Epigenetic changes are plausible molecular sources of clinical heterogeneity in schizophrenia. A subgroup of schizophrenia patients with elevated inflammatory or immune-dysregulation has been reported by previous studies. However, little is known about epigenetic changes in genes related to immune activation in never-treated first-episode patients with schizophrenia (FES) and its consistency with that in treated long-term ill (LTS) patients.

In this study, epigenome-wide profiling with a DNA methylation array was applied using blood samples of both FES and LTS patients, as well as their corresponding healthy controls. Non-negative matrix factorization (NMF) and k -means clustering were performed to parse heterogeneity of schizophrenia, and the consistency of subtyping results from two cohorts. was tested.

This study identified a subtype of patients in FES participants (47.5%) that exhibited widespread methylation level alterations of genes enriched in immune cell activity and a significantly higher proportion of neutrophils. This clustering of FES patients was validated in LTS patients, with high correspondence in epigenetic and clinical features across two cohorts

In summary, this study demonstrated a subtype of schizophrenia patients across both FES and LTS cohorts, defined by widespread alterations in methylation profile of genes related to immune function and distinguishing clinical features. This finding illustrates the promise of novel treatment strategies targeting immune dysregulation for a subpopulation of schizophrenia patients.

Alterations in brain functional connectivity (FC) have been frequently reported in adolescent major depressive disorder (MDD). However, there are few studies of dynamic FC analysis, which can provide information about fluctuations in neural activity related to cognition and behavior. The goal of the present study was therefore to investigate the dynamic aspects of FC in adolescent MDD patients.

Resting-state functional magnetic resonance imaging data were acquired from 94 adolescents with MDD and 78 healthy controls. Independent component analysis, a sliding-window approach, and graph-theory methods were used to investigate the potential differences in dynamic FC properties between the adolescent MDD patients and controls.

Three main FC states were identified, State 1 which was predominant, and State 2 and State 3 which occurred less frequently. Adolescent MDD patients spent significantly more time in the weakly-connected and relatively highly-modularized State 1, spent significantly less time in the strongly-connected and low-modularized State 2, and had significantly higher variability of both global and local efficiency, compared to the controls. Classification of patients with adolescent MDD was most readily performed based on State 1 which exhibited disrupted intra- and inter-network FC involving multiple functional networks.

Our study suggests local segregation and global integration impairments and segregation-integration imbalance of functional networks in adolescent MDD patients from the perspectives of dynamic FC. These findings may provide new insights into the neurobiology of adolescent MDD.

The neuroanatomical alteration in bipolar II depression (BDII-D) and its associations with inflammation, childhood adversity, and psychiatric symptoms are currently unclear. We hypothesize that neuroanatomical deficits will be related to higher inflammation, greater childhood adversity, and worse psychiatric symptoms in BDII-D.

Voxel- and surface-based morphometry was performed using the CAT toolbox in 150 BDII-D patients and 155 healthy controls (HCs). Partial Pearson correlations followed by multiple comparison correction was used to indicate significant relationships between neuroanatomy and inflammation, childhood adversity, and psychiatric symptoms.

Compared with HCs, the BDII-D group demonstrated significantly smaller gray matter volumes (GMVs) in frontostriatal and fronto-cerebellar area, insula, rectus, and temporal gyrus, while significantly thinner cortices were found in frontal and temporal areas. In BDII-D, smaller GMV in the right middle frontal gyrus (MFG) was correlated with greater sexual abuse (r = −0.348, q < 0.001) while larger GMV in the right orbital MFG was correlated with greater physical neglect (r = 0.254, q = 0.03). Higher WBC count (r = −0.227, q = 0.015) and IL-6 levels (r = −0.266, q = 0.015) was associated with smaller GMVs in fronto-cerebellar area in BDII-D. Greater positive symptoms was correlated with larger GMVs of the left middle temporal pole (r = 0.245, q = 0.03).

Neuroanatomical alterations in frontostriatal and fronto-cerebellar area, insula, rectus, temporal gyrus volumes, and frontal-temporal thickness may reflect a core pathophysiological mechanism of BDII-D, which are related to inflammation, trauma, and psychiatric symptoms in BDII-D.

