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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).)

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).)

Reduced fractional anisotropy (FA) associated with Major Depressive Disorder (MDD) overlaps anatomically with effects of childhood maltreatment experiences. The aim of this study was, therefore, to replicate the negative effect of childhood maltreatment on white matter fiber structure and to demonstrate, that alterations in MDD might be partially attributed to the higher occurrence of childhood maltreatment in MDD. Two independent cohorts (total N = 1 256) were investigated in a diffusion tensor imaging study: The Münster Neuroimaging Cohort (MNC, N = 186 MDD, N = 210 healthy controls, HC) as discovery sample and the Marburg-Münster Affective Disorders Cohort Study (MACS, N = 397 MDD, N = 462 HC) as replication sample. The effects of diagnosis (HC vs. MDD) and Childhood Trauma Questionnaire (CTQ) scores on FA were analyzed. A main effect of diagnosis with higher FA in MDD patients compared with HC was found in the MNC (p FWE  = 0.021), but not in the MACS (p FWE  = 0.52) before correcting for CTQ. A significant negative correlation of FA with CTQ emerged in both cohorts (MNC: p FWE  = 0.006, MACS: p FWE  = 0.012) in several tracts previously described in the literature. No CTQ × diagnosis interaction could be detected. Any main effect of diagnosis was abolished after correcting for CTQ (MNC: p FWE  = 0.562, MACS: p FWE  = 0.115). No differences in FA between MDD and HC could be found after correcting for childhood maltreatment, suggesting that previously reported group differences might be attributed partially to higher levels of maltreatment experiences in MDD rather than diagnosis itself. Furthermore, a well-established finding of reduced FA following childhood maltreatment experiences was replicated.

Background: Cross-sectional studies have repeatedly shown impaired white matter integrity in patients with major depressive disorder. Longitudinal analyses are missing from the current research and are crucial to elucidating the impact of disease trajectories on white matter impairment in major depressive disorder., Methods: Fifty-nine patients with major depressive disorder receiving inpatient treatment, as well as 49 healthy controls, took part in a prospective study. Participants were scanned twice (baseline and follow-up), approximately 2.25 years apart, using diffusion tensor imaging. We analyzed diffusion metrics using tract-based spatial statistics., Results: At baseline, patients had higher mean diffusivity in a large bilateral frontal cluster comprising the body and genu of the corpus callosum, the anterior and superior corona radiata, and the superior longitudinal fasciculus. A significant group × time interaction revealed a decrease of mean diffusivity in patients with major depressive disorder over time, abolishing group differences at follow-up. This effect was observed irrespective of disease course in the follow-up period., Limitations: Analyzing the course of illness is challenging because of recollection biases in patients with major depressive disorder., Conclusion: This study reports follow-up diffusion tensor imaging data in patients with major depressive disorder after an acute depressive episode. We demonstrated impaired prefrontal white matter microstructure (higher mean diffusivity) at baseline in patients with major depressive disorder, which normalized at follow-up after 2 years, irrespective of disease course. This might have been due to a general treatment effect and might have reflected recovery of white matter integrity., Competing Interests: H. Kugel has received consultation fees from MR:comp GmbH, Testing Services for MR Safety, outside the submitted work. V. Arolt is a member of the advisory boards of Allergan, Janssen-Cilag, Lundbeck, Otsuka, Servier and Trommsdorff and has received speaker fees from Janssen-Cilag, Lundbeck, Otsuka, Servier, outside the submitted work. No other competing interests declared., (© 2019 Joule Inc. or its licensors)

Background: Childhood maltreatment is a leading environmental risk factor for an unfavourable course of disease in major depressive disorder. Both maltreatment and major depressive disorder are associated with similar brain structural alterations suggesting that brain structural changes could mediate the adverse influence of maltreatment on clinical outcome in major depressive disorder. However, longitudinal studies have not been able to confirm this hypothesis. We therefore aimed to clarify the relationship between childhood trauma, brain structural alterations, and depression relapse in a longitudinal design., Methods: We recruited participants at the Department of Psychiatry, University of Münster, Germany, from the Münster Neuroimage Cohort for whom 2-year longitudinal clinical data were available. Baseline data acquisition comprised clinical assessments, structural MRI, and retrospective assessment of the extent of childhood maltreatment experiences using the Childhood Trauma Questionnaire. Clinical follow-up assessments were conducted in all participants 2 years after initial recruitment., Findings: Initial recruitment was March 21, 2010-Jan 29, 2016; follow-up reassessment Sept 7, 2012-March 9, 2018. 110 patients with major depressive disorder participated in this study. 35 patients were relapse-free, whereas 75 patients had experienced depression relapse within the 2-year follow-up period. Childhood maltreatment was significantly associated with depression relapse during follow-up (odds ratio [OR] 1·035, 95% CI 1·001-1·070; p=0·045). Both previous childhood maltreatment experiences and future depression relapse were associated with reduced cortical surface area (OR 0·996, 95% CI 0·994-0·999; p=0·001), primarily in the right insula at baseline (r=-0·219, p=0·023). Insular surface area was shown to mediate the association between maltreatment and future depression relapse (indirect effect: coefficient 0·0128, SE 0·0081, 95% CI 0·0024-0·0333)., Interpretation: Early life stress has a detrimental effect on brain structure, which increases the risk of unfavourable disease courses in major depression. Clinical and translational research should explore the role of childhood maltreatment as causing a potential clinically and biologically distinct subtype of major depressive disorder., Funding: The German Research Foundation, the Interdisciplinary Centre for Clinical Research, and the Deanery of the Medical Faculty of the University of Münster., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Obesity is a clinically relevant and highly prevalent somatic comorbidity of major depression (MDD). Genetic predisposition and history of childhood trauma have both independently been demonstrated to act as risk factors for obesity and to be associated with alterations in reward related brain structure and function. We therefore aimed to investigate the influence of childhood maltreatment and genetic risk for obesity on structural and functional imaging correlates associated with reward processing in MDD. 161 MDD patients underwent structural and functional MRI during a frequently used card guessing paradigm. Main and interaction effects of a polygenic risk score for obesity (PRS) and childhood maltreatment experiences as assessed using the Childhood Trauma Questionnaire (CTQ) were investigated. We found that maltreatment experiences and polygenic risk for obesity significantly interacted on a) body mass index b) gray matter volume of the orbitofrontal cortex as well as on c) BOLD response in the right insula during reward processing. While polygenic risk for obesity was associated with elevated BMI as well as with decreased OFC gray matter and increased insular BOLD response in non-maltreated patients, these associations were absent in patients with a history of childhood trauma. No significant main effect of PRS or maltreatment on gray matter or BOLD response could be detected at the applied thresholds. The present study suggests that childhood maltreatment moderates the influence of genetic load for obesity on BMI as well as on altered brain structure and function in reward related brain circuits in MDD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)