response to the stressor. We found a group by stress interaction effect in the dorsal anterior cingulate cortex (dACC), such that psychological distress reduced dACC reactivity to emotionally salient pictures in OCD participants, whereas it increased dACC reactivity in healthy controls. LIMITATIONS: A considerable proportion of OCD participants was on medication, and the neuroimaging session was conducted more than 1 h after the initial stressor. CONCLUSIONS: Considering this timeline, we speculate that the blunted dACC reactivity towards emotionally salient pictures in OCD participants may reflect impaired emotion regulation in the aftermath of stress.

Electroencephalography for predicting antidepressant treatment success: A systematic review and meta-analysis.

BACKGROUND: Patients suffering from major depressive disorder (MDD) regularly experience non-response to treatment for their depressive episode. Personalized clinical decision making could shorten depressive episodes and reduce patient suffering. Although no clinical tools are currently available, machine learning analysis of electroencephalography (EEG) shows promise in treatment response prediction. METHODS: With a systematic review and meta-analysis, we evaluated the accuracy of EEG for individual patient response prediction. Importantly, we included only prediction studies that used cross-validation. We used a bivariate model to calculate prediction success, as expressed by area-under the curve, sensitivity and specificity. Furthermore, we analyzed prediction success for separate antidepressant interventions. RESULTS: 15 studies with 12 individual patient samples and a total of 479 patients were included. Research methods varied considerably between studies. Meta-analysis of results from this heterogeneous set of studies resulted in an area under the curve of 0.91, a sensitivity of 83 % (95 % CI 74-89 %), and a specificity of 86 % (95 % CI 81-90 %). Classification performance did not significantly differ between treatments. Although studies were all internally validated, no externally validated studies have been reported. We found substantial risk of bias caused by methodological shortcomings such as non-independent feature selection, though performance of non-biased studies was comparable. LIMITATIONS: Sample sizes were relatively small and no study used external validation, increasing the risk of overestimation of accuracy. CONCLUSIONS: Electroencephalography can predict the response to antidepressant treatment with high accuracy. However, future studies with more rigorous validation are needed to produce a clinical tool to guide interventions in MDD. PROSPERO REGISTRATION NUMBER: CRD42021268169.

Psychopathological and Neurobiological Overlap Between Anorexia Nervosa and Self-Injurious Behavior: A Narrative Review and Conceptual Hypotheses.

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.

Evidence for Distinct Forms of Compulsivity in the SAPAP3 Mutant-Mouse Model for Obsessive-Compulsive Disorder.

The specific mechanisms underlying compulsive behavior in obsessive-compulsive disorder (OCD) are unknown. It has been suggested that such compulsivity may have its origin in cognitive dysfunction such as impaired processing of feedback information, received after the completion of goal-directed actions. The signal attenuation (SA) task models such a processing deficit in animals by attenuating the association strength between food reward and audiovisual feedback (signal) presented after performance of an operant response. The compulsive-like responding resulting from SA is well characterized in rats, but was so far not established in mice, a species for which powerful genetic OCD models exist. Thus, first, we demonstrate that the SA task can be implemented in mice and show that attenuation of reward-associated response feedback produces similar behavior in C57BL/6 mice as previously reported in rats. Second, we tested the hypothesis that SAPAP3 knock-out mice (SAPAP3-/-), prone to exhibit several OCD-like abnormalities including excessive grooming, show enhanced compulsive-like behavior in the SA task compared with their wild-type (WT) littermates. However, task-related compulsivity measures in SAPAP3-/- and WT did not yield significant differences, neither following SA nor during "regular" extinction of operant behavior. Thus, compulsive-like instrumental behavior following feedback distortion was not potentiated in compulsively grooming mice, implicating specifically that (1) a general deficit in feedback processing is not related to excessive grooming in SAPAP3-/- and (2) different manifestations of compulsivity may be driven by independent mechanisms.

Attachment in OCD: A meta-analysis.

INTRODUCTION: It has been proposed to extend the cognitive-behavioural model of obsessive-compulsive disorder (OCD) with attachment theory to shed light on the affective and developmental factors underlying the disease. With a growing number of empirical studies on the subject, this meta-analysis aims to quantify a possible relationship between attachment insecurity and OCD. METHODS: A systematic search was conducted for studies in adult populations of patients with OCD as well as general populations displaying symptoms of OCD. Effect sizes of attachment anxiety and attachment avoidance were calculated separately. Covariates of demographic variables were used in meta-regressions. RESULTS: Sixteen studies were included. Meta-analyses showed an association of medium to large effect size (Hedges' g = 0.69; 95 % CI 0.58 - 0.80; p < 0.001) between OCD and attachment anxiety, and an association of medium effect size (Hedges' g = 0.47; 95 % CI 0.39 - 0.54; p < 0.001) between OCD and attachment avoidance. Effect sizes in OCD population and general population studies did not differ significantly. DISCUSSION: Robust effect sizes of both attachment anxiety and avoidance in relation to OCD symptomatology corroborate an attachment-centred view of OCD. These findings furthermore suggest that integrating cognitive and attachment-based therapeutic approaches to OCD may benefit patients in which developmental or emotional factors hinder successful treatment.

Instrumental learning in a mouse model for obsessive-compulsive disorder: Impaired habit formation in Sapap3 mutants.

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.

[Reaction on 'Persistant underuse of ECT for persistant depressive disorder?'] / Reactie op 'Persisterend ondergebruik van ECT bij persisterende depressieve stoornis?'.

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Monitoring deep brain stimulation by measuring regional brain oxygen responses in freely moving mice.

