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Importance: Major depressive disorder (MDD) is characterized by a substantial burden on health, including changes in appetite and body weight. Heterogeneity of depressive symptoms has hampered the identification of biomarkers that robustly generalize to most patients, thus calling for symptom-based mapping.Objective: To define the functional architecture of the reward circuit subserving increases vs decreases in appetite and body weight in patients with MDD by specifying their contributions and influence on disease biomarkers using resting-state functional connectivity (FC).Design, Setting, and Participants: In this case-control study, functional magnetic resonance imaging (fMRI) data were taken from the Marburg-Münster FOR 2107 Affective Disorder Cohort Study (MACS), collected between September 2014 and November 2016. Cross-sectional data of patients with MDD (n = 407) and healthy control participants (n = 400) were analyzed from March 2018 to June 2022.Main Outcomes and Measures: Changes in appetite during the depressive episode and their association with FC were examined using fMRI. By taking the nucleus accumbens (NAcc) as seed of the reward circuit, associations with opposing changes in appetite were mapped, and a sparse symptom-specific elastic-net model was built with 10-fold cross-validation.Results: Among 407 patients with MDD, 249 (61.2%) were women, and the mean (SD) age was 36.79 (13.4) years. Reduced NAcc-based FC to the ventromedial prefrontal cortex (vmPFC) and the hippocampus was associated with reduced appetite (vmPFC: bootstrap r = 0.13; 95% CI, 0.02-0.23; hippocampus: bootstrap r = 0.15; 95% CI, 0.05-0.26). In contrast, reduced NAcc-based FC to the insular ingestive cortex was associated with increased appetite (bootstrap r = -0.14; 95% CI, -0.24 to -0.04). Critically, the cross-validated elastic-net model reflected changes in appetite based on NAcc FC and explained variance increased with increasing symptom severity (all patients: bootstrap r = 0.24; 95% CI, 0.16-0.31; patients with Beck Depression Inventory score of 28 or greater: bootstrap r = 0.42; 95% CI, 0.25-0.58). In contrast, NAcc FC did not classify diagnosis (MDD vs healthy control).Conclusions and Relevance: In this study, NAcc-based FC reflected important individual differences in appetite and body weight in patients with depression that can be leveraged for personalized prediction. However, classification of diagnosis using NAcc-based FC did not exceed chance levels. Such symptom-specific associations emphasize the need to map biomarkers onto more confined facets of psychopathology to improve the classification and treatment of MDD. [ABSTRACT FROM AUTHOR]

Importance: Identifying neurobiological differences between patients with major depressive disorder (MDD) and healthy individuals has been a mainstay of clinical neuroscience for decades. However, recent meta-analyses have raised concerns regarding the replicability and clinical relevance of brain alterations in depression.Objective: To quantify the upper bounds of univariate effect sizes, estimated predictive utility, and distributional dissimilarity of healthy individuals and those with depression across structural magnetic resonance imaging (MRI), diffusion-tensor imaging, and functional task-based as well as resting-state MRI, and to compare results with an MDD polygenic risk score (PRS) and environmental variables.Design, Setting, and Participants: This was a cross-sectional, case-control clinical neuroimaging study. Data were part of the Marburg-Münster Affective Disorders Cohort Study. Patients with depression and healthy controls were recruited from primary care and the general population in Münster and Marburg, Germany. Study recruitment was performed from September 11, 2014, to September 26, 2018. The sample comprised patients with acute and chronic MDD as well as healthy controls in the age range of 18 to 65 years. Data were analyzed from October 29, 2020, to April 7, 2022.Main Outcomes and Measures: Primary analyses included univariate partial effect size (η2), classification accuracy, and distributional overlapping coefficient for healthy individuals and those with depression across neuroimaging modalities, controlling for age, sex, and additional modality-specific confounding variables. Secondary analyses included patient subgroups for acute or chronic depressive status.Results: A total of 1809 individuals (861 patients [47.6%] and 948 controls [52.4%]) were included in the analysis (mean [SD] age, 35.6 [13.2] years; 1165 female patients [64.4%]). The upper bound of the effect sizes of the single univariate measures displaying the largest group difference ranged from partial η2 of 0.004 to 0.017, and distributions overlapped between 87% and 95%, with classification accuracies ranging between 54% and 56% across neuroimaging modalities. This pattern remained virtually unchanged when considering either only patients with acute or chronic depression. Differences were comparable with those found for PRS but substantially smaller than for environmental variables.Conclusions and Relevance: Results of this case-control study suggest that even for maximum univariate biological differences, deviations between patients with MDD and healthy controls were remarkably small, single-participant prediction was not possible, and similarity between study groups dominated. Biological psychiatry should facilitate meaningful outcome measures or predictive approaches to increase the potential for a personalization of the clinical practice. [ABSTRACT FROM AUTHOR]

