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Background: Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset., Methods: In the naturalistic, observational, prospective, case-control Marburg-Münster Affective Disorders Cohort Study, individuals aged 18-65 years and of Caucasian ancestry were recruited from local psychiatric hospitals in Münster and Marburg, Germany, and newspaper advertisements. Individuals diagnosed with MDD and individuals without any history of psychiatric disorder (ie, healthy controls) were included in this subsample analysis. Participants had diffusion-weighted imaging, a battery of neuropsychological tests, and detailed clinical data collected at baseline and at 2 years of follow-up. We used linear mixed-effect models to compare changes in cognitive performance and white matter integrity between participants with MDD and healthy controls. Diffusion-weighted imaging analyses were conducted using tract-based spatial statistics. To correct for multiple comparisons, threshold free cluster enhancement (TFCE) was used to correct α-values at the family-wise error rate (FWE; p tfce-FWE ). Effect sizes were estimated by conditional, partial R 2 values (sr 2 ) following the Nakagawa and Schielzeth method to quantify explained variance. The association between changes in cognitive performance and changes in white matter integrity was analysed. Finally, we examined whether the depressive disease course between assessments predicted cognitive performance at follow-up and whether white matter integrity mediated this association. People with lived experience were not involved in the research and writing process., Findings: 881 participants were selected for our study, of whom 418 (47%) had MDD (mean age 36·8 years [SD 13·4], 274 [66%] were female, and 144 [34%] were male) and 463 (53%) were healthy controls (mean age 35·6 years [13·5], 295 [64%] were female, and 168 [36%] were male). Baseline assessments were done between Sept 11, 2014, and June 3, 2019, and after a mean follow-up of 2·20 years (SD 0·19), follow-up assessments were done between Oct 6, 2016, and May 31, 2021. Participants with MDD had lower cognitive performance than did healthy controls (p<0·0001, sr 2 =0·056), regardless of timepoint. Analyses of diffusion-weighted imaging indicated a significant diagnosis × time interaction with a steeper decline in white matter integrity of the superior longitudinal fasciculus over time in participants with MDD than in healthy controls (p tfce-FWE =0·026, sr 2 =0·002). Furthermore, cognitive decline was robustly associated with the decline in white matter integrity over time across both groups (p tfce-FWE <0·0001, sr 2 =0·004). In participants with MDD, changes in white matter integrity (p=0·0040, β=0·071) and adverse depressive disease course (p=0·0022, β=-0·073) independently predicted lower cognitive performance at follow-up., Interpretation: Alterations of white matter integrity occurred over time to a greater extent in participants with MDD than in healthy controls, and decline in white matter integrity was associated with a decline in cognitive performance across groups. Our findings emphasise the crucial role of white matter microstructure and disease progression in depression-related cognitive dysfunction, making both priority targets for future treatment development., Funding: German Research Foundation (DFG)., Competing Interests: Declaration of interests TK has received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, and neuraxpharm. JR has received speaking honoraria from Janssen, Hexal, and Novartis. MPvdH has worked as a consultant for Roche on an unrelated project and is an editor for Human Brain Mapping. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required., (© 2024. The Author(s).)

Childhood maltreatment (CM) is associated with increased limbic activity, while social support is linked to decreased limbic activity towards negative stimuli. Our study aimed to explore the interaction of perceived social support with CM, and their combined impact on limbic activity in negative emotion processing. A total of 130 healthy individuals (HC) underwent a negative emotional face processing paradigm. They were divided into two groups based on the Childhood Trauma Questionnaire: n = 65 HC without CM matched with n = 65 HC with CM. In a region-of-interest approach of the bilateral amygdala-hippocampus-complex (AHC), regression analyses investigating the association of CM and perceived social support with limbic activity and a social support x CM ANCOVA were conducted. CM was associated with increased AHC activity, while perceived social support tended to be associated with decreased AHC activity during negative emotion processing. The ANCOVA showed a significant interaction in bilateral AHC activity (p FWE  ≤ 0.024) driven by a negative association between perceived social support and bilateral AHC activity in HC without CM. No significant association was observed in HC with CM. Exploratory analyses using continuous CM scores support this finding. Our results suggest that CM moderates the link between perceived social support and limbic activity, with a protective effect of perceived social support only in HC without CM. The lack of this effect in HC with CM suggests that CM may alter the buffering effect of perceived social support on limbic functioning, highlighting the potential need for preventive interventions targeting social perception of HC with CM., (© 2024. The Author(s).)

