Voxel-based texture similarity networks reveal individual variability and correlate with biological ontologies.

The human brain is organized as a complex, hierarchical network. However, the structural covariance patterns among brain regions and the underlying biological substrates of such covariance networks remain to be clarified. The present study proposed a novel individualized structural covariance network termed voxel-based texture similarity networks (vTSNs) based on 76 refined voxel-based textural features derived from structural magnetic resonance images. Validated in three independent longitudinal healthy cohorts (40, 23, and 60 healthy participants, respectively) with two common brain atlases, we found that the vTSN could robustly resolve inter-subject variability with high test-retest reliability. In contrast to the regional-based texture similarity networks (rTSNs) that calculate radiomic features based on region-of-interest information, vTSNs had higher inter- and intra-subject variability ratios and test-retest reliability in connectivity strength and network topological properties. Moreover, the Spearman correlation indicated a stronger association of the gene expression similarity network (GESN) with vTSNs than with rTSNs (vTSN: r = 0.600, rTSN: r = 0.433, z = 39.784, P < 0.001). Hierarchical clustering identified 3 vTSN subnets with differential association patterns with 13 coexpression modules, 16 neurotransmitters, 7 electrophysiology, 4 metabolism, and 2 large-scale structural and 4 functional organization maps. Moreover, these subnets had unique biological hierarchical organization from the subcortex-limbic system to the ventral neocortex and then to the dorsal neocortex. Based on 424 unrelated, qualified healthy subjects from the Human Connectome Project, we found that vTSNs could sensitively represent sex differences, especially for connections in the subcortex-limbic system and between the subcortex-limbic system and the ventral neocortex. Moreover, a multivariate variance component model revealed that vTSNs could explain a significant proportion of inter-subject behavioral variance in cognition (80.0 %) and motor functions (63.4 %). Finally, using 494 healthy adults (aged 19-80 years old) from the Southwest University Adult Lifespan Dataset, the Spearman correlation identified a significant association between aging and vTSN strength, especially within the subcortex-limbic system and between the subcortex-limbic system and the dorsal neocortex. In summary, our proposed vTSN is robust in uncovering individual variability and neurobiological brain processes, which can serve as biologically plausible measures for linking biological processes and human behavior.

Covariation of preadult environmental exposures, adult brain imaging phenotypes, and adult personality traits.

Exposure to preadult environmental exposures may have long-lasting effects on mental health by affecting the maturation of the brain and personality, two traits that interact throughout the developmental process. However, environment-brain-personality covariation patterns and their mediation relationships remain unclear. In 4297 healthy participants (aged 18-30 years), we combined sparse multiple canonical correlation analysis with independent component analysis to identify the three-way covariation patterns of 59 preadult environmental exposures, 760 adult brain imaging phenotypes, and five personality traits, and found two robust environment-brain-personality covariation models with sex specificity. One model linked greater stress and less support to weaker functional connectivity and activity in the default mode network, stronger activity in subcortical nuclei, greater thickness and volume in the occipital, parietal and temporal cortices, and lower agreeableness, consciousness and extraversion as well as higher neuroticism. The other model linked higher urbanicity and better socioeconomic status to stronger functional connectivity and activity in the sensorimotor network, smaller volume and surface area and weaker functional connectivity and activity in the medial prefrontal cortex, lower white matter integrity, and higher openness to experience. We also conducted mediation analyses to explore the potential bidirectional mediation relationships between adult brain imaging phenotypes and personality traits with the influence of preadult environmental exposures and found both environment-brain-personality and environment-personality-brain pathways. We finally performed moderated mediation analyses to test the potential interactions between macro- and microenvironmental exposures and found that one category of exposure moderated the mediation pathways of another category of exposure. These results improve our understanding of the effects of preadult environmental exposures on the adult brain and personality traits and may facilitate the design of targeted interventions to improve mental health by reducing the impact of adverse environmental exposures.

Local dynamic spontaneous brain activity changes in first-episode, treatment-naïve patients with major depressive disorder and their associated gene expression profiles.