Factorial dimensions and neurobiological underpinnings of formal thought disorders (FTD) have been extensively investigated in schizophrenia spectrum disorders (SSD). However, FTD are also highly prevalent in other disorders. Still, there is a lack of knowledge about transdiagnostic, structural brain correlates of FTD. In N = 1071 patients suffering from DSM-IV major depressive disorder, bipolar disorder, or SSD, we calculated a psychopathological factor model of FTD based on the SAPS and SANS scales. We tested the association of FTD dimensions with 3 T MRI measured gray matter volume (GMV) and white matter fractional anisotropy (FA) using regression and interaction models in SPM12. We performed post hoc confirmatory analyses in diagnostically equally distributed, age- and sex-matched sub-samples to test whether results were driven by diagnostic categories. Cross-validation (explorative and confirmatory) factor analyses revealed three psychopathological FTD factors: disorganization, emptiness, and incoherence. Disorganization was negatively correlated with a GMV cluster comprising parts of the middle occipital and angular gyri and positively with FA in the right posterior cingulum bundle and inferior longitudinal fascicle. Emptiness was negatively associated with left hippocampus and thalamus GMV. Incoherence was negatively associated with FA in bilateral anterior thalamic radiation, and positively with the hippocampal part of the right cingulum bundle. None of the gray or white matter associations interacted with diagnosis. Our results provide a refined mapping of cross-disorder FTD phenotype dimensions. For the first time, we demonstrated that their neuroanatomical signatures are associated with language-related gray and white matter structures independent of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Eighty percent of all patients suffering from major depressive disorder (MDD) relapse at least once in their lifetime. Thus, understanding the neurobiological underpinnings of the course of MDD is of utmost importance. A detrimental course of illness in MDD was most consistently associated with superior longitudinal fasciculus (SLF) fiber integrity. As similar associations were, however, found between SLF fiber integrity and acute symptomatology, this study attempts to disentangle associations attributed to current depression from long-term course of illness. Methods: A total of 531 patients suffering from acute (N = 250) or remitted (N = 281) MDD from the FOR2107-cohort were analyzed in this cross-sectional study using tract-based spatial statistics for diffusion tensor imaging. First, the effects of disease state (acute v. remitted), current symptom severity (BDI-score) and course of illness (number of hospitalizations) on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity were analyzed separately. Second, disease state and BDI-scores were analyzed in conjunction with the number of hospitalizations to disentangle their effects. Results: Disease state (pFWE < 0.042) and number of hospitalizations (pFWE< 0.032) were associated with decreased FA and increased MD and RD in the bilateral SLF. A trend was found for the BDI-score (pFWE > 0.067). When analyzed simultaneously only the effect of course of illness remained significant (pFWE < 0.040) mapping to the right SLF. Conclusions: Decreased FA and increased MD and RD values in the SLF are associated with more hospitalizations when controlling for current psychopathology. SLF fiber integrity could reflect cumulative illness burden at a neurobiological level and should be targeted in future longitudinal analyses. [ABSTRACT FROM AUTHOR]

Background: Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood. Methods: We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors. Results: We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy. Conclusions: This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences). [ABSTRACT FROM AUTHOR]

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD‐related differences in subcortical regions using shape analysis. In this meta‐analysis of subcortical shape from the ENIGMA‐MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta‐analysis. Relative to CTL, patients with adolescent‐onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = −0.164 to −0.180). Relative to first‐episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = −0.173 to −0.184). Our results suggest that previously reported MDD‐associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features. [ABSTRACT FROM AUTHOR]

