Evidence from comprehensive independent validation studies for smooth pursuit dysfunction as a sensorimotor biomarker for psychosis.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Inhibitory control and its modification in spider phobia - Study protocol for an antisaccade training trial.

OBJECTIVES: Inhibitory control deficits are considered a key pathogenic factor in anxiety disorders. To assess inhibitory control, the antisaccade task is a well-established measure that assesses antisaccade performance via latencies and error rates. The present study follows three aims: (1) to investigate inhibitory control via antisaccade latencies and errors in an antisaccade task, and their associations with multiple measures of fear in patients with spider phobia (SP) versus healthy controls (HC), (2) to investigate the modifiability of antisaccade performance via a fear-specific antisaccade training in patients with SP and HC, and (3) to explore associations between putative training-induced changes in antisaccade performance in SPs and changes in diverse measures of fear. METHODS: Towards aim 1, we assess antisaccade latencies (primary outcome) and error rates (secondary outcome) in an emotional antisaccade task. Further, the baseline assessment includes assessments of psychophysiological, behavioral, and psychometric indices of fear in patients with SP and HCs. To address aim 2, we compare effects of a fear-specific antisaccade training with effects of a prosaccade training as a control condition. The primary and secondary outcomes are reassessed at a post-1-assessment in both SPs and HCs. Aim 3 employs a cross-over design and is piloted in patients with SP, only. Towards this aim, primary and secondary outcomes, as well as psychophysiological, behavioral, and psychometric measures of fear are reassessed at a post-2-assessment after the second training block. CONCLUSION: This study aims to better understand inhibitory control processes and their modifiability in spider phobia. If successful, antisaccade training may assist in the treatment of specific phobia by directly targeting the putative underlying inhibitory control deficits. This study has been preregistered with ISRCTN (ID: ISRCTN12918583) on 28th February 2022.

Cognitive performance and brain structural connectome alterations in major depressive disorder.

BACKGROUND: Cognitive dysfunction and brain structural connectivity alterations have been observed in major depressive disorder (MDD). However, little is known about their interrelation. The present study follows a network approach to evaluate alterations in cognition-related brain structural networks. METHODS: Cognitive performance of n = 805 healthy and n = 679 acutely depressed or remitted individuals was assessed using 14 cognitive tests aggregated into cognitive factors. The structural connectome was reconstructed from structural and diffusion-weighted magnetic resonance imaging. Associations between global connectivity strength and cognitive factors were established using linear regressions. Network-based statistics were applied to identify subnetworks of connections underlying these global-level associations. In exploratory analyses, effects of depression were assessed by evaluating remission status-related group differences in subnetwork-specific connectivity. Partial correlations were employed to directly test the complete triad of cognitive factors, depressive symptom severity, and subnetwork-specific connectivity strength. RESULTS: All cognitive factors were associated with global connectivity strength. For each cognitive factor, network-based statistics identified a subnetwork of connections, revealing, for example, a subnetwork positively associated with processing speed. Within that subnetwork, acutely depressed patients showed significantly reduced connectivity strength compared to healthy controls. Moreover, connectivity strength in that subnetwork was associated to current depressive symptom severity independent of the previous disease course. CONCLUSIONS: Our study is the first to identify cognition-related structural brain networks in MDD patients, thereby revealing associations between cognitive deficits, depressive symptoms, and reduced structural connectivity. This supports the hypothesis that structural connectome alterations may mediate the association of cognitive deficits and depression severity.

Reduced fractional anisotropy in bipolar disorder v. major depressive disorder independent of current symptoms.

BACKGROUND: Patients with bipolar disorder (BD) show reduced fractional anisotropy (FA) compared to patients with major depressive disorder (MDD). Little is known about whether these differences are mood state-independent or influenced by acute symptom severity. Therefore, the aim of this study was (1) to replicate abnormalities in white matter microstructure in BD v. MDD and (2) to investigate whether these vary across depressed, euthymic, and manic mood. METHODS: In this cross-sectional diffusion tensor imaging study, n = 136 patients with BD were compared to age- and sex-matched MDD patients and healthy controls (HC) (n = 136 each). Differences in FA were investigated using tract-based spatial statistics. Using interaction models, the influence of acute symptom severity and mood state on the differences between patient groups were tested. RESULTS: Analyses revealed a main effect of diagnosis on FA across all three groups (ptfce-FWE = 0.003). BD patients showed reduced FA compared to both MDD (ptfce-FWE = 0.005) and HC (ptfce-FWE < 0.001) in large bilateral clusters. These consisted of several white matter tracts previously described in the literature, including commissural, association, and projection tracts. There were no significant interaction effects between diagnosis and symptom severity or mood state (all ptfce-FWE > 0.704). CONCLUSIONS: Results indicated that the difference between BD and MDD was independent of depressive and manic symptom severity and mood state. Disruptions in white matter microstructure in BD might be a trait effect of the disorder. The potential of FA values to be used as a biomarker to differentiate BD from MDD should be further addressed in future studies using longitudinal designs.