BACKGROUND: Major depressive disorder (MDD) is a common debilitating disorder characterized by impaired spontaneous brain activity, yet little is known about its alterations in dynamic properties and the molecular mechanisms associated with these changes. METHODS: Based on the resting-state functional MRI data of 65 first-episode, treatment-naïve patients with MDD and 66 healthy controls, we compared dynamic regional homogeneity (dReHo) of spontaneous brain activity between the two groups, and we investigated gene expression profiles associated with dReHo alterations in MDD by leveraging transcriptional data from the Allen Human Brain Atlas and weighted gene co-expression network analysis. RESULTS: Compared with healthy controls, patients with MDD consistently showed reduced dReHo in both fusiform gyri and in the right temporal pole and hippocampus. The expression profiles of 16 gene modules were correlated with dReHo alterations in MDD. These gene modules were enriched for various biological process terms, including immune, synaptic signalling, ion channels, mitochondrial function and protein metabolism, and were preferentially expressed in different cell types. CONCLUSIONS: Patients with MDD have reduced dReHo in brain areas associated with emotional and cognitive regulation, and these changes may be related to complex polygenetic and polypathway mechanisms.

Genes associated with gray matter volume alterations in schizophrenia.

Although both schizophrenia and gray matter volume (GMV) show high heritability, however, genes accounting for GMV alterations in schizophrenia remain largely unknown. Based on risk genes identified in schizophrenia by the genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium, we used transcription-neuroimaging association analysis to test that which of these genes are associated with GMV changes in schizophrenia. For each brain tissue sample, the expression profiles of 196 schizophrenia risk genes were extracted from six donated normal brains of the Allen Human Brain Atlas, and GMV differences between patients with schizophrenia and healthy controls were calculated based on five independent case-control structural MRI datasets (276 patients and 284 controls). Genes associated with GMV changes in schizophrenia were identified by performing cross-sample spatial correlations between expression levels of each gene and case-control GMV difference derived from the five MRI datasets integrated by harmonization and meta-analysis. We found that expression levels of 98 genes consistently showed significant cross-sample spatial correlations with GMV changes in schizophrenia. These genes were functionally enriched for chemical synaptic transmission, central nervous system development, and cell projection. Overall, this study provides a set of genes possibly associated with GMV changes in schizophrenia, which could be used as candidate genes to explore biological mechanisms underlying the structural impairments in schizophrenia.

Correlation between cortical gene expression and resting-state functional network centrality in healthy young adults.

Resting-state functional connectivity in the human brain is heritable, and previous studies have investigated the genetic basis underlying functional connectivity. However, at present, the molecular mechanisms associated with functional network centrality are still largely unknown. In this study, functional networks were constructed, and the graph-theory method was employed to calculate network centrality in 100 healthy young adults from the Human Connectome Project. Specifically, functional connectivity strength (FCS), also known as the "degree centrality" of weighted networks, is calculated to measure functional network centrality. A multivariate technique of partial least squares regression (PLSR) was then conducted to identify genes whose spatial expression profiles best predicted the FCS distribution. We found that FCS spatial distribution was significantly positively correlated with the expression of genes defined by the first PLSR component. The FCS-related genes we identified were significantly enriched for ion channels, axon guidance, and synaptic transmission. Moreover, FCS-related genes were preferentially expressed in cortical neurons and young adulthood and were enriched in numerous neurodegenerative and neuropsychiatric disorders. Furthermore, a series of validation and robustness analyses demonstrated the reliability of the results. Overall, our results suggest that the spatial distribution of FCS is modulated by the expression of a set of genes associated with ion channels, axon guidance, and synaptic transmission.

Schizophrenia mediating the effect of smoking phenotypes on antisocial behavior: A Mendelian randomization analysis.