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms., (© 2024. The Author(s).)

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome., (© 2024. The Author(s).)

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia ( p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores ( p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression., (© 2024. The Author(s).)

Background: Depressive symptoms seem to be interrelated in a complex and self-reinforcing way. To gain a better understanding of this complexity, the inclusion of theoretically relevant constructs (such as risk and protective factors) offers a comprehensive view into the complex mechanisms underlying depression., Methods: Cross-sectional data from individuals diagnosed with a major depressive disorder (N = 986) and healthy controls (N = 1049) were analyzed. Participants self-reported their depressive symptoms, as well as several risk factors and protective factors. Regularized partial correlation networks were estimated for each group and compared using a network comparison test., Results: Symptoms of depression were more strongly connected in the network of depressed patients than in healthy controls. Among the risk factors, perceived stress, the experience of negative life events, emotional neglect, and emotional abuse were the most centrally embedded in both networks. However, the centrality of risk factors did not significantly differ between the two groups. Among the protective factors, social support, personal competence, and acceptance were the most central in both networks, where the latter was significantly more strongly associated with the symptom of self-hate in depressed patients., Conclusion: The network analysis revealed that key symptoms of depression were more strongly connected for depressed patients than for healthy controls, and that risk and protective factors play an important role, particularly perceived stress in both groups and an accepting attitude for depressed patients. However, the purpose of this study is hypothesis generating and assisting in the potential selection of non-symptom nodes for future research., Competing Interests: Declaration of competing interest We report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Importance: Biological psychiatry aims to understand mental disorders in terms of altered neurobiological pathways. However, for one of the most prevalent and disabling mental disorders, major depressive disorder (MDD), no informative biomarkers have been identified., Objective: To evaluate whether machine learning (ML) can identify a multivariate biomarker for MDD., Design, Setting, and Participants: This study used data from the Marburg-Münster Affective Disorders Cohort Study, a case-control clinical neuroimaging study. Patients with acute or lifetime MDD and healthy controls aged 18 to 65 years were recruited from primary care and the general population in Münster and Marburg, Germany, from September 11, 2014, to September 26, 2018. The Münster Neuroimaging Cohort (MNC) was used as an independent partial replication sample. Data were analyzed from April 2022 to June 2023., Exposure: Patients with MDD and healthy controls., Main Outcome and Measure: Diagnostic classification accuracy was quantified on an individual level using an extensive ML-based multivariate approach across a comprehensive range of neuroimaging modalities, including structural and functional magnetic resonance imaging and diffusion tensor imaging as well as a polygenic risk score for depression., Results: Of 1801 included participants, 1162 (64.5%) were female, and the mean (SD) age was 36.1 (13.1) years. There were a total of 856 patients with MDD (47.5%) and 945 healthy controls (52.5%). The MNC replication sample included 1198 individuals (362 with MDD [30.1%] and 836 healthy controls [69.9%]). Training and testing a total of 4 million ML models, mean (SD) accuracies for diagnostic classification ranged between 48.1% (3.6%) and 62.0% (4.8%). Integrating neuroimaging modalities and stratifying individuals based on age, sex, treatment, or remission status does not enhance model performance. Findings were replicated within study sites and also observed in structural magnetic resonance imaging within MNC. Under simulated conditions of perfect reliability, performance did not significantly improve. Analyzing model errors suggests that symptom severity could be a potential focus for identifying MDD subgroups., Conclusion and Relevance: Despite the improved predictive capability of multivariate compared with univariate neuroimaging markers, no informative individual-level MDD biomarker-even under extensive ML optimization in a large sample of diagnosed patients-could be identified.