Resting-state functional connectivity patterns associated with childhood maltreatment in a large bicentric cohort of adults with and without major depression.

BACKGROUND: Childhood maltreatment (CM) represents a potent risk factor for major depressive disorder (MDD), including poorer treatment response. Altered resting-state connectivity in the fronto-limbic system has been reported in maltreated individuals. However, previous results in smaller samples differ largely regarding localization and direction of effects. METHODS: We included healthy and depressed samples [n = 624 participants with MDD; n = 701 healthy control (HC) participants] that underwent resting-state functional MRI measurements and provided retrospective self-reports of maltreatment using the Childhood Trauma Questionnaire. A-priori defined regions of interest [ROI; amygdala, hippocampus, anterior cingulate cortex (ACC)] were used to calculate seed-to-voxel connectivities. RESULTS: No significant associations between maltreatment and resting-state connectivity of any ROI were found across MDD and HC participants and no interaction effect with diagnosis became significant. Investigating MDD patients only yielded maltreatment-associated increased connectivity between the amygdala and dorsolateral frontal areas [pFDR < 0.001; η2partial = 0.050; 95%-CI (0.023-0.085)]. This effect was robust across various sensitivity analyses and was associated with concurrent and previous symptom severity. Particularly strong amygdala-frontal associations with maltreatment were observed in acutely depressed individuals [n = 264; pFDR < 0.001; η2partial = 0.091; 95%-CI (0.038-0.166)). Weaker evidence - not surviving correction for multiple ROI analyses - was found for altered supracallosal ACC connectivity in HC individuals associated with maltreatment. CONCLUSIONS: The majority of previous resting-state connectivity correlates of CM could not be replicated in this large-scale study. The strongest evidence was found for clinically relevant maltreatment associations with altered adult amygdala-dorsolateral frontal connectivity in depression. Future studies should explore the relevance of this pathway for a maltreated subgroup of MDD patients.

Shared and Specific Patterns of Structural Brain Connectivity Across Affective and Psychotic Disorders.

BACKGROUND: Altered brain structural connectivity has been implicated in the pathophysiology of psychiatric disorders including schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). However, it is unknown which part of these connectivity abnormalities are disorder specific and which are shared across the spectrum of psychotic and affective disorders. We investigated common and distinct brain connectivity alterations in a large sample (N = 1743) of patients with SZ, BD, or MDD and healthy control (HC) subjects. METHODS: This study examined diffusion-weighted imaging-based structural connectome topology in 720 patients with MDD, 112 patients with BD, 69 patients with SZ, and 842 HC subjects (mean age of all subjects: 35.7 years). Graph theory-based network analysis was used to investigate connectome organization. Machine learning algorithms were trained to classify groups based on their structural connectivity matrices. RESULTS: Groups differed significantly in the network metrics global efficiency, clustering, present edges, and global connectivity strength with a converging pattern of alterations between diagnoses (e.g., efficiency: HC > MDD > BD > SZ, false discovery rate-corrected p = .028). Subnetwork analysis revealed a common core of edges that were affected across all 3 disorders, but also revealed differences between disorders. Machine learning algorithms could not discriminate between disorders but could discriminate each diagnosis from HC. Furthermore, dysconnectivity patterns were found most pronounced in patients with an early disease onset irrespective of diagnosis. CONCLUSIONS: We found shared and specific signatures of structural white matter dysconnectivity in SZ, BD, and MDD, leading to commonly reduced network efficiency. These results showed a compromised brain communication across a spectrum of major psychiatric disorders.

Familial risk for major depression: differential white matter alterations in healthy and depressed participants.