AIMS: Previous studies have indicated that smoking is linked to an increased risk of developing schizophrenia, and that individuals with schizophrenia are more prone to engaging in antisocial behavior. However, the causal effects of smoking behaviors on antisocial behavior and the potential mediating role of schizophrenia remains largely unclear. METHODS: In the present study, using the summary data from genome wide association studies of smoking phenotypes (N = 323,386-805,431), schizophrenia (Ncases = 53,386, Ncontrols = 77,258), and antisocial behavior (N = 85,359), we assessed bidirectional causality between smoking phenotypes and schizophrenia by the Mendelian randomization (MR) approach. Using a two-step MR approach, we further examined whether causal effects of smoking phenotypes/schizophrenia on antisocial behavior were mediated by schizophrenia/smoking phenotypes. RESULTS: The results showed that smoking initiation (SmkInit) and age of smoking initiation (AgeSmk) causally increase the risk of schizophrenia (SmkInit: OR = 2.06, 95% CI = 1.77-2.39, p = 4.36 × 10-21 ; AgeSmk: OR = 0.32, 95% CI = 0.16-0.62, p = 8.11 × 10-4 , Bonferroni corrected). However, there was no causal effect that liability to schizophrenia leads to smoking phenotypes. MR evidence also revealed causal influences of SmkInit and the amount smoked (CigDay) on antisocial behavior (SmkInit: OR = 1.28, 95% CI = 1.17-1.41, p = 2.53 × 10-7 ; CigDay: OR = 1.16, 95% CI = 1.06-1.27, p = 1.60 × 10-3 , Bonferroni corrected). Furthermore, the mediation analysis indicated that the relationship between SmkInit and antisocial behavior was partly mediated by schizophrenia (mediated proportion = 6.92%, 95% CI = 0.004-0.03, p = 9.66 × 10-3 ). CONCLUSIONS: These results provide compelling evidence for taking smoking interventions as a prevention strategy for schizophrenia and its related antisocial behavior.

Unraveling multi-scale neuroimaging biomarkers and molecular foundations for schizophrenia: A combined multivariate pattern analysis and transcriptome-neuroimaging association study.

AIMS: Schizophrenia is characterized by alterations in resting-state spontaneous brain activity; however, it remains uncertain whether variations at diverse spatial scales are capable of effectively distinguishing patients from healthy controls. Additionally, the genetic underpinnings of these alterations remain poorly elucidated. We aimed to address these questions in this study to gain better understanding of brain alterations and their underlying genetic factors in schizophrenia. METHODS: A cohort of 103 individuals with diagnosed schizophrenia and 110 healthy controls underwent resting-state functional MRI scans. Spontaneous brain activity was assessed using the regional homogeneity (ReHo) metric at four spatial scales: voxel-level (Scale 1) and regional-level (Scales 2-4: 272, 53, 17 regions, respectively). For each spatial scale, multivariate pattern analysis was performed to classify schizophrenia patients from healthy controls, and a transcriptome-neuroimaging association analysis was performed to establish connections between gene expression data and ReHo alterations in schizophrenia. RESULTS: The ReHo metrics at all spatial scales effectively discriminated schizophrenia from healthy controls. Scale 2 showed the highest classification accuracy at 84.6%, followed by Scale 1 (83.1%) and Scale 3 (78.5%), while Scale 4 exhibited the lowest accuracy (74.2%). Furthermore, the transcriptome-neuroimaging association analysis showed that there were not only shared but also unique enriched biological processes across the four spatial scales. These related biological processes were mainly linked to immune responses, inflammation, synaptic signaling, ion channels, cellular development, myelination, and transporter activity. CONCLUSIONS: This study highlights the potential of multi-scale ReHo as a valuable neuroimaging biomarker in the diagnosis of schizophrenia. By elucidating the complex molecular basis underlying the ReHo alterations of this disorder, this study not only enhances our understanding of its pathophysiology, but also pave the way for future advancements in genetic diagnosis and treatment of schizophrenia.

Genes associated with spontaneous brain activity changes in clinically different patients with major depressive disorder: A transcription-neuroimaging association study.