Aberrant brain structural connectivity in major depressive disorder (MDD) has been repeatedly reported, yet many previous studies lack integration of different features of MDD with structural connectivity in multivariate modeling approaches. In n = 595 MDD patients, we used structural equation modeling (SEM) to test the intercorrelations between anhedonia, anxiety, neuroticism, and cognitive control in one comprehensive model. We then separately analyzed diffusion tensor imaging (DTI) connectivity measures in association with those clinical variables, and finally integrated brain connectivity associations, clinical/cognitive variables into a multivariate SEM. We first confirmed our clinical/cognitive SEM. DTI analyses (FWE‐corrected) showed a positive correlation of anhedonia with fractional anisotropy (FA) in the right anterior thalamic radiation (ATR) and forceps minor/corpus callosum, while neuroticism was negatively correlated with axial diffusivity (AD) in the left uncinate fasciculus (UF) and inferior fronto‐occipital fasciculus (IFOF). An extended SEM confirmed the associations of ATR FA with anhedonia and UF/IFOF AD with neuroticism impacting on cognitive control. Our findings provide evidence for a differential impact of state and trait variables of MDD on brain connectivity and cognition. The multivariate approach shows feasibility of explaining heterogeneity within MDD and tracks this to specific brain circuits, thus adding to better understanding of heterogeneity on the biological level. [ABSTRACT FROM AUTHOR]

Brain morphology and its relation to endocrine parameters were examined, in order to determine the link of these parameters to treatment outcome to psychopharmacological treatment in depressed patients. We examined the potentially predictive value of Magnetic Resonance Imaging (MRI) parameters related to mineralocorticoid receptor (MR) function on the treatment outcome of depression. 16 inpatients with a major depressive episode (MDE) were studied at baseline and 14 of them approximately six weeks later. Physiological biomarkers and 3-T-structural MRI based volume measures, using FreeSurfer 6.0 software, were determined. Non-responders (<50% reduction of HAMD-21; n = 6) had a significantly smaller volume of the right anterior cingulate cortex, a significantly larger ventricle to brain ratio (VBR) and third ventricle volume, and smaller volumes of the central and central-anterior corpus callosum (CC) in comparison to responders (n = 7; all p ≤ 0.05). Correlational analysis (Spearman) demonstrated that larger ventricle volume was correlated to a worse treatment outcome, higher body mass index (BMI) and smaller CC segment volume, whereas the total CC volume was negatively correlated to the saliva aldosterone/cortisol concentration ratio (AC-ratio). Large ventricular volume may be a predictive marker for worse treatment response to standard antidepressant treatment, potentially via compression of white matter structures. A mediating role of the previously identified markers BMI and the AC-ratio, is suggested. [ABSTRACT FROM AUTHOR]

Similar to patients with Major depressive disorder (MDD), healthy subjects at risk for depression show hyperactivation of the amygdala as a response to negative emotional expressions. The medial prefrontal cortex is responsible for amygdala control. Analyzing a large cohort of healthy subjects, we aimed to delineate malfunction in amygdala regulation by the medial prefrontal cortex in subjects at increased risk for depression, i.e., with a family history of affective disorders or a personal history of childhood maltreatment. We included a total of 342 healthy subjects from the FOR2107 cohort (www.for2107.de). An emotional face-matching task was used to identify the medial prefrontal cortex and right amygdala. Dynamic Causal Modeling (DCM) was conducted and neural coupling parameters were obtained for healthy controls with and without particular risk factors for depression. We assigned a genetic risk if subjects had a first-degree relative with an affective disorder and an environmental risk if subjects experienced childhood maltreatment. We then compared amygdala inhibition during emotion processing between groups. Amygdala inhibition by the medial prefrontal cortex was present in subjects without those two risk factors, as indicated by negative model parameter estimates. Having a genetic risk (i.e., a family history) did not result in changes in amygdala inhibition compared to no risk subjects. In contrast, childhood maltreatment as environmental risk has led to a significant reduction of amygdala inhibition by the medial prefrontal cortex. We propose a mechanistic explanation for the amygdala hyperactivity in subjects with particular risk for depression, in particular childhood maltreatment, caused by a malfunctioned amygdala downregulation via the medial prefrontal cortex. As childhood maltreatment is a major environmental risk factor for depression, we emphasize the importance of this potential early biomarker. [ABSTRACT FROM AUTHOR]