Background: Magnetic resonance imaging (MRI) studies on major depressive disorder (MDD) have predominantly found short-term electroconvulsive therapy (ECT)-related gray matter volume (GMV) increases, but research on the long-term stability of such changes is missing. Our aim was to investigate long-term GMV changes over a 2-year period after ECT administration and their associations with clinical outcome., Methods: In this nonrandomized longitudinal study, patients with MDD undergoing ECT ( n = 17) are assessed three times by structural MRI: Before ECT ( t 0 ), after ECT ( t 1 ) and 2 years later ( t 2 ). A healthy ( n = 21) and MDD non-ECT ( n = 33) control group are also measured three times within an equivalent time interval. A 3(group) × 3(time) ANOVA on whole-brain level and correlation analyses with clinical outcome variables is performed., Results: Analyses yield a significant group × time interaction ( p FWE < 0.001) resulting from significant volume increases from t 0 to t 1 and decreases from t 1 to t 2 in the ECT group, e.g., in limbic areas. There are no effects of time in both control groups. Volume increases from t 0 to t 1 correlate with immediate and delayed symptom increase, while volume decreases from t 1 to t 2 correlate with long-term depressive outcome (all p ⩽ 0.049)., Conclusions: Volume increases induced by ECT appear to be a transient phenomenon as volume strongly decreased 2 years after ECT. Short-term volume increases are associated with less symptom improvement suggesting that the antidepressant effect of ECT is not due to volume changes. Larger volume decreases are associated with poorer long-term outcome highlighting the interplay between disease progression and structural changes.

Background: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy., Methods: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined., Results: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure., Conclusions: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

Background: The psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders., Methods: Using FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n= 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic to identify subnetworks of white matter fiber tracts associated with FTD symptomatology., Results: Three psychopathological FTD dimensions were delineated, i.e., disorganization, emptiness, and incoherence. Disorganization and incoherence were associated with global dysconnectivity. Network-based statistics identified subnetworks associated with the FTD dimensions disorganization and emptiness but not with the FTD dimension incoherence. Post hoc analyses on subnetworks did not reveal diagnosis × FTD dimension interaction effects. Results remained stable after correcting for medication and disease severity. Confirmatory analyses showed a substantial overlap of nodes from both subnetworks with cortical brain regions previously associated with FTD in SZ., Conclusions: We demonstrated white matter subnetwork dysconnectivity in major depressive disorder, bipolar disorder, and SZ associated with FTD dimensions that predominantly comprise brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology-informed, dimensional studies in pathogenetic research., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols., (© 2024. The Author(s).)

Up to 70% of patients with major depressive disorder present with psychomotor disturbance (PmD), but at the present time understanding of its pathophysiology is limited. In this study, we capitalized on a large sample of patients to examine the neural correlates of PmD in depression. This study included 820 healthy participants and 699 patients with remitted (n = 402) or current (n = 297) depression. Patients were further categorized as having psychomotor retardation, agitation, or no PmD. We compared resting-state functional connectivity (ROI-to-ROI) between nodes of the cerebral motor network between the groups, including primary motor cortex, supplementary motor area, sensory cortex, superior parietal lobe, caudate, putamen, pallidum, thalamus, and cerebellum. Additionally, we examined network topology of the motor network using graph theory. Among the currently depressed 55% had PmD (15% agitation, 29% retardation, and 11% concurrent agitation and retardation), while 16% of the remitted patients had PmD (8% retardation and 8% agitation). When compared with controls, currently depressed patients with PmD showed higher thalamo-cortical and pallido-cortical connectivity, but no network topology alterations. Currently depressed patients with retardation only had higher thalamo-cortical connectivity, while those with agitation had predominant higher pallido-cortical connectivity. Currently depressed patients without PmD showed higher thalamo-cortical, pallido-cortical, and cortico-cortical connectivity, as well as altered network topology compared to healthy controls. Remitted patients with PmD showed no differences in single connections but altered network topology, while remitted patients without PmD did not differ from healthy controls in any measure. We found evidence for compensatory increased cortico-cortical resting-state functional connectivity that may prevent psychomotor disturbance in current depression, but may perturb network topology. Agitation and retardation show specific connectivity signatures. Motor network topology is slightly altered in remitted patients arguing for persistent changes in depression. These alterations in functional connectivity may be addressed with non-invasive brain stimulation., (© 2023. The Author(s).)