AIMS: The amplitude of low-frequency fluctuations (ALFF) of resting-state functional MRI signals is a reliable neuroimaging measure of spontaneous brain activity. Inconsistent ALFF alterations have been reported in major depressive disorder (MDD) possibly due to clinical heterogeneity. This study was designed to investigate clinically sensitive and insensitive genes associated with ALFF alterations in MDD and the potential mechanisms. METHODS: Transcription-neuroimaging association analyses of case-control ALFF differences from two independent neuroimaging datasets with gene expression data from Allen Human Brain Atlas were performed to identify the two gene sets. Various enrichment analyses were conducted to characterize their preference in biological functions, cell types, temporal stages, and shared effects with other psychiatric disorders. RESULTS: Compared with controls, first-episode and drug-naïve patients showed more extensive ALFF alterations than patients with varied clinical features. We identified 903 clinically sensitive genes and 633 clinically insensitive genes, and the former was enriched for genes with down-regulated expression in the cerebral cortex of MDD patients. Despite shared functions of cell communication, signaling, and transport, clinically sensitive genes were enriched for cell differentiation and development whereas clinically insensitive genes were for ion transport and synaptic signaling. Clinically sensitive genes showed enrichment for microglia and macrophage from childhood to young adulthood in contrast to clinically insensitive genes for neurons before early infancy. Clinically sensitive genes (15.2%) were less likely correlated with ALFF alterations in schizophrenia than clinically insensitive genes (66.8%), and both were not relevant to bipolar disorder and adult attention deficit and hyperactivity disorder based on a third independent neuroimaging dataset. CONCLUSIONS: Present results provide novel insights into the molecular mechanisms of spontaneous brain activity changes in clinically different patients with MDD.

Transcriptional signatures of the cortical morphometric similarity network gradient in first-episode, treatment-naive major depressive disorder.

Recent studies have shown that major depressive disorder (MDD) is accompanied by alterations in functional and structural network gradients. However, whether changes are present in the cortical morphometric similarity (MS) network gradient, and the relationship between alterations of the gradient and gene expression remains largely unknown. In this study, the MS network was constructed, and its gradient was calculated in 71 patients with first-episode, treatment-naive MDD, and 69 demographically matched healthy controls. Between-group comparisons were performed to investigate abnormalities in the MS network gradient, and partial least squares regression analysis was conducted to explore the association between gene expression profiles and MS network gradient-based alternations in MDD. We found that the gradient was primarily significantly decreased in sensorimotor regions in patients with MDD compared with healthy controls, and increased in visual-related regions. In addition, the altered principal MS network gradient in the left postcentral cortex and right lingual cortex exhibited significant correlations with symptom severity. The abnormal gradient pattern was spatially correlated with the brain-wide expression of genes enriched for neurobiologically relevant pathways, downregulated in the MDD postmortem brain, and preferentially expressed in different cell types and cortical layers. These results demonstrated alterations of the principal MS network gradient in MDD and suggested the molecular mechanisms for structural alternations underlying MDD.

Association between gray matter atrophy, cerebral hypoperfusion, and cognitive impairment in Alzheimer's disease.

Background: Alzheimer's disease (AD) is one of the most severe neurodegenerative diseases leading to dementia in the elderly. Cerebral atrophy and hypoperfusion are two important pathophysiological characteristics. However, it is still unknown about the area-specific causal pathways between regional gray matter atrophy, cerebral hypoperfusion, and cognitive impairment in AD patients. Method: Forty-two qualified AD patients and 49 healthy controls (HC) were recruited in this study. First, we explored voxel-wise inter-group differences in gray matter volume (GMV) and arterial spin labeling (ASL) -derived cerebral blood flow (CBF). Then we explored the voxel-wise associations between GMV and Mini-Mental State Examination (MMSE) score, GMV and CBF, and CBF and MMSE to identify brain targets contributing to cognitive impairment in AD patients. Finally, a mediation analysis was applied to test the causal pathways among atrophied GMV, hypoperfusion, and cognitive impairment in AD. Results: Voxel-wise permutation test identified that the left middle temporal gyrus (MTG) had both decreased GMV and CBF in the AD. Moreover, the GMV of this region was positively correlated with MMSE and its CBF, and CBF of this region was also positively correlated with MMSE in AD (p < 0.05, corrected). Finally, mediation analysis revealed that gray matter atrophy of left MTG drives cognitive impairment of AD via the mediation of CBF (proportion of mediation = 55.82%, ß = 0.242, 95% confidence interval by bias-corrected and accelerated bootstrap: 0.082 to 0.530). Conclusion: Our findings indicated suggested that left MTG is an important hub linking gray matter atrophy, hypoperfusion, and cognitive impairment for AD, and might be a potential treatment target for AD.