Attention-deficit/hyperactivity disorder (ADHD) is a clinically heterogeneous neurodevelopmental disorder defined by characteristic behavioral and cognitive features. Abnormal brain dynamic functional connectivity (dFC) has been associated with the disorder. The full spectrum of ADHD-related variation of brain dynamics and its association with behavioral and cognitive features remain to be established.

We sought to identify patterns of brain dynamics linked to specific behavioral and cognitive dimensions using sparse canonical correlation analysis across a cohort of children with and without ADHD (122 children in total, 63 with ADHD). Then, using mediation analysis, we tested the hypothesis that cognitive deficits mediate the relationship between brain dynamics and ADHD-associated behaviors.

We identified four distinct patterns of dFC, each corresponding to a specific dimension of behavioral or cognitive function (r = 0.811–0.879). Specifically, the inattention/hyperactivity dimension was positively associated with dFC within the default mode network (DMN) and negatively associated with dFC between DMN and the sensorimotor network (SMN); the somatization dimension was positively associated with dFC within DMN and SMN; the inhibition and flexibility dimension and fluency and memory dimensions were both positively associated with dFC within DMN and between DMN and SMN, and negatively associated with dFC between DMN and the fronto-parietal network. Furthermore, we observed that cognitive functions of inhibition and flexibility mediated the relationship between brain dynamics and behavioral manifestations of inattention and hyperactivity.

These findings document the importance of distinct patterns of dynamic functional brain activity for different cardinal behavioral and cognitive features related to ADHD.

Although aberrant brain regional responses are reported in social anxiety disorder (SAD), little is known about resting-state functional connectivity at the macroscale network level. This study aims to identify functional network abnormalities using a multivariate data-driven method in a relatively large and homogenous sample of SAD patients, and assess their potential diagnostic value.

Forty-six SAD patients and 52 demographically-matched healthy controls (HC) were recruited to undergo clinical evaluation and resting-state functional MRI scanning. We used group independent component analysis to characterize the functional architecture of brain resting-state networks (RSNs) and investigate between-group differences in intra-/inter-network functional network connectivity (FNC). Furtherly, we explored the associations of FNC abnormalities with clinical characteristics, and assessed their ability to discriminate SAD from HC using support vector machine analyses.

SAD patients showed widespread intra-network FNC abnormalities in the default mode network, the subcortical network and the perceptual system (i.e. sensorimotor, auditory and visual networks), and large-scale inter-network FNC abnormalities among those high-order and primary RSNs. Some aberrant FNC signatures were correlated to disease severity and duration, suggesting pathophysiological relevance. Furthermore, intrinsic FNC anomalies allowed individual classification of SAD v. HC with significant accuracy, indicating potential diagnostic efficacy.

SAD patients show distinct patterns of functional synchronization abnormalities both within and across large-scale RSNs, reflecting or causing a network imbalance of bottom-up response and top-down regulation in cognitive, emotional and sensory domains. Therefore, this could offer insights into the neurofunctional substrates of SAD.

Persistent psychological distress associated with the coronavirus disease 2019 (COVID-19) pandemic has been well documented. This study aimed to identify pre-COVID brain functional connectome that predicts pandemic-related distress symptoms among young adults.

Baseline neuroimaging studies and assessment of general distress using the Depression, Anxiety and Stress Scale were performed with 100 healthy individuals prior to wide recognition of the health risks associated with the emergence of COVID-19. They were recontacted for the Impact of Event Scale-Revised and the Posttraumatic Stress Disorder Checklist in the period of community-level outbreaks, and for follow-up distress evaluation again 1 year later. We employed the network-based statistic approach to identify connectome that predicted the increase of distress based on 136-region-parcellation with assigned network membership. Predictive performance of connectome features and causal relations were examined by cross-validation and mediation analyses.

The connectome features that predicted emergence of distress after COVID contained 70 neural connections. Most within-network connections were located in the default mode network (DMN), and affective network-DMN and dorsal attention network-DMN links largely constituted between-network pairs. The hippocampus emerged as the most critical hub region. Predictive models of the connectome remained robust in cross-validation. Mediation analyses demonstrated that COVID-related posttraumatic stress partially explained the correlation of connectome to the development of general distress.

Brain functional connectome may fingerprint individuals with vulnerability to psychological distress associated with the COVID pandemic. Individuals with brain neuromarkers may benefit from the corresponding interventions to reduce the risk or severity of distress related to fear of COVID-related challenges.

