Cortical surface area alterations shaped by genetic load for neuroticism.

Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n = 746 healthy controls (HC) and n = 268 MDD patients. Findings were validated in an independent replication sample (n = 341 HC and n = 263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

Influence of electroconvulsive therapy on white matter structure in a diffusion tensor imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) is a fast-acting intervention for major depressive disorder. Previous studies indicated neurotrophic effects following ECT that might contribute to changes in white matter brain structure. We investigated the influence of ECT in a non-randomized prospective study focusing on white matter changes over time. METHODS: Twenty-nine severely depressed patients receiving ECT in addition to inpatient treatment, 69 severely depressed patients with inpatient treatment (NON-ECT) and 52 healthy controls (HC) took part in a non-randomized prospective study. Participants were scanned twice, approximately 6 weeks apart, using diffusion tensor imaging, applying tract-based spatial statistics. Additional correlational analyses were conducted in the ECT subsample to investigate the effects of seizure duration and therapeutic response. RESULTS: Mean diffusivity (MD) increased after ECT in the right hemisphere, which was an ECT-group-specific effect. Seizure duration was associated with decreased fractional anisotropy (FA) following ECT. Longitudinal changes in ECT were not associated with therapy response. However, within the ECT group only, baseline FA was positively and MD negatively associated with post-ECT symptomatology. CONCLUSION: Our data suggest that ECT changes white matter integrity, possibly reflecting increased permeability of the blood-brain barrier, resulting in disturbed communication of fibers. Further, baseline diffusion metrics were associated with therapy response. Coherent fiber structure could be a prerequisite for a generalized seizure and inhibitory brain signaling necessary to successfully inhibit increased seizure activity.

Replication of a hippocampus specific effect of the tescalcin regulating variant rs7294919 on gray matter structure.

While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association.

Predicting rehospitalization within 2 years of initial patient admission for a major depressive episode: a multimodal machine learning approach.

Machine learning methods show promise to translate univariate biomarker findings into clinically useful multivariate decision support systems. At current, works in major depressive disorder have predominantly focused on neuroimaging and clinical predictor modalities, with genetic, blood-biomarker, and cardiovascular modalities lacking. In addition, the prediction of rehospitalization after an initial inpatient major depressive episode is yet to be explored, despite its clinical importance. To address this gap in the literature, we have used baseline clinical, structural imaging, blood-biomarker, genetic (polygenic risk scores), bioelectrical impedance and electrocardiography predictors to predict rehospitalization within 2 years of an initial inpatient episode of major depression. Three hundred and eighty patients from the ongoing 12-year Bidirect study were included in the analysis (rehospitalized: yes = 102, no = 278). Inclusion criteria was age ≥35 and <66 years, a current or recent hospitalisation for a major depressive episode and complete structural imaging and genetic data. Optimal performance was achieved with a multimodal panel containing structural imaging, blood-biomarker, clinical, medication type, and sleep quality predictors, attaining a test AUC of 67.74 (p = 9.99-05). This multimodal solution outperformed models based on clinical variables alone, combined biomarkers, and individual data modality prognostication for rehospitalization prediction. This finding points to the potential of predictive models that combine multimodal clinical and biomarker data in the development of clinical decision support systems.

Childhood maltreatment moderates the influence of genetic load for obesity on reward related brain structure and function in major depression.

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.

Mediation of the influence of childhood maltreatment on depression relapse by cortical structure: a 2-year longitudinal observational study.

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.

Apolipoprotein E Homozygous ε4 Allele Status: A Deteriorating Effect on Visuospatial Working Memory and Global Brain Structure.

Theoretical background: The Apolipoprotein E (APOE) ε4 genotype is known to be one of the strongest single-gene predictors for Alzheimer disease, which is characterized by widespread brain structural degeneration progressing along with cognitive impairment. The ε4 allele status has been associated with brain structural alterations and lower cognitive ability in non-demented subjects. However, it remains unclear to what extent the visuospatial cognitive domain is affected, from what age onward changes are detectable and if alterations may interact with cognitive deficits in major depressive disorder (MDD). The current work investigated the effect of APOE ε4 homozygosity on visuospatial working memory (vWM) capacity, and on hippocampal morphometry. Furthermore, potential moderating roles of age and MDD were assessed. Methods: A sample of n = 31 homozygous ε4 carriers was contrasted with n = 31 non-ε4 carriers in a cross-sectional design. The sample consisted of non-demented, young to mid-age participants (mean age = 34.47; SD = 13.48; 51.6% female). Among them were n = 12 homozygous ε4 carriers and n = 12 non-ε4 carriers suffering from MDD (39%). VWM was assessed using the Corsi block-tapping task. Region of interest analyses of hippocampal gray matter density and volume were conducted using voxel-based morphometry (CAT12), and Freesurfer, respectively. Results: Homozygous ε4 carriers showed significantly lower Corsi span capacity than non-ε4 carriers did, and Corsi span capacity was associated with higher gray matter density of the hippocampus. APOE group differences in hippocampal volume could be detected but were no longer present when controlling for total intracranial volume. Hippocampal gray matter density did not differ between APOE groups. We did not find any interaction effects of age and MDD diagnosis on hippocampal morphometry. Conclusion: Our results point toward a negative association of homozygous ε4 allele status with vWM capacity already during mid-adulthood, which emerges independently of MDD diagnosis and age. APOE genotype seems to be associated with global brain structural rather than hippocampus specific alterations in young- to mid-age participants.

Elevated body-mass index is associated with reduced white matter integrity in two large independent cohorts.

Obesity has been associated with a variety of neurobiological alterations. Recent neuroimaging research has pointed to the relevance of brain structural and functional alterations in the development of obesity. However, while the role of gray matter atrophy in obesity has been evidenced in several well powered studies, large scale evidence for altered white matter integrity in obese subjects is still absent. With this study, we therefore aimed to investigate potential associations between white matter abnormalities and body mass index (BMI) in two large independent samples of healthy adults. Associations between BMI values and whole brain fractional anisotropy (FA) were investigated in two independent cohorts: A sample of n = 369 healthy subjects from the Münster Neuroimaging Cohort (MNC), as well as a public available sample of n = 1064 healthy subjects of the Humane Connectome Project (HCP) were included in the present study. Tract based spatial statistics (TBSS) analyses of BMI on whole brain FA were conducted including age and sex as nuisance covariates using the FMRIB library (FSL Version 5.0). Threshold-free cluster enhancement was applied to control for multiple comparisons. In both samples higher BMI was significantly associated with strong and widespread FA reductions. These effects were most pronounced in the corpus callosum, bilateral posterior thalamic radiation, bilateral internal capsule and external capsule, bilateral inferior longitudinal fasciculus and inferior fronto-occipital fasciculus. The association was found to be independent of age, sex and other cardiovascular risk factors. No significant positive associations between BMI and FA occurred. With this highly powered study, we provide robust evidence for globally reduced white matter integrity associated with elevated BMI including replication in an independent sample. The present work thus points out the relevance of white matter alterations as a neurobiological correlate of obesity.