BACKGROUND: Major depressive disorder (MDD) has been associated with alterations in brain white matter (WM) microstructure. However, diffusion tensor imaging studies in biological relatives have presented contradicting results on WM alterations and their potential as biomarkers for vulnerability or resilience. To shed more light on associations between WM microstructure and resilience to familial risk, analyses including both healthy and depressed relatives of MDD patients are needed. METHODS: In a 2 (MDD v. healthy controls, HC) × 2 (familial risk yes v. no) design, we investigated fractional anisotropy (FA) via tract-based spatial statistics in a large well-characterised adult sample (N = 528), with additional controls for childhood maltreatment, a potentially confounding proxy for environmental risk. RESULTS: Analyses revealed a significant main effect of diagnosis on FA in the forceps minor and the left superior longitudinal fasciculus (ptfce-FWE = 0.009). Furthermore, a significant interaction of diagnosis with familial risk emerged (ptfce-FWE = 0.036) Post-hoc pairwise comparisons showed significantly higher FA, mainly in the forceps minor and right inferior fronto-occipital fasciculus, in HC with as compared to HC without familial risk (ptfce-FWE < 0.001), whereas familial risk played no role in MDD patients (ptfce-FWE = 0.797). Adding childhood maltreatment as a covariate, the interaction effect remained stable. CONCLUSIONS: We found widespread increased FA in HC with familial risk for MDD as compared to a HC low-risk sample. The significant effect of risk on FA was present only in HC, but not in the MDD sample. These alterations might reflect compensatory neural mechanisms in healthy adults at risk for MDD potentially associated with resilience.

Brain structural correlates of recurrence following the first episode in patients with major depressive disorder.

Former prospective studies showed that the occurrence of relapse in Major Depressive Disorder (MDD) is associated with volume loss in the insula, hippocampus and dorsolateral prefrontal cortex (DLPFC). However, these studies were confounded by the patient's lifetime disease history, as the number of previous episodes predict future recurrence. In order to analyze neural correlates of recurrence irrespective of prior disease course, this study prospectively examined changes in brain structure in patients with first-episode depression (FED) over 2 years. N = 63 FED patients and n = 63 healthy controls (HC) underwent structural magnetic resonance imaging at baseline and after 2 years. According to their disease course during the follow-up interval, patients were grouped into n = 21 FED patients with recurrence (FEDrec) during follow-up and n = 42 FED patients with stable remission (FEDrem). Gray matter volume changes were analysed using group by time interaction analyses of covariance for the DLPFC, hippocampus and insula. Significant group by time interactions in the DLPFC and insula emerged. Pairwise comparisons showed that FEDrec had greater volume decline in the DLPFC and insula from baseline to follow-up compared with FEDrem and HC. No group by time interactions in the hippocampus were found. Cross-sectional analyses at baseline and follow-up revealed no differences between groups. This longitudinal study provides evidence for neural alterations in the DLPFC and insula related to a detrimental course in MDD. These effects of recurrence are already detectable at initial stages of MDD and seem to occur without any prior disease history, emphasizing the importance of early interventions preventing depressive recurrence.

Reduced hippocampal gray matter volume is a common feature of patients with major depression, bipolar disorder, and schizophrenia spectrum disorders.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD, schizophrenia, and schizoaffective disorder) overlap in symptomatology, risk factors, genetics, and other biological measures. Based on previous findings, it remains unclear what transdiagnostic regional gray matter volume (GMV) alterations exist across these disorders, and with which factors they are associated. GMV (3-T magnetic resonance imaging) was compared between healthy controls (HC; n = 110), DSM-IV-TR diagnosed MDD (n = 110), BD (n = 110), and SSD patients (n = 110), matched for age and sex. We applied a conjunction analysis to identify shared GMV alterations across the disorders. To identify potential origins of identified GMV clusters, we associated them with early and current risk and protective factors, psychopathology, and neuropsychology, applying multiple regression models. Common to all diagnoses (vs. HC), we identified GMV reductions in the left hippocampus. This cluster was associated with the neuropsychology factor working memory/executive functioning, stressful life events, and with global assessment of functioning. Differential effects between groups were present in the left and right frontal operculae and left insula, with volume variances across groups highly overlapping. Our study is the first with a large, matched, transdiagnostic sample to yield shared GMV alterations in the left hippocampus across major mental disorders. The hippocampus is a major network hub, orchestrating a range of mental functions. Our findings underscore the need for a novel stratification of mental disorders, other than categorical diagnoses.