Identification of treatment-specific predictors of drug therapies for bipolar disorder (BD) is important because only about half of individuals respond to any specific medication. However, medication response in pediatric BD is variable and not well predicted by clinical characteristics.

A total of 121 youth with early course BD (acute manic/mixed episode) were prospectively recruited and randomized to 6 weeks of double-blind treatment with quetiapine (n = 71) or lithium (n = 50). Participants completed structural magnetic resonance imaging (MRI) at baseline before treatment and 1 week after treatment initiation, and brain morphometric features were extracted for each individual based on MRI scans. Positive antimanic treatment response at week 6 was defined as an over 50% reduction of Young Mania Rating Scale scores from baseline. Two-stage deep learning prediction model was established to distinguish responders and non-responders based on different feature sets.

Pre-treatment morphometry and morphometric changes occurring during the first week can both independently predict treatment outcome of quetiapine and lithium with balanced accuracy over 75% (all p < 0.05). Combining brain morphometry at baseline and week 1 allows prediction with the highest balanced accuracy (quetiapine: 83.2% and lithium: 83.5%). Predictions in the quetiapine and lithium group were found to be driven by different morphometric patterns.

These findings demonstrate that pre-treatment morphometric measures and acute brain morphometric changes can serve as medication response predictors in pediatric BD. Brain morphometric features may provide promising biomarkers for developing biologically-informed treatment outcome prediction and patient stratification tools for BD treatment development.

Major depressive disorder (MDD) is a clinically and biologically heterogeneous syndrome. Identifying discrete subtypes of illness with distinguishing neurobiological substrates and clinical features is a promising strategy for guiding personalised therapeutics.

This study aimed to identify depression subtypes with correlated patterns of functional network connectivity and clinical symptoms by clustering patients according to a weighted linear combination of both features in a relatively large, medication-naïve depression sample.

We recruited 115 medication-naïve adults with MDD and 129 matched healthy controls, and evaluated all participants with magnetic resonance imaging. We used regularised canonical correlation analysis to identify component mapping relationships between functional network connectivity and symptom profiles, and K-means clustering was used to define distinct subtypes of patients.

Two subtypes of MDD were identified: insomnia-dominated subtype 1 and anhedonia-dominated subtype 2. Subtype 1 was characterised by abnormal hyperconnectivity within the ventral attention network and sleep maintenance insomnia. Subtype 2 was characterised by abnormal hypoconnectivity in the subcortical and dorsal attention networks, and prominent anhedonia symptoms.

Our study identified two distinct subtypes of patients with specific neurobiological and clinical symptom profiles. These findings advance understanding of the biological and clinical heterogeneity of MDD, offering a pathway for defining categorical subtypes of illness via consideration of both biological and clinical features.

There is increasing evidence that blood oxygenation level-dependent signaling in white matter (WM) reflects WM functional activity. Whether this activity is altered in schizophrenia remains uncertain, as does whether it is related to established alterations of gray matter (GM) or the microstructure of WM tracts.

A total of 153 antipsychotic-naïve schizophrenia patients and 153 healthy comparison subjects were assessed by resting-state functional magnetic resonance imaging, diffusion tensor imaging, and high-resolution T1-weighted imaging. We tested for case–control differences in the functional activity of WM, and examined their relation to the functional activity of GM and WM microstructure. The relations between fractional anisotropy (FA) in WM and GM–WM functional synchrony were investigated as well. Then, we examined the associations of identified abnormalities to age, duration of untreated psychosis (DUP), and symptom severity.

Schizophrenia patients displayed reductions of the amplitude of low-frequency fluctuations (ALFF), GM–WM functional synchrony, and FA in widespread regions. Specifically, the genu of corpus callosum not only had weakening in the synchrony of functional activity but also had reduced ALFF and FA. Positive associations were found between FA and functional synchrony in the genu of corpus callosum as well. No significant association was found between identified abnormalities and DUP, and symptom severity.

The widespread weakening in the synchrony of functional activity of GM and WM provided novel evidence for functional alterations in schizophrenia. Regarding the WM function as a component of brain systems and investigating its alternation represent a promising direction for future research.

Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples.

Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons.

FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms.

This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient.

Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology.

Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions.

These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the ‘dysconnectivity hypothesis’ of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.