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.

Most cognitive studies of bipolar disorder (BD) have examined case–control differences on cognitive tests using measures of central tendency, which do not consider intraindividual variability (IIV); a distinct cognitive construct that reliably indexes meaningful cognitive differences between individuals. In this study, we sought to characterize IIV in BD by examining whether it differs from healthy controls (HCs) and is associated with other cognitive measures, clinical variables, and white matter microstructure.

Two hundred and seventeen adults, including 100 BD outpatients and 117 HCs, completed processing speed, sustained attention, working memory, and executive function tasks. A subsample of 55 BD participants underwent diffusion tensor imaging. IIV was operationalized as the individual standard deviation in reaction time on the Continuous Performance Test-Identical Pairs version.

BD participants had significantly increased IIV compared to age-matched controls. Increased IIV was associated with poorer mean performance scores on processing speed, sustained attention, working memory, and executive function tasks, as well as two whole-brain white matter indices: fractional anisotropy and radial diffusivity.

IIV is increased in BD and appears to correlate with other cognitive variables, as well as white matter measures that index reduced structural integrity and demyelination. Thus, IIV may represent a neurobiologically informative cognitive measure for BD research that is worthy of further investigation.

Childhood trauma (CT) is related to altered fractional anisotropy (FA) in individuals with schizophrenia (SZ). However, it remains unclear whether CT may influence specific cellular or extracellular compartments of FA in SZ with CT experience. We extended our previous study on FA in SZ (Costello et al., 2023) and examined the impact of CT on hypothesized lower free water-corrected FA (FAT) and higher extracellular free water (FW).

Thirty-seven SZ and 129 healthy controls (HC) were grouped into the ‘none/low’ or ‘high’ CT group. All participants underwent diffusion-weighted magnetic resonance imaging. We performed tract-based spatial statistics to study the main effects of diagnostic group and CT, and the interaction between CT and diagnostic group across FAT and FW.

SZ displayed lower FAT within the corpus callosum and corona radiata compared to HC (p < 0.05, Threshold-Free Cluster Enhancement (TFCE)). Independent of diagnosis, we observed lower FAT (p < 0.05, TFCE) and higher FW (p < 0.05, TFCE) in both SZ and HC with high CT levels compared to SZ and HC with none or low CT levels. Furthermore, we did not identify an interaction between CT and diagnostic group (p > 0.05, TFCE).

These novel findings suggest that the impact of CT on lower FAT may reflect cellular rather than extracellular alterations in established schizophrenia. This highlights the impact of CT on white matter microstructure, regardless of diagnostic status.

Increasing numbers of adolescents seek help for gender-identity questions. Consequently, requests for medical treatments, such as puberty suppression, are growing. However, studies investigating the neurobiological substrate of gender incongruence (when birth-assigned sex and gender identity do not align) are scarce, and knowledge about the effects of puberty suppression on the developing brain of transgender youth is limited.

Here we cross-sectionally investigated sex and gender differences in regional fractional anisotropy (FA) as measured by diffusion MR imaging, and the impact of puberty on alterations in the white-matter organization of 35 treatment-naive prepubertal children and 41 adolescents with gender incongruence, receiving puberty suppression. The transgender groups were compared with 79 age-matched, treatment-naive cisgender (when sex and gender align) peers.

We found that transgender adolescents had lower FA in the bilateral inferior fronto-occipital fasciculus (IFOF), forceps major and corpus callosum than cisgender peers. In addition, average FA values of the right IFOF correlated negatively with adolescents' cumulative dosage of puberty suppressants received. Of note, prepubertal children also showed significant FA group differences in, again, the right IFOF and left cortico-spinal tract, but with the reverse pattern (transgender > cisgender) than was seen in adolescents.

Importantly, our results of lower FA (indexing less longitudinal organization, fiber coherence, and myelination) in the IFOF of gender-incongruent adolescents replicate prior findings in transgender adults, suggesting a salient neural correlate of gender incongruence. Findings highlight the complexity with which (pubertal) sex hormones impact white-matter development and add important insight into the neurobiological substrate associated with gender incongruence.

Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22–31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging.

We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal–Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational.

Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex.

In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.

Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported.

Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts.

Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)–left inferior temporal gyrus (ITG), right IFG–left ITG, right IFG–left middle frontal gyrus (MFG), and right IFG–right MFG in the FES group.

Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.

