There is a considerable overlap in clinical features and genetics between schizophrenia (SZ) and bipolar disorder (BD). Previous neuroimaging research has demonstrated common and distinct brain damage patterns between relatives (RELs) of SZ and BD patients, suggesting shared and differential genetic influences on the brain. Despite an increasing recognition that disorders localize better to distributed brain networks than individual brain regions, studies investigating network localization of genetic risk for SZ and BD are still lacking.

To address this gap, we initially identified brain functional and structural damage locations in SZ- and BD-RELs from 103 published studies with 2364 SZ-RELs, 864 BD-RELs, and 4114 healthy controls. By applying novel functional connectivity network mapping to large-scale discovery and validation resting-state functional MRI datasets, we mapped these affected brain locations to four disorder-susceptibility networks.

SZ-susceptibility functional damage network primarily involved the executive control and salience networks, while its BD-counterpart principally implicated the default mode and basal ganglia networks. SZ-susceptibility structural damage network predominantly involved the auditory and default mode networks, yet its BD-counterpart mainly implicated the language and executive control networks. Although these networks showed cross-disorder inconsistencies when focusing on either imaging modality alone, the combined SZ- and BD-susceptibility brain damage networks had a substantially increased spatial similarity.

These findings may support the concept that SZ and BD represent distinct diagnostic categories from a neurobiological perspective, helping to clarify the common network substrates via which the shared genetic mechanisms underlying both disorders give rise to their overlapping clinical phenotypes.

Although perceived threats in a child’s social environment, including in the family, school, and neighborhood, are known to increase risk for adolescent psychopathology, the underlying biological mechanisms remain unclear. To investigate, we examined whether perceived social threats were associated with the functional connectivity of large-scale cortical networks in early adolescence, and whether such connectivity differences mediated the development of subsequent mental health problems in youth.

Structural equation models were used to analyze data from 8,690 youth (50% female, 45% non-White, age 9–10 years) drawn from the large-scale, nationwide Adolescent Brain Cognitive Development study that has 21 clinical and research sites across the United States. Data were collected from 2016 to 2018.

Consistent with Social Safety Theory, perceived social threats were prospectively associated with mental health problems both 6 months (standardized $ \beta =0.27,p<.001 $) and 30 months ($ \beta =0.14,p<.001 $) later. Perceived social threats predicted altered connectivity patterns within and between the default mode (DMN), dorsal attention (DAN), frontoparietal (FPN), and cingulo-opercular (CON) networks. In turn, hypoconnectivity within the DMN and FPN – and higher (i.e., less negative) connectivity between DMN-DAN, DMN-CON, and FPN-CON – mediated the association between perceived social threats and subsequent mental health problems.

Perceiving social threats in various environments may alter neural connectivity and increase the risk of psychopathology in youth. Therefore, parenting, educational, and community-based interventions that bolster social safety may be helpful.

Developmental trauma increases psychosis risk in adulthood and is associated with poor prognosis and treatment response. It has been proposed that developmental trauma may give rise to a distinct psychosis phenotype. Our aim was to explore this by systematically reviewing neuroimaging studies of brain structure and function in adults with psychosis diagnoses, according to whether or not they had survived developmental trauma. We registered our search protocol in PROSPERO (CRD42018105021).

We systematically searched literature databases for relevant studies published before May 2024. We identified 31 imaging studies (n = 1,761 psychosis patients, n = 1,775 healthy controls or healthy siblings).

Developmental trauma was associated with global and regional differences in gray matter; corticolimbic structural dysconnectivity; a potentiated threat detection system; dysfunction in regions associated with mentalization; and elevated striatal dopamine synthesis capacity.

These findings warrant further research to elucidate vulnerability and resilience mechanisms for psychosis in developmental trauma survivors.

Identifying key areas of brain dysfunction in mental illness is critical for developing precision diagnosis and treatment. This study aimed to develop region-specific brain aging trajectory prediction models using multimodal magnetic resonance imaging (MRI) to identify similarities and differences in abnormal aging between bipolar disorder (BD) and major depressive disorder (MDD) and pinpoint key brain regions of structural and functional change specific to each disorder.

Neuroimaging data from 340 healthy controls, 110 BD participants, and 68 MDD participants were included from the Taiwan Aging and Mental Illness cohort. We constructed 228 models using T1-weighted MRI, resting-state functional MRI, and diffusion tensor imaging data. Gaussian process regression was used to train models for estimating brain aging trajectories using structural and functional maps across various brain regions.

