Mindfulness-based cognitive therapy neurobiology in treatment-resistant obsessive-compulsive disorder: A domain-related resting-state networks approach.

Mindfulness-based cognitive therapy (MBCT) stands out as a promising augmentation psychological therapy for patients with obsessive-compulsive disorder (OCD). To identify potential predictive and response biomarkers, this study examines the relationship between clinical domains and resting-state network connectivity in OCD patients undergoing a 3-month MBCT programme. Twelve OCD patients underwent two resting-state functional magnetic resonance imaging sessions at baseline and after the MBCT programme. We assessed four clinical domains: positive affect, negative affect, anxiety sensitivity, and rumination. Independent component analysis characterised resting-state networks (RSNs), and multiple regression analyses evaluated brain-clinical associations. At baseline, distinct network connectivity patterns were found for each clinical domain: parietal-subcortical, lateral prefrontal, medial prefrontal, and frontal-occipital. Predictive and response biomarkers revealed significant brain-clinical associations within two main RSNs: the ventral default mode network (vDMN) and the frontostriatal network (FSN). Key brain nodes -the precuneus and the frontopolar cortex- were identified within these networks. MBCT may modulate vDMN and FSN connectivity in OCD patients, possibly reducing symptoms across clinical domains. Each clinical domain had a unique baseline brain connectivity pattern, suggesting potential symptom-based biomarkers. Using these RSNs as predictors could enable personalised treatments and the identification of patients who would benefit most from MBCT.

Impact of Stress on Brain Morphology: Insights into Structural Biomarkers of Stress-related Disorders.

Exposure to acute and chronic stress has a broad range of structural effects on the brain. The brain areas commonly targeted in the stress response models include the hippocampus, the amygdala, and the prefrontal cortex. Studies in patients suffering from the so-called stress-related disorders -embracing post-traumatic stress, major depressive and anxiety disorders- have fairly replicated animal models of stress response -particularly the neuroendocrine and the inflammatory models- by finding alterations in different brain areas, even in the early neurodevelopment. Therefore, this narrative review aims to provide an overview of structural neuroimaging findings and to discuss how these studies have contributed to our knowledge of variability in response to stress and the ulterior development of stress-related disorders. There are a gross number of studies available but neuroimaging research of stress-related disorders as a single category is still in its infancy. Although the available studies point at particular brain circuitries involved in stress and emotion regulation, the pathophysiology of these abnormalities -involving genetics, epigenetics and molecular pathways-, their relation to intraindividual stress responses -including personality characteristics, self-perception of stress conditions…-, and their potential involvement as biomarkers in diagnosis, treatment prescription and prognosis are discussed.

The pituitary adenylate cyclase-activating polypeptide system as a sex-specific modulator of hippocampal response to threat stimuli.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor gene polymorphism has been postulated as a potential sex-specific diagnostic biomarker of trauma-related disorders. However, no research to date has evaluated whether the PACAPergic system may act as a vulnerability/resilience neuromechanism to trauma-induced psychopathology in healthy participants without heightened risk to experience traumatic events. Methods: Here, we compared the amygdala and hippocampus response to fearful faces in participants with at-risk genotype versus non-risk participants from the Human Connectome Project (n = 991; 53.4% female). Results: Increased hippocampal response to fearful faces in the female risk group emerged in sex by genetic risk interaction. Conclusions: Our findings revealed the first sex-specific neurogenetic vulnerability factor to trauma-related disorders, and emphasize the importance of prevention-based strategies to ameliorate neuropsychiatric pathophysiology.

Barriers, facilitators, and proposals for improvement in the implementation of a collaborative care program for depression: a qualitative study of primary care physicians and nurses.

BACKGROUND: Primary care plays a central role in the treatment of depression. Nonetheless, shortcomings in its management and suboptimal outcomes have been identified. Collaborative care models improve processes for the management of depressive disorders and associated outcomes. We developed a strategy to implement the INDI collaborative care program for the management of depression in primary health care centers across Catalonia. The aim of this qualitative study was to evaluate a trial implementation of the program to identify barriers, facilitators, and proposals for improvement. METHODS: One year after the implementation of the INDI program in 18 public primary health care centers we performed a qualitative study in which the opinions and experiences of 23 primary care doctors and nurses from the participating centers were explored in focus groups. We performed thematic content analysis of the focus group transcripts. RESULTS: The results were organized into three categories: facilitators, barriers, and proposals for improvement as perceived by the health care professionals involved. The most important facilitator identified was the perception that the INDI collaborative care program could be a useful tool for reorganizing processes and improving the management of depression in primary care, currently viewed as deficient. The main barriers identified were of an organizational nature: heavy workloads, lack of time, high staff turnover and shortages, and competing demands. Additional obstacles were inertia and resistance to change among health care professionals. Proposals for improvement included institutional buy-in to guarantee enduring support and the organizational changes needed for successful implementation. CONCLUSIONS: The INDI program is perceived as a useful, viable program for improving the management of depression in primary care. Uptake by primary care centers and health care professionals, however, was poor. The identification and analysis of barriers and facilitators will help refine the strategy to achieve successful, widespread implementation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03285659 ; Registered 18th September, 2017.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Efficacy and fMRI-based response predictors to mindfulness-based cognitive therapy in obsessive-compulsive disorder: Study protocol for a randomised clinical trial.

