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

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

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

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

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

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

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

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

Emotion processing in depression with and without comorbid anxiety disorder.

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, nMDD = 90 and nCOM-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.

Dimensions of Formal Thought Disorder and Their Relation to Gray- and White Matter Brain Structure in Affective and Psychotic Disorders.

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.

Brain structural connectivity, anhedonia, and phenotypes of major depressive disorder: A structural equation model approach.

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.

DLPFC volume is a neural correlate of resilience in healthy high-risk individuals with both childhood maltreatment and familial risk for depression.

BACKGROUND: Two prominent risk factors for major depressive disorder (MDD) are childhood maltreatment (CM) and familial risk for MDD. Despite having these risk factors, there are individuals who maintain mental health, i.e. are resilient, whereas others develop MDD. It is unclear which brain morphological alterations are associated with this kind of resilience. Interaction analyses of risk and diagnosis status are needed that can account for complex adaptation processes, to identify neural correlates of resilience. METHODS: We analyzed brain structural data (3T magnetic resonance imaging) by means of voxel-based morphometry (CAT12 toolbox), using a 2 × 2 design, comparing four groups (N = 804) that differed in diagnosis (healthy v. MDD) and risk profiles (low-risk, i.e. absence of CM and familial risk v. high-risk, i.e. presence of both CM and familial risk). Using regions of interest (ROIs) from the literature, we conducted an interaction analysis of risk and diagnosis status. RESULTS: Volume in the left middle frontal gyrus (MFG), part of the dorsolateral prefrontal cortex (DLPFC), was significantly higher in healthy high-risk individuals. There were no significant results for the bilateral superior frontal gyri, frontal poles, pars orbitalis of the inferior frontal gyri, and the right MFG. CONCLUSIONS: The healthy high-risk group had significantly higher volumes in the left DLPFC compared to all other groups. The DLPFC is implicated in cognitive and emotional processes, and higher volume in this area might aid high-risk individuals in adaptive coping in order to maintain mental health. This increased volume might therefore constitute a neural correlate of resilience to MDD in high risk.