Identifying the mediating role of socioeconomic status on the relationship between schizophrenia and major depressive disorder: a Mendelian randomisation analysis.

Depressive disorder prevalence in patients with schizophrenia has been reported to be 40%. People with low socioeconomic status (SES) are more likely to suffer from schizophrenia and major depressive disorder (MDD). However, the causal relationship between schizophrenia and depression and the potential mediating role of SES remains unclear. Two-sample Mendelian randomization (MR) analyses were conducted to explore the bidirectional causal relationship between schizophrenia and MDD with the largest sample size of European ancestry from public genome-wide association studies (sample size ranged from 130,644 to 480,359). Inverse variance weighted (IVW) method was used as the primary analysis, and several canonical MR methods were used as validation analyses. The mediating role of SES (educational years, household income, employment status, and Townsend deprivation index) was estimated by the two-step MR method. MR analyses showed that genetically predicted schizophrenia was associated with an increased risk of MDD (IVW odds ratio [OR] = 1.137 [95% CI 1.095, 1.181]). Reversely, MDD was also associated with an increased risk of schizophrenia (IVW OR = 1.323 [95% CI 1.118, 1.565]). The mediation analysis via the two-step MR method revealed that the causal effect of schizophrenia on MDD was partly mediated by the Townsend deprivation index with a proportion of 10.27%, but no significant mediation effect was found of SES on the causal effect of MDD on schizophrenia. These results suggest a robust bidirectional causal effect between schizophrenia and MDD. Patients with schizophrenia could benefit from the early and effective intervention of the Townsend deprivation index.

Individual-level brain morphological similarity networks: Current methodologies and applications.

AIMS: The human brain is an extremely complex system in which neurons, clusters of neurons, or regions are connected to form a complex network. With the development of neuroimaging techniques, magnetic resonance imaging (MRI)-based brain networks play a key role in our understanding of the intricate architecture of human brain. Among them, the structural MRI-based brain morphological network approach has attracted increasing attention due to the advantages in data acquisition, image quality, and in revealing the structural organizing principles intrinsic to the brain. This review is to summarize the methodology and related applications of individual-level morphological networks. BACKGROUND: There have been a growing number of studies related to brain morphological similarity networks. Conventional morphological networks are intersubject covariance networks constructed using a certain morphological indicator of a group of subjects; individual-level morphological networks, on the other hand, measure the morphological similarity between brain regions for individual brains and can reflect the morphological information of single subjects. In recent years, individual morphological networks have demonstrated significant worth in exploring the topological changes of the human brain under both normal and disease conditions. Such studies provided novel perspectives for understanding human brain development and exploring the pathological mechanisms of neuropsychiatric disorders. CONCLUSION: This paper mainly focuses on the studies of brain morphological networks at the individual level, introduces several ways for network construction, reviews representative work in this field, and finally points out current problems and future directions.

Transcriptional signatures of the whole-brain voxel-wise resting-state functional network centrality alterations in schizophrenia.

Neuroimaging studies have revealed that patients with schizophrenia exhibit disrupted resting-state functional connectivity. However, the inconsistent findings across these studies have hindered our comprehensive understanding of the functional connectivity changes associated with schizophrenia, and the molecular mechanisms associated with these alterations remain largely unclear. A quantitative meta-analysