Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations.

In 410 male and female participants aged 17–35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites.

Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake.

Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood.

We extracted cortical complexity values from structural MRI data of 580 healthy participants using the CAT12 toolbox. Polygenic risk scores (PRS) for schizophrenia, bipolar disorder, major depression, and cross-disorder (incorporating cumulative genetic risk for depression, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder) were computed and used in separate general linear models with cortical complexity as the regressand. In brain regions that showed a significant association between polygenic risk for mental disorders and cortical complexity, volume of interest (VOI)/region of interest (ROI) analyses were conducted to investigate additional changes in their volume and cortical thickness.

The PRS for depression was associated with cortical complexity in the right orbitofrontal cortex (right hemisphere: p = 0.006). A subsequent VOI/ROI analysis showed no association between polygenic risk for depression and either grey matter volume or cortical thickness. We found no associations between cortical complexity and polygenic risk for either schizophrenia, bipolar disorder or psychiatric cross-disorder when correcting for multiple testing.

Changes in cortical complexity associated with polygenic risk for depression might facilitate well-established volume changes in orbitofrontal cortices in depression. Despite the absence of psychopathology, changed cortical complexity that parallels polygenic risk for depression might also change reward systems, which are also structurally affected in patients with depressive syndrome.

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.

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.

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.

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.

Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood.

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.

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.

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).

Subclinical psychotic-like experiences (PLE), resembling key symptoms of psychotic disorders, are common throughout the general population and possibly associated with psychosis risk. There is evidence that such symptoms are also associated with structural brain changes.

In 672 healthy individuals, we assessed PLE and associated distress with the symptom-checklist-90R (SCL-90R) scales ‘schizotypal signs’ (STS) and ‘schizophrenia nuclear symptoms’ (SNS) and analysed associations with voxel- and surfaced-based brain structural parameters derived from structural magnetic resonance imaging at 3 T with CAT12.

For SNS, we found a positive correlation with the volume in the left superior parietal lobule and the precuneus, and a negative correlation with the volume in the right inferior temporal gyrus [p < 0.05 cluster-level Family Wise Error (FWE-corrected]. For STS, we found a negative correlation with the volume of the left and right precentral gyrus (p < 0.05 cluster-level FWE-corrected). Surface-based analyses did not detect any significant clusters with the chosen statistical threshold of p < 0.05. However, in exploratory analyses (p < 0.001, uncorrected), we found a positive correlation of SNS with gyrification in the left insula and rostral middle frontal gyrus and of STS with the left precuneus and insula, as well as a negative correlation of STS with gyrification in the left temporal pole.

Our results show that brain structures in areas implicated in schizophrenia are also related to PLE and its associated distress in healthy individuals. This pattern supports a dimensional model of the neural correlates of symptoms of the psychotic spectrum.

Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.

Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.

CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.

Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

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.

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.

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.

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.