BACKGROUND: Around 40-50% of patients with obsessive-compulsive disorder (OCD) suffer from obsessions and compulsions after receiving first-line treatments. Mindfulness-based cognitive therapy (MBCT) has been proposed as a reasonable augmentation strategy for OCD. MBCT trains to decentre from distressful thoughts and emotions by focusing on them voluntarily and with consciousness. This practice develops alternative ways to deal with obsessions, which could increase non-reactivity behaviours and, in turn, reduce compulsions. This study aims to investigate the efficacy of MBCT to improve OCD symptoms. Secondly, it pursues to investigate which socio-demographic, clinical, and neurobiological characteristics mediate or moderate the MBCT response; and identify potential biomarkers of positive/negative response. METHODS: This study is a randomised clinical trial (RCT) of 60 OCD patients who do not respond to first-line treatments. Participants will be randomised to either an MBCT program or treatment as usual. The MBCT group will undergo 10 weekly sessions of 120min. Principal outcome: change in OCD severity symptoms using clinician and self-reported measures. Also, participants will undergo a comprehensive evaluation assessing comorbid clinical variables, neuropsychological functioning and thought content. Finally, a comprehensive neuroimaging protocol using structural and functional magnetic resonance imaging will be acquired in a 3T scanner. All data will be obtained at baseline and post-intervention. DISCUSSION: This study will assess the efficacy of mindfulness in OCD patients who do not achieve clinical recovery after usual treatment. It is the first RCT in this subject examining clinical, neuropsychological and neuroimaging variables to examine the neural patterns associated with the MBCT response. CLINICAL TRIALS REGISTRATION: NCT03128749.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

The Neurobiological Basis of Cognitive Side Effects of Electroconvulsive Therapy: A Systematic Review.

Decades of research have consistently demonstrated the efficacy of electroconvulsive therapy (ECT) for the treatment of major depressive disorder (MDD), but its clinical use remains somewhat restricted because of its cognitive side effects. The aim of this systematic review is to comprehensively summarize current evidence assessing potential biomarkers of ECT-related cognitive side effects. Based on our systematic search of human studies indexed in PubMed, Scopus, and Web of Knowledge, a total of 29 studies evaluating patients with MDD undergoing ECT were reviewed. Molecular biomarkers studies did not consistently identify concentration changes in plasma S-100 protein, neuron-specific enolase (NSE), or Aß peptides significantly associated with cognitive performance after ECT. Importantly, these findings suggest that ECT-related cognitive side effects cannot be explained by mechanisms of neural cell damage. Notwithstanding, S-100b protein and Aß40 peptide concentrations, as well as brain-derived neurotrophic factor (BDNF) polymorphisms, have been suggested as potential predictive biomarkers of cognitive dysfunction after ECT. In addition, recent advances in brain imaging have allowed us to identify ECT-induced volumetric and functional changes in several brain structures closely related to memory performance such as the hippocampus. We provide a preliminary framework to further evaluate neurobiological cognitive vulnerability profiles of patients with MDD treated with ECT.

Non-communicable diseases among women survivors of intimate partner violence: Critical review from a chronic stress framework.

A neurobiological framework of chronic stress proposes that the stress-response system can be functionally altered by the repeated presentation of highly stressful situations over time. These functional alterations mainly affect brain processing and include the dysregulation of the hypothalamic-pituitary-adrenal axis and associated processes. In the present critical review, we translate these results to inform the clinical presentation of women survivors of intimate partner violence (IPV). We approach IPV as a scenario of chronic stress where women are repetitively exposed to threat and coping behaviours that progressively shape their neurobiological response to stress. The changes at the central and peripheral levels in turn correlate with the phenotypes of non-communicable diseases. The reviewed studies clarify the extent of the impact of IPV on women's health in large (N > 10,000) population-based designs, and provide observations on experimental neuroendocrine, immune, neurocognitive and neuroimaging research linking alterations of the stress-response system and disease. This evidence supports the prevention of violence against women as a fundamental action to reduce the prevalence of non-communicable diseases.

Structural brain correlates in major depression, anxiety disorders and post-traumatic stress disorder: A voxel-based morphometry meta-analysis.

The high comorbidity of Major Depressive Disorder (MDD), Anxiety Disorders (ANX), and Posttraumatic Stress Disorder (PTSD) has hindered the study of their structural neural correlates. The authors analyzed specific and common grey matter volume (GMV) characteristics by comparing them with healthy controls (HC). The meta-analysis of voxel-based morphometry (VBM) studies showed unique GMV diminutions for each disorder (p < 0.05, corrected) and less robust smaller GMV across diagnostics (p < 0.01, uncorrected). Pairwise comparison between the disorders showed GMV differences in MDD versus ANX and in ANX versus PTSD. These results endorse the hypothesis that unique clinical features characterizing MDD, ANX, and PTSD are also reflected by disorder specific GMV correlates.

A multimetric systematic review of fMRI findings in patients with MDD receiving ECT.

BACKGROUND: Electroconvulsive therapy (ECT) is considered the most effective treatment for major depressive disorder (MDD). In recent years, the pursuit of the neurobiological mechanisms of ECT action has generated a significant amount of functional magnetic resonance imaging (fMRI) research. OBJECTIVE: In this systematic review, we integrated all fMRI research in patients with MDD receiving ECT and, importantly, evaluated the level of convergence and replicability across multiple fMRI metrics. RESULTS: While according to most studies changes in patients with MDD after ECT appear to be widely distributed across the brain, our multimetric review revealed specific changes involving functional connectivity increases in the superior and middle frontal gyri as the most replicated and across-modality convergent findings. Although this modulation of prefrontal connectivity was associated to ECT outcome, we also identified fMRI measurements of the subgenual anterior cingulate cortex as the fMRI signals most significantly linked to clinical response. CONCLUSION: We identified specific prefrontal and cingulate territories which activity and connectivity with other brain regions is modulated by ECT, critically accounting for its mechanism of action.