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure., Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference., Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness., Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment., (Copyright © 2023. Published by Elsevier Inc.)

Background: Narcissistic personality traits have been theorised to negatively affect depressive symptoms, therapeutic alliance, and treatment outcome, even in the absence of narcissistic personality disorder. We aimed to examine how the dimensional narcissistic facets of admiration and rivalry affect depressive symptoms across treatment modalities in two transdiagnostic samples., Methods: We did a naturalistic, observational prospective cohort study in two independent adult samples in Germany: one sample pooled from an inpatient psychiatric clinic and an outpatient treatment service offering cognitive behavioural treatment (CBT), and one sample from an inpatient clinic providing psychoanalytic interactional therapy (PIT). Inpatients treated with CBT had an affective or psychotic disorder. For the other two sites, data from all service users were collected. We examined the effect of core narcissism and its facets admiration and rivalry, measured by Narcissistic Admiration and Rivalry Questionnaire-short version, on depressive symptoms, measured by Beck's Depression Inventory and Patient Health Questionnaire-Depression Scale, at baseline and after treatment in patients treated with CBT and PIT. Primary analyses were regression models, predicting baseline and post-treatment depression severity from core narcissism and its facets. Mediation analysis was done in the outpatient CBT group for the effect of the therapeutic alliance on the association between narcissism and depression severity after treatment., Findings: The sample included 2371 patients (1423 [60·0%] female and 948 [40·0%] male; mean age 33·13 years [SD 13·19; range 18-81), with 517 inpatients and 1052 outpatients in the CBT group, and 802 inpatients in the PIT group. Ethnicity data were not collected. Mean treatment duration was 300 days (SD 319) for CBT and 67 days (SD 26) for PIT. Core narcissism did not predict depression severity before treatment in either group, but narcissistic rivalry was associated with higher depressive symptom load at baseline (β 2·47 [95% CI 1·78 to 3·12] for CBT and 1·05 [0·54 to 1·55] for PIT) and narcissistic admiration showed the opposite effect (-2·02 [-2·62 to -1·41] for CBT and -0·64 [-1·11 to -0·17] for PIT). Poorer treatment response was predicted by core narcissism (β 0·79 [0·10 to 1·47]) and narcissistic rivalry (0·89 [0·19 to 1·58]) in CBT, whereas admiration showed no effect. No effect of narcissism on treatment outcome was discernible in PIT. Therapeutic alliance mediated the effect of narcissism on post-treatment depression severity in the outpatient CBT sample., Interpretation: As narcissism affects depression severity before and after treatment with CBT across psychiatric disorders, even in the absence of narcissistic personality disorder, the inclusion of dimensional assessments of narcissism should be considered in future research and clinical routines. The relevance of the therapeutic alliance and therapeutic strategy could be used to guide treatment approaches., Funding: IZKF Münster., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Childhood maltreatment (CM) has been associated with changes in structural brain connectivity even in the absence of mental illness. Social support, an important protective factor in the presence of childhood maltreatment, has been positively linked to white matter integrity. However, the shared effects of current social support and CM and their association with structural connectivity remain to be investigated. They might shed new light on the neurobiological basis of the protective mechanism of social support. Using connectome-based predictive modeling (CPM), we analyzed structural connectomes of N = 904 healthy adults derived from diffusion-weighted imaging. CPM predicts phenotypes from structural connectivity through a cross-validation scheme. Distinct and shared networks of white matter tracts predicting childhood trauma questionnaire scores and the social support questionnaire were identified. Additional analyses were applied to assess the stability of the results. CM and social support were predicted significantly from structural connectome data (all rs ≥ 0.119, all ps ≤ 0.016). Edges predicting CM and social support were inversely correlated, i.e., positively correlated with CM and negatively with social support, and vice versa, with a focus on frontal and temporal regions including the insula and superior temporal lobe. CPM reveals the predictive value of the structural connectome for CM and current social support. Both constructs are inversely associated with connectivity strength in several brain tracts. While this underlines the interconnectedness of these experiences, it suggests social support acts as a protective factor following adverse childhood experiences, compensating for brain network alterations. Future longitudinal studies should focus on putative moderating mechanisms buffering these adverse experiences., (© 2023. The Author(s).)