Genetic (G) and environmental (E) factors are involved in the etiology and course of the major psychoses (MP), i.e. major depressive disorder (MDD), bipolar disorder (BD), schizoaffective disorder (SZA) and schizophrenia (SZ). The neurobiological correlates by which these predispositions exert their influence on brain structure, function and course of illness are poorly understood. In the FOR2107 consortium, animal models and humans are investigated. A human cohort of MP patients, healthy subjects at genetic and/or environmental risk, and control subjects (N = 2500) has been established. Participants are followed up after 2 years and twice underwent extensive deep phenotyping (MR imaging, clinical course, neuropsychology, personality, risk/protective factors, biomaterials: blood, stool, urine, hair, saliva). Methods for data reduction, quality assurance for longitudinal MRI data, and (deep) machine learning techniques are employed. In the parallelised animal cluster, genetic risk was introduced by a rodent model (Cacna1c deficiency) and its interactions with environmental risk and protective factors are studied. The animals are deeply phenotyped regarding cognition, emotion, and social function, paralleling the variables assessed in humans. A set of innovative experimental projects connect and integrate data from the human and animal parts, investigating the role of microRNA, neuroplasticity, immune signatures, (epi-)genetics and gene expression. Biomaterial from humans and animals are analyzed in parallel. The FOR2107 consortium will delineate pathophysiological entities with common neurobiological underpinnings ("biotypes") and pave the way for an etiologic understanding of the MP, potentially leading to their prevention, the prediction of individual disease courses, and novel therapies in the future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Polymorphisms in the G72 (also named d-amino acid oxidase activator, DAOA) gene increase the vulnerability for schizophrenia and affective psychosis. Three recent genetic neuroimaging studies showed that variation in G72 influences the brain activity in the medial temporal lobe (MTL), supporting the hypothesis that G72 might play a modulatory role on brain activity in MTL structures. In the present study we therefore investigated the effect of G72 on the neural correlates of long-term memory encoding and retrieval in a large sample of healthy subjects (n =83) using functional magnetic resonance imaging. A face encoding and a face retrieval memory task were chosen because on the one hand they specifically activate MTL structures and on the other hand they tap into memory processes that are compromised in patients with schizophrenia and affective disorder. Despite a strong a-priori hypothesis of genotype group activation differences in the MTL along with a large sample size we did neither find an effect of G72 genotype status on brain activity in the MTL nor in any other brain regions. The present data therefore do not support the view of a general modulatory role of G72 on MTL brain activity, at least not in the domain of long-term memory encoding and retrieval. Our results highlight the importance of replication studies in genetic neuroimaging. [Copyright &y& Elsevier]

Our goal was to assess treatment effects of electroconvulsive therapy (ECT) on acoustic processing in major depression. We hypothesized that (1) depression is related to functional alterations in auditory networks, and that (2) pre-treatment alterations in auditory networks are reversible through treatment with ECT. Acoustic perception of 20 severely depressed and 20 age and gender matched healthy controls was investigated by 3 T functional magnetic resonance imaging employing repeated stimulation by sine tones. Prior to ECT, depressed patients presented a multimodal recruitment of additional brain areas including regions of the secondary visual system (cuneus, lingualis) and the medial frontal cortex. During ECT, signal intensities were reduced compared to pre-ECT values and controls. Activation of several regions increased after ECT. Our data suggest that depression is accompanied by cortical dysfunction including impaired auditory processing of non-speech stimuli. This might be based on overall alterations of brain metabolism indicating functional impairment. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Symptoms of depression are interrelated in a complex and self-reinforcing way. • The inclusion of risk and protective factors offers a more comprehensive view into depression. • Key symptoms of depression were indecisiveness and lack of satisfaction. • Perceived stress plays an important role in healthy controls and depressed patients. • An accepting attitude seems especially beneficial for depressed patients. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions "Depression", "Negative syndrome", "Positive formal thought disorder", "Paranoid-hallucinatory syndrome", and "Increased appetite" in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with "Positive formal thought disorder", the PRS for SZ was positively associated with "Paranoid-hallucinatory syndrome", and the PRS for BD was negatively associated with "Depression". The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e−6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be overrepresented in patients suffering from bipolar disorder, schizophrenia or major depression. While the functions underlying the pathophysiology of these psychiatric disorders are yet unknown, impaired performance in verbal fluency tasks is an often replicated finding. We investigated the influence of the rs1006737 single nucleotide polymorphism (SNP) on verbal fluency and its neural correlates. Methods: Brain activation was measured with functional magnetic resonance imaging (fMRI) during a semantic verbal fluency task in 63 healthy male individuals. They additionally performed more demanding verbal fluency tasks outside the scanner. All subjects were genotyped for CACNA1C rs1006737. Results: For the behavioral measures outside the scanner, rs1006737genotype had an effect on semantic but not on lexical verbal fluency with decreased performance in risk-allele carriers. In the fMRI experiment, while there were no differences in behavioural performance, increased activation in the left inferior frontal gyrus as well as the left precuneus was found in risk-allele carriers in the semantic verbal fluency task. Conclusions: The rs1006737 variant does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in bipolar disorder, schizophrenia and major depression and may explain some of the cognitive and brain activation variation found in these disorders. [Copyright &y& Elsevier]