BACKGROUND: Translational studies investigating the effects of deep brain stimulation (DBS) on brain function up to now mainly relied on BOLD responses measured with fMRI. However, fMRI studies in rodents face technical and practical limitations (e.g., immobilization, sedation or anesthesia, spatial and temporal resolution of data). Direct measurement of oxygen concentration in the brain using electrochemical sensors is a promising alternative to the use of fMRI. Here, we tested for the first time if such measurements can be combined with DBS. NEW METHOD: We combined bilateral DBS in the internal capsule (IC-DBS) with simultaneous amperometric measurements of oxygen in the medial prefrontal cortex (prelimbic area) and striatum of freely moving mice. Using a two-day within-animal experimental design, we tested the effects of DBS on baseline oxygen concentrations, and on novelty- and restraint-induced increases in oxygen concentration. RESULTS: Basal oxygen levels were stable across the daily sampling periods. Exposure to novelty and immobilization reproducibly increased oxygen concentrations in both areas. IC-DBS did not significantly alter basal oxygen, but reduced the novelty-induced increase in the striatum. COMPARISON WITH EXISTING METHOD(S): Amperometric detection of brain oxygen concentration with high temporal and spatial resolution can be performed in a number of key brain areas to study the effects of DBS in animal models of disease. The method is easily implemented and does not require expensive equipment or complicated data analysis processes. CONCLUSIONS: Direct and simultaneous measurement of brain oxygen concentration in multiple brain areas can be used to study the effects of bilateral DBS neuromodulation on brain activity in freely moving mice.

[Electroconvulsion therapy for persistent depression in the Netherlands; very low application rate]. / Elektroconvulsietherapie bij persisterende depressie in Nederland; zeer lage toepassingsgraad.

BACKGROUND: Of all depressive disorders, 20% has a persistent course. For persistent depressive patients, electroconvulsive therapy (ect) is recommended for this patient population, since it is the most potent treatment for depression. The Dutch depression guideline advises the use of ect for persistent depressive disorder at approximately 12 months after inadequate efficacy of psychotherapy and/or pharmacological treatment.
AIM: To quantify the use of electroconvulsive therapy in persistent depressive patients in the Netherlands.
METHOD: Quantitative research using the Dutch registration system (diagnosis-treatment-combination; dbc) information system (dis) of the Dutch Healthcare Authority (nza).
RESULTS: Of the patients within the dbc system (in 2014) with the main diagnosis of unipolar depression, 23,597 (26%) were registered for more than two years and could be classified as having a persistent depressive episode. Of these latter patients, only 278 (1.2%) received ect.
CONCLUSION: In the Netherlands, only 1.2% of patients with a persistent depression received ect, whereas this treatment could have been considered for 26% of this group. The low application rate might be caused by professionals' inadequate knowledge about ect and the premature use of the handicap model.

Individual white matter bundle trajectories are associated with deep brain stimulation response in obsessive-compulsive disorder.

BACKGROUND: The ventral anterior limb of the internal capsule (vALIC) is a target for deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD). Conventional surgical planning is based on anatomical landmarks. OBJECTIVE/HYPOTHESIS: We hypothesized that treatment response depends on the location of the active DBS contacts with respect to individual white matter bundle trajectories. This study thus aimed to elucidate whether vALIC DBS can benefit from bundle-specific targeting. METHODS: We performed tractography analysis of two fiber bundles, the anterior thalamic radiation (ATR) and the supero-lateral branch of the medial forebrain bundle (MFB), using diffusion-weighted magnetic resonance imaging (DWI) data. Twelve patients (10 females) who had received bilateral vALIC DBS for at least 12 months were included. We related the change in OCD symptom severity on the Yale-Brown obsessive-compulsive scale (Y-BOCS) between baseline and one-year follow-up with the distances from the active contacts to the ATR and MFB. We further analyzed the relation between treatment response and stimulation sites in standard anatomical space. RESULTS: We found that active stimulation of the vALIC closer to the MFB than the ATR was associated with better treatment outcome (p = 0.04; r2 = 0.34). In standard space, stimulation sites were largely overlapping between treatment (non)responders, suggesting response is independent of the anatomically defined electrode position. CONCLUSION: These findings suggest that vALIC DBS for OCD may benefit from MFB-specific implantation and highlight the importance of corticolimbic connections in OCD response to DBS. Prospective investigation is necessary to validate the clinical use of MFB targeting.

[Does psychiatry revert to subjectivity?] / Keert nieuwe psychiatrie terug naar de betekenis?

BACKGROUND: Psychiatry is currently challenged by two main issues, subjectivity and non-exclusivity.
AIM: The re-appraisal of phenomenological psychiatry.
METHOD: Personal reflection.
RESULTS: Phenomenology may contribute to psychiatry by 1. offering a method, 2. focusing on descriptive observation, and 3. taking a neutral stance.
CONCLUSION: By emphasizing the subjective experience, phenomenology offers psychiatry an opportunity to become proficient and to distinguish itself from other disciplines through the continued development of insight and understanding of mental disorders.

[Deep brain stimulation for psychiatric disorders]. / Diepe hersenstimulatie bij psychiatrische aandoeningen.

- Deep brain stimulation (DBS) corrects pathological activity of neuropsychiatric brain networks with high frequency current via implanted brain electrodes.- DBS is an effective and safe treatment for therapy-refractory obsessive-compulsive disorder and potentially also for therapy-refractory major depressive disorder.- Experimental psychiatric indications for DBS are Tourette syndrome, addiction, anorexia nervosa, post-traumatic stress disorder, autism and schizophrenia.- DBS influences brain networks that are relevant for a variety of psychiatric symptoms. Potentially, in the future this interventional technique may therefore be deployed more broadly.