Background: Negative stressful life events and deprivation of social support play critical roles in the development and maintenance of major depressive disorder (MDD). The present study aimed to investigate in a large sample of patients with MDD and healthy control participants (HCs) whether these effects are also reflected in white matter (WM) integrity., Methods: In this diffusion tensor imaging study, 793 patients with MDD and 793 age- and sex-matched HCs were drawn from the Marburg-Münster Affective Disorders Cohort Study (MACS) and completed the Life Events Questionnaire (LEQ) and Social Support Questionnaire (SSQ). Generalized linear models were performed to test voxelwise associations between fractional anisotropy (FA) and diagnosis (analysis 1), LEQ (analysis 2), and SSQ (analysis 3). We examined whether SSQ interacts with LEQ on FA or is independently associated with improved WM integrity (analysis 4)., Results: Patients with MDD showed lower FA in several frontotemporal association fibers compared with HCs (p TFCE-FWE  = .028). Across both groups, LEQ correlated negatively with FA in widely distributed WM tracts (p TFCE-FWE  = .023), while SSQ correlated positively with FA in the corpus callosum (p TFCE-FWE  = .043). Modeling the combined association of both variables on FA revealed significant-and antagonistic-main effects of LEQ (p TFCE-FWE  = .031) and SSQ (p TFCE-FWE  = .037), but no interaction of SSQ × LEQ., Conclusions: Our results indicate that negative stressful life events and social support are both related to WM integrity in opposing directions. The associations did not differ between patients with MDD and HCs, suggesting more general, rather than depression-specific, mechanisms. Furthermore, social support appears to contribute to improved WM integrity independent of stressful life events., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Obesity is associated with alterations in brain structure and function, particularly in areas related to reward processing. Although brain structural investigations have demonstrated a continuous association between higher body weight and reduced gray matter in well-powered samples, functional neuroimaging studies have typically only contrasted individuals from the normal weight and obese body mass index (BMI) ranges with modest sample sizes. It remains unclear, whether the commonly found hyperresponsiveness of the reward circuit can (a) be replicated in well-powered studies and (b) be found as a function of higher body weight even below the threshold of clinical obesity. 383 adults across the weight spectrum underwent functional magnetic resonance imaging during a common card-guessing paradigm simulating monetary reward. Multiple regression was used to investigate the association of BMI and neural activation in the reward circuit. In addition, a one-way ANOVA model comparing three weight groups (normal weight, overweight, obese) was calculated. Higher BMI was associated with higher reward response in the bilateral insula. This association could no longer be found when participants with obesity were excluded from the analysis. The ANOVA revealed higher activation in obese vs. lean, but no difference between lean and overweight participants. The overactivation of reward-related brain areas in obesity is a consistent finding that can be replicated in large samples. In contrast to brain structural aberrations associated with higher body weight, the neurofunctional underpinnings of reward processing in the insula appear to be more pronounced in the higher body weight range., (© 2023. The Author(s).)

