Lejla Colic

Bipolar disorder (BD) is a prevalent psychiatric condition characterized by marked clinical and neuroanatomical heterogeneity. Prior neuroimaging studies have used case-control comparisons yielding small to moderate effect sizes for group differences. Large and diverse samples are needed to map heterogeneity within BD. Here, we used individualized brain morphometry deviations derived from normative modeling for three MRI-based measures (regional cortical thickness, regional surface area, and subcortical volumes). We applied this approach to a large international sample of 4 660 individuals (1 145 with bipolar I disorder and 3 515 healthy controls) from the ENIGMA Bipolar Disorder Working Group consortium (age range = 8–80, female = 53.15%) and examined the distribution of deviations within the bipolar disorder group, differences between healthy controls and individuals with bipolar disorder, and associations between neuroanatomical deviations and clinical variables. We found that individuals with bipolar disorder showed a higher proportion of localized extreme deviations, notably negative cortical thickness deviations in regions consistently reported as thinner in prior studies (the left superior frontal gyrus, bilateral inferior frontal gyrus (pars opercularis), left precuneus) and subcortical volume negative deviations in the left hippocampus. In addition, ROI-level deviations in the left middle temporal gyrus and the left inferior temporal gyrus were associated with longer illness duration. This is the largest study to date exploring individualized deviations as neuroanatomical features associated with bipolar disorder. Our findings suggest that neuroanatomical heterogeneity is a core feature of bipolar disorder, with preferential left-lateralized cortical-hippocampal involvement pointing to spatially structured heterogeneity.

Background: Depressive symptoms cut across bipolar disorder (BD) and major depressive disorder (MDD), yet the extent to which the neurobiology of depressive severity is shared or diagnosis-specific is not well established. Progress is limited because multisite studies pool data from different depression rating scales, obscuring symptom-brain relationships. We used item response theory (IRT), which places these instruments on a single metric, to harmonise depressive symptom severity across five rating scales, and to identify shared and disorder-specific brain correlates of depression across BD and MDD.Methods: This cross-sectional mega-analysis of individual participant data from 52 international ENIGMA MDD and BD Working Group sites studied 11 999 individuals (6,789 healthy controls, 3,307 with BD, 1,903 with MDD) who had completed a depression measure and undergone T1-weighted MRI. We derived general and five symptom-specific IRT scores harmonised across five instruments (HDRS, MADRS, BDI-II, IDS, CES-D), and related them to cortical thickness, surface area, and subcortical volume, adjusting for age, sex, and global brain measures.Findings: Harmonising symptom scores strengthened brain-symptom associations beyond unharmonised total scores. Higher general depression severity was linked to lower cortical thickness, which strengthened after accounting for BD-MDD item-level differences. The disorders diverged: depressive severity was more tightly linked to subcortical structure, especially the hippocampus and thalamus, in MDD than BD, while BD showed lower cortical thickness across a wider cortical extent and more heterogeneous structural variability. Symptom dimensions diverged too: mood/motivational symptoms tracked cortical thickness in both disorders, while anxiety, cognitive-affective, and suicidal-ideation symptoms showed more disorder-specific subcortical and surface-area patterns.Interpretation: IRT harmonisation identified overlapping and disorder-specific associations between depressive severity and brain structure in BD and MDD, highlighting shared neurobiological features while demonstrating meaningful differences between disorders and supporting global efforts to integrate dimensional symptom measures across large-scale, multiscale studies.Funding: This work was supported by the US National Institute of Mental Health (R0I MH129742), including subaward SCON-00003343 awarded to Colm McDonald and Dara Cannon.

Background: Older adults with bipolar disorder ( BD ) are at high risk for severe mood symptoms, cognitive difficulties, and early mortality; however, underlying brain alterations have received little study. Gray matter decreases in ventral prefrontal cortex ( VPFC ) seen in younger persons with BD , and additionally in dorsal PFC ( DPFC ), are implicated. Here, cortical thickness was examined in an international sample. Methods: Cortical thickness in 34 regions was measured from structural magnetic resonance imaging data using enhancing neuroImaging genetics through meta‐analysis pipelines for individuals with BD ( n = 308) and non‐psychiatric comparison participants ( n = 287), ages 40–70y, from six Global Aging and Geriatric Experiments in BD ( GAGE ‐ BD ) consortium sites. Group differences were assessed for VPFC , DPFC and remaining cortical regions, covarying for scanner, age and sex. Results were considered significant corrected for false discovery fate ( FDR ) at p _FDR < 0.05. Relationships with demographic and clinical factors were explored. Results: Cortical thickness was significantly lower among BD in VPFC and DPFC , and additional distributed regions ( p _FDR < 0.05) and negatively associated with age ( p < 0.05); group and age did not interact significantly. Relationships with BD subtype and medications were observed; lithium was associated with higher frontal pole and anterior cingulate thickness ( p _FDR < 0.05). Conclusions: In this international middle and older aged adult BD sample, lower VPFC cortical thickness was observed, suggesting these deficits persist from younger age. DPFC and additional regions of reduced cortical thickness could contribute to the older adult BD phenotype. Cortical thinning was more pronounced among older individuals regardless of diagnosis. Lithium may lessen cortical thinning.