Association between stressful life events and grey matter volume in the medial prefrontal cortex: A 2-year longitudinal study.

Stressful life events (SLEs) in adulthood are a risk factor for various disorders such as depression, cancer or infections. Part of this risk is mediated through pathways altering brain physiology and structure. There is a lack of longitudinal studies examining associations between SLEs and brain structural changes. High-resolution structural magnetic resonance imaging data of 212 healthy subjects were acquired at baseline and after 2 years. Voxel-based morphometry was used to identify associations between SLEs using the Life Events Questionnaire and grey matter volume (GMV) changes during the 2-year period in an ROI approach. Furthermore, we assessed adverse childhood experiences as a possible moderator of SLEs-GMV change associations. SLEs were negatively associated with GMV changes in the left medial prefrontal cortex. This association was stronger when subjects had experienced adverse childhood experiences. The medial prefrontal cortex has previously been associated with stress-related disorders. The present findings represent a potential neural basis of the diathesis-stress model of various disorders.

The Course of Disease in Major Depressive Disorder Is Associated With Altered Activity of the Limbic System During Negative Emotion Processing.

BACKGROUND: Brain functional alterations during emotion processing in patients with major depressive disorder (MDD) compared with healthy control subjects (HCs) are frequently reported. However, evidence for functional correlates of emotion processing with regard to MDD trajectories is scarce. This study investigates the role of lifetime disease course for limbic brain activation during negative emotional face processing in patients with MDD. METHODS: In a large sample of patients with MDD (n = 333; 58.55% female) and HCs (n = 333; 60.06% female), brain activation was investigated during a negative emotional face-processing task within a cross-sectional design. Differences between HC and MDD groups were analyzed. Previous disease course, characterized by 2 components, namely hospitalization and duration of illness, was regressed on brain activation of the amygdala, (para-)hippocampus, and insula in patients with MDD. RESULTS: Patients with MDD showed increased activation in the amygdala, insula, and hippocampus compared with HCs (all p values corrected for familywise error [pFWE] < .045). The hospitalization component showed negative associations with brain activation in the bilateral insula (right: pFWE = .026, left: pFWE = .019) and (para-)hippocampus (right: pFWE = .038, left: pFWE = .031). No significant association was found for the duration of illness component (all pFWE > .057). CONCLUSIONS: This study investigated negative emotion processing in a large sample of patients with MDD and HCs. Our results confirm limbic hyperactivation in patients with MDD during negative emotion processing; however, this hyperactivation may resolve with a more severe lifetime disease course in the insula and (para-)hippocampus-brain regions involved in emotion processing and regulation. These findings need further replication in longitudinal studies.

Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group.

BACKGROUND: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. METHODS: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. RESULTS: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18

Caught in a web of trauma: Network analysis of childhood adversity and adult mental ill-health.

BACKGROUND: Current interventions for adverse childhood experiences have only limited effectiveness. OBJECTIVE: We sought to identify optimal targets for the development of new interventions against adverse childhood experiences (ACE), that is, ACEs that a) are so central in the network of childhood adversity that curbing them is likely to impact other types of adversity, too, and b) are so central to the link of childhood adversity and adult mental ill-health that curbing them is likely to prevent this negative long-term effect from developing. PARTICIPANTS AND SETTING: 384 adult psychiatric inpatients. METHODS: Using the R packages qgraph and IsingFit, we analyzed the ACE network and the common network of ACEs and adult mental disorders. RESULTS: We found two clusters of ACEs: direct interactions with the child and indirect traumatization via adverse circumstances. When controlling for interrelatedness, the associations of sexual abuse with posttraumatic stress disorder and borderline personality disorder were the only direct links between ACEs and adult mental disorders. CONCLUSIONS: As neglect and violence against the mother were the most influential ACEs, curbing them is likely to destabilize the whole network of adversity. Thus, neglect and violence against the mother lend themselves as candidate targets for the development of new interventions. As sexual abuse was the only link between childhood adversity and adult mental ill-health, interventions against it seem most likely to keep this negative long-term effect from developing. Further, ideally prospective, research is needed to corroborate these findings.