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity., (© 2023. The Author(s).)

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 [ p FDR < 0.001; η 2 partial = 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; p FDR < 0.001; η 2 partial = 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.

Background: The second-generation antipsychotic (SGA) quetiapine is an essential option for antidepressant augmentation therapy in major depressive disorder (MDD), yet neurobiological mechanisms behind its antidepressant properties remain unclear. As SGAs interfere with activity in reward-related brain areas, including the anterior cingulate cortex (ACC) - a key brain region in antidepressant interventions, this study examined whether quetiapine treatment affects ACC activity during reward processing in MDD patients., Methods: Using the ACC as region of interest, an independent t-test comparing reward-related BOLD response of 51 quetiapine-taking and 51 antipsychotic-free MDD patients was conducted. Monetary reward outcome feedback was measured in a card-guessing paradigm using pseudorandom blocks. Participants were matched for age, sex, and depression severity and analyses were controlled for confounding variables, including total antidepressant medication load, illness chronicity and acute depression severity. Potential dosage effects were examined in a 3 × 1 ANOVA. Differences in ACC-related functional connectivity were assessed in psycho-physiological interaction (PPI) analyses., Results: Left subgenual ACC activity was significantly higher in the quetiapine group compared to antipsychotic-free participants and dependent on high-dose quetiapine intake. Results remained significant after controlling for confounding variables. The PPI analysis did not yield significant group differences in ACC-related functional connectivity., Limitations: Causal interpretation is limited due to cross-sectional findings., Conclusion: Elevated subgenual ACC activity to rewarding stimuli may represent a neurobiological marker and potential key interface of quetiapine's antidepressant effects in MDD. These results underline ACC activity during reward processing as an investigative avenue for future research and therapeutic interventions to improve MDD treatment outcomes., Competing Interests: Conflict of interest All authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact., Methods: We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations., Results: BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI., Conclusions: We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.

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.

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., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Retrospective self-reports of childhood maltreatment (CM) are widely used. However, their validity has been questioned due to potential depressive bias. Yet, investigations of this matter are sparse. Thus, we investigated to what extent retrospective maltreatment reports vary in relation to longitudinal changes in depressive symptomatology. Two-year temporal stability of maltreatment reports was assessed via the Childhood Trauma Questionnaire (CTQ). Diagnosis of major depressive disorder (MDD) and depressive symptoms were assessed using the Structured Clinical Interview for DSM-IV and the Beck Depression Inventory (BDI). We included a total of n = 419 healthy controls (HC), n = 347 MDD patients, and a subsample with an initial depressive episode between both assessments ( n = 27), from two independent cohorts (Marburg-Münster-affective-disorders-cohort-study and Münster-Neuroimaging-cohort). Analysis plan and hypotheses were preregistered prior to data analysis. Dimensional CTQ scores were highly stable in HC and MDD across both cohorts (ICC = .956; 95% CI [.949, .963] and ICC = .950; 95% CI [.933, .963]) and temporal stability did not differ between groups. Stability was lower for cutoff-based binary CTQ scores ( K = .551; 95% CI [.479, .622] and K = .507; 95% CI [.371, .640]). Baseline dimensional CTQ scores were associated with concurrent and future BDI scores. However, longitudinal changes in BDI scores predicted variability in dimensional CTQ scores only to a small extent across cohorts ( b = 0.101, p = .009, R ² = .021 and b = 0.292, p = .320), with the effect being driven by emotional maltreatment subscales. Findings suggest that the CTQ provides temporally stable self-reports of CM in healthy and depressed populations and is only marginally biased by depressive symptomatology. A dimensional rather than binary conceptualization of maltreatment is advised for improving psychometric quality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Digital acquisition of patients' self-reports on individual risk factors and symptom severity represents a promising, cost-efficient, and increasingly prevalent approach for standardized data collection in psychiatric clinical routine. Yet, studies investigating digital data collection in patients with a schizophrenia spectrum disorder (PSSDs) are scarce. The objective of this study was to explore the feasibility of digitally acquired self-report assessments of risk and symptom profiles at the time of admission into inpatient treatment in an age-representative sample of hospitalized PSSDs. We investigated the required support, the data entry pace, and the subjective user experience. Findings were compared with those of patients with an affective disorder (PADs). Of 82 PSSDs who were eligible for inclusion, 59.8% (n=49) agreed to participate in the study, of whom 54.2% (n=26) could enter data without any assistance. Inclusion rates, drop-out rates, and subjective experience ratings did not differ between PSSDs and PADs. Patients reported high satisfaction with the assessment. PSSDs required more support and time for the data entry than PADs. Our results indicate that digital data collection is a feasible and well-received method in PSSDs. Future clinical and research efforts on digitized assessments in psychiatry should include PSSDs and offer support to reduce digital exclusion., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2022. Published by Elsevier B.V.)