Our models demonstrated robust performance, revealing accelerated aging in 66 gray matter regions in BD and 67 in MDD, with 13 regions common to both disorders. The BD group showed accelerated aging in 17 regions on functional maps, whereas no such regions were found in MDD. Fractional anisotropy analysis identified 43 aging white matter tracts in BD and 39 in MDD, with 16 tracts common to both disorders. Importantly, there were also unique brain regions with accelerated aging specific to each disorder.

These findings highlight the potential of brain aging trajectories as biomarkers for BD and MDD, offering insights into distinct and overlapping neuroanatomical changes. Incorporating region-specific changes in brain structure and function over time could enhance the understanding and treatment of mental illness.

Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).

This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.

T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).

PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).

PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.

Stress leads to neurobiological changes, and failure to regulate these can contribute to chronic psychiatric issues. Despite considerable research, the relationship between neural alterations in acute stress and coping with chronic stress is unclear. This longitudinal study examined whole-brain network dynamics following induced acute stress and their role in predicting chronic stress vulnerability.

Sixty military pre-deployment soldiers underwent a lab-induced stress task where subjective stress and resting-state functional magnetic resonance imaging were acquired repeatedly (before stress, after stress, and at recovery, 90 min later). Baseline depression and post-traumatic stress symptoms were assessed, and again a year later during military deployment. We used the Leading Eigenvector Dynamic Analysis framework to characterize changes in whole-brain dynamics over time. Time spent in each state was compared across acute stress conditions and correlated with psychological outcomes.

Findings reveal significant changes at the network level from acute stress to recovery, where the frontoparietal and subcortical states decreased in dominance in favor of the default mode network, sensorimotor, and visual states. A significant normalization of the frontoparietal state activity was related to successful psychological recovery. Immediately after induced stress, a significant increase in the lifetimes of the frontoparietal state was associated with higher depression symptoms (r = 0.49, p < .02) and this association was also observed a year later following combat exposure (r = 0.49, p < .009).

This study revealed how acute stress-related neural alterations predict chronic stress vulnerability. Successful recovery from acute stress involves reducing cognitive–emotional states and enhancing self-awareness and sensory–perceptual states. Elevated frontoparietal activity is suggested as a neural marker of vulnerability to chronic stress.

Predicting long-term outcome trajectories in psychosis remains a crucial and challenging goal in clinical practice. The identification of reliable neuroimaging markers has often been hindered by the clinical and biological heterogeneity of psychotic disorders and the limitations of traditional case-control methodologies, which often mask individual variability. Recently, normative brain charts derived from extensive magnetic resonance imaging (MRI) data-sets covering the human lifespan have emerged as a promising biologically driven solution, offering a more individualised approach.

To examine how deviations from normative cortical and subcortical grey matter volume (GMV) at first-episode psychosis (FEP) onset relate to symptom and functional trajectories.

We leveraged the largest available brain normative model (N > 100 000) to explore normative deviations in a sample of over 240 patients with schizophrenia spectrum disorders who underwent MRI scans at the onset of FEP and received clinical follow-up at 1, 3 and 10 years.

Our findings reveal that deviations in regional normative GMV at FEP onset are significantly linked to overall long-term clinical trajectories, modulating the effect of time on both symptom and functional outcome. Specifically, negative deviations in the left superior temporal gyrus and Broca’s area at FEP onset were notably associated with a more severe progression of positive and negative symptoms, as well as with functioning trajectories over time.

These results underscore the potential of brain developmental normative approaches for the early prediction of disorder progression, and provide valuable insights for the development of preventive and personalised therapeutic strategies.

The brain’s default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. However, the genetic basis linking sociability with DMN function remains underexplored. This study aimed to elucidate the shared genetics and causal relationship between sociability and DMN-related resting-state functional MRI (rs-fMRI) traits.

We conducted a comprehensive genomic analysis using large-scale genome-wide association study (GWAS) summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N = 34,691–342,461). We performed global and local genetic correlations analyses and bi-directional Mendelian randomization (MR) to assess shared and causal effects. We prioritized genes influencing both sociability and rs-fMRI traits by combining expression quantitative trait loci MR analyses, the CELLECT framework – integrating single-nucleus RNA sequencing (snRNA-seq) data with GWAS – and network propagation within a protein–protein interaction network.

Significant local genetic correlations were identified between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the cingulate and angular/temporal cortices. MR analyses suggested potential causal effects of sociability on 12 rs-fMRI traits. Seventeen genes were highly prioritized, with LINGO1, ELAVL2, and CTNND1 emerging as top candidates. Among these, DRD2 was also identified, serving as a robust internal validation of our approach.

By combining genomic and transcriptomic data, our gene prioritization strategy may serve as a blueprint for future studies. Our findings can guide further research into the biological mechanisms underlying sociability and its role in the development, prognosis, and treatment of neuropsychiatric disorders.