Bipolar disorder (BD) is a severe psychiatric disorder associated with structural and functional brain abnormalities, some of which have been found in unaffected relatives as well. In this study, we examined the potential role of decreased fractional anisotropy (FA) as a BD endophenotype, in adolescents at high risk for BD.

We included 15 offspring of patients with BD, 16 pediatric BD patients, and 16 matched controls. Diffusion weighted scans were obtained on a 3T scanner using an echo-planar sequence. Scans were segmented using FreeSurfer.

Our results showed significantly decreased FA in six brain areas of offspring group; left superior temporal gyrus (LSTG; P < .0001), left transverse temporal gyrus (LTTG; P = .002), left banks of the superior temporal sulcus (LBSTS; P = .002), left anterior cingulum (LAC; P = .003), right temporal pole (RTP; P = .004) and left frontal pole (LFP; P = .017). On analysis, LSTG, LAC, and RTP demonstrated a potential to be an endophenotype when comparing all three groups. FA values in three regions, LBSTS, LTTG, and LFP were increased only in controls.

Our findings point at decreased FA as a possible endophenotype for BD, as they were found in children of patients with BD. Most of these areas were previously found to have morphological and functional changes in adult and pediatric BD, and are thought to play important roles in affected domains of functioning. Prospective follow up studies should be performed to detect reliability of decreased FA as an endophenotype and effects of treatment on FA.

Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non–treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values.

TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB’s Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05.

We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC.

Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.

The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.

There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.

Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.

Fractional anisotropy in the uncinate fasciculus and the cingulum may be biomarkers for bipolar disorder and may even be distinctly affected in different subtypes of bipolar disorder, an area in need of further research.

This study aims to establish if fractional anisotropy in the uncinate fasciculus and cingulum shows differences between healthy controls, patients with bipolar disorder type I (BD-I) and type II (BD-II), and their unaffected siblings.

Fractional anisotropy measures from the uncinate fasciculus, cingulum body and parahippocampal cingulum were compared with tractography methods in 40 healthy controls, 32 patients with BD-I, 34 patients with BD-II, 17 siblings of patients with BD-I and 14 siblings of patients with BD-II.

The main effects were found in both the right and left uncinate fasciculus, with patients with BD-I showing significantly lower fractional anisotropy than both patients with BD-II and healthy controls. Participants with BD-II did not differ from healthy controls. Siblings showed similar effects in the left uncinate fasciculus. In a subsequent complementary analysis, we investigated the association between fractional anisotropy in the uncinate fasciculus and polygenic risk for bipolar disorder and psychosis in a large cohort (n = 570) of healthy participants. However, we found no significant association.

Fractional anisotropy in the uncinate fasciculus differs significantly between patients with BD-I and patients with BD-II and healthy controls. This supports the hypothesis of differences in the physiological sub-tract between bipolar disorder subtypes. Similar results were found in unaffected siblings, suggesting the potential for this biomarker to represent an endophenotype for BD-I. However, fractional anisotropy in the uncinate fasciculus seems unrelated to polygenic risk for bipolar disorder or psychosis.

None.

Two single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia.

Structural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain.

Individuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, padj = 0.01) and left (up to 45%, padj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles.

Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

To investigate the relationship between the severities of symptom dimensions in obsessive-compulsive disorder (OCD) and white matter alterations.

We applied tract-based spatial statistics for diffusion tensor imaging (DTI) acquired by 3T magnetic resonance imaging. First, we compared fractional anisotropy (FA) between 20 OCD patients and 30 healthy controls (HC). Then, applying whole brain analysis, we searched the brain regions showing correlations between the severities of symptom dimensions assessed by Obsessive-Compulsive Inventory-Revised and FA in all participants. Finally, we calculated the correlations between the six symptom dimensions and multiple DTI measures [FA, axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD)] in a region-of-interest (ROI) analysis and explored the differences between OCD patients and HC.

There were no between-group differences in FA or brain region correlations between the severities of symptom dimensions and FA in any of the participants. ROI analysis revealed negative correlations between checking severity and left inferior frontal gyrus white matter and left middle temporal gyrus white matter and a positive correlation between ordering severity and right precuneus in FA in OCD compared with HC. We also found negative correlations between ordering severity and right precuneus in RD, between obsessing severities and right supramarginal gyrus in AD and MD, and between hoarding severity and right insular gyrus in AD.

Our study supported the hypothesis that the severities of respective symptom dimensions are associated with different patterns of white matter alterations.