Background: Among mental disorders, major depressive disorder (MDD) is highly prevalent and associated with emotional dysfunctions linked to activity alterations in the brain, mainly in prefrontal regions, the insula, the anterior cingulate cortex and the amygdala. However, this evidence is heterogeneous, perhaps because magnetic resonance imaging (MRI) studies on MDD tend to neglect comorbid anxiety (COM-A)., Methods: To address this, here a sample of age- and sex-matched patients, n MDD  = 90 and n COM-A  = 85, underwent functional MRI to assess neurofunctional group differences during a negative emotional face-matching task using a hypothesis-driven region of interest approach (dorsolateral prefrontal cortex, insula, anterior cingulate cortex, amygdala) and an explorative whole-brain approach. We also assessed these relationships with state-trait anxiety measures, a state depression measure, general functioning and medication load., Results: During face processing, COM-A (compared to MDD) had significantly increased bilateral insula activity. No activity differences were found in the anterior cingulate cortex or the amygdala. Whole-brain analyses revealed increased inferior temporal activation and frontal activation (comprising the inferior and middle frontal gyrus) in COM-A that was positively linked to state anxiety as well as general functioning across groups., Limitations: Still, the lack of a healthy control and small effects mean this study should be replicated to further interpret the results., Conclusions: The findings highlight a discriminative activation pattern between MDD and COM-A regarding emotion processing and may present a correlate of potentially anxiety-related psychopathology. In future, further investigations in potential discriminative activity patterns could help to elucidate the origin, development and treatment of depression., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The diathesis-stress model of major depressive disorder (MDD) predicts interactions of recent stressful life events (SLEs) in adulthood and early developmental risk factors. We tested, for the first time, the diathesis stress model on brain structure in a large group of MDD patients., Methods: Structural magnetic resonance imaging data of 1465 participants (656 with lifetime diagnosis MDD; 809 healthy controls) were analyzed using voxel-based morphometry to identify clusters associated with recent SLEs (Life Events Questionnaire). Those clusters were then examined for group (healthy/MDD) × early developmental risk (operationalized as childhood abuse [Childhood Trauma Questionnaire] and a major psychiatric disorder [i.e., MDD, bipolar disorder, schizophrenia, and schizoaffective disorder] in a first-degree relative) × recent SLEs three-way interactions on grey matter volume., Results: There was a group × childhood abuse × recent SLEs interaction on left medial orbitofrontal cortex grey matter volume. This three-way interaction arose because childhood abuse and recent SLEs interacted in MDD subjects but not in healthy subjects., Limitations: We are not able to draw conclusions about the cause and effect relationship due to our cross-sectional study design., Conclusions: Our data provides evidence for an interplay between orbitofrontal cortex structure, childhood abuse and recent SLEs. These factors have previously been linked to MDD and their complex interaction contributes to the pathogenesis of MDD., (Copyright © 2022 Elsevier B.V. All rights reserved.)