Background: Childhood adversity (CA) is recognized as a distal risk-factor for suicide attempts (SA) in individuals with psychiatric disorders. However, not all individuals with experiences of CA will engage in SA. Contributing to this relationship may be proximal factors such as impulsivity, inward anger and self-aggression. However, these factors are often conceptually blended and measured in different samples. We sought to clarify association among CA and personality factors in persons with SA. Methods: Participants from two studies comprised individuals with a diagnosed psychiatric disorder and history of SA (n= 139) and individuals with depressive disorder (clinical controls, CC; n= 24). We investigated self-reported levels of CA, impulsivity, inward anger, and self-aggression between the SA and CC (p _corr < .012). We tested the relationship among the factors using regression (p _corr <.017) and mediation model (indirect effects, p<.05) within the SA group. Sensitivity models were run controlling for age, gender, symptom severity, trait anger, and externally oriented aggression. Results: SA group had higher impulsivity (p _corr =.067) in a model controlled for age and gender. Other factors did not differ among groups. Within the SA group the analyses revealed positive association among CA and personality factors (p _corr ’s<.06) in basic and model with age and gender, however the association was not specific for internally (self) oriented factors (coefficient comparison, p<.07). Parallel mediation model indicated that CA had indirect effect on self-aggression through impulsivity (p=.001) and to a lesser extent through inward anger (p=.066). Generally, models controlling for cognitive depression symptoms showed less prominent effects (p _corr >.1). Limitations: The study was cross-sectional and did not include behavioral tasks (state) measures of proximal factors. Conclusions: CA and personality factors showed similar severity levels among the SA and CC groups suggesting they may relate to broader psychopathologies, rather than specifically to SA. The association of CA with anger and aggression was unspecific to internally oriented factors indicating the need for more precise measuring instruments developed specifically for individuals with SA. Overall, the study highlights personality factors as being associated with risk in broader vulnerable populations.

Chronic psychosocial stress (CPS) is associated with adverse brain and mental health outcomes. Effects on the cerebral microvasculature have been proposed as an underlying mechanism, although this remains to be established. Here, we examined the association between CPS and an early marker of microvascular dysfunction, magnetic resonance imaging (MRI)-visible perivascular spaces (PVS). Analyses were conducted in two cohorts of healthy young adults (N = 61; ages 18-43 years; 88% male) using high-resolution 3T MRI and an automated PVS quantification pipeline. CPS was assessed using the Perceived Stress Scale (PSS-10). We applied a two-step meta-analytic framework and controlled for known allostatic factors impacting PVS, including age, body mass index and mean arterial pressure. In accordance with our hypothesis, individuals with higher CPS had significantly higher fractional PVS volumes in the centrum semiovale (CSO), in particular in the frontal and occipital lobes (p _FDR < .05). No such effect was found in the basal ganglia, or in the CSO subdivision, parietal, and temporal lobes (p _FDR > .09). Our findings indicate that CPS may contribute to subtle, centrum semiovale specific microvascular alterations even in healthy young adults. Future multimodal research including inflammatory marker and blood-brain barrier measures may help to elucidate mechanistic pathways.

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt ( n = 652; mean age = 35.4 ± 14.7; female = 71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n = 1871; mean age = 34 ± 14.8; female = 59.8%), and individuals with no psychiatric diagnosis and no STB (i.e., healthy controls; n = 642; mean age = 29.6 ± 13.1; female = 62.9%). We also compared these measures among individuals with recent suicidal ideation ( n = 714; mean age = 36.3 ± 15.3; female = 66.1%), clinical controls ( n = 1184; mean age = 36.8 ± 15.6; female = 63.1%), and healthy controls ( n = 1240; mean age = 31.6 ± 15.5; female = 61.0%). We found subtle but statistically significant effects, such as lower FA associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Recent suicidal ideation was associated with higher AD in the cingulum. Effect sizes were small (partial eta-squared < 0.015). This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt and recent suicidal ideation. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour or ideation.

Gonadal hormone receptors are widely distributed across the brain, yet their influence on brain structure remains understudied. Here, using precision imaging, we examined four females, including one with endometriosis and one using oral contraceptives (OC), across a monthly period. Whole-brain analyses revealed spatiotemporal patterns of brain volume changes, with substantial variations across the monthly period. In typical cycles, spatiotemporal patterns were associated with serum progesterone levels, while in cycles with endometriosis and during OC intake, patterns were associated with serum estradiol levels. The volume changes were widely distributed rather than region-specific, suggesting a widespread but coordinated influence of hormonal fluctuations. These findings underscore the importance of considering diverse hormonal milieus beyond typical menstrual cycles in understanding structural brain dynamics and suggest that hormonal rhythms may drive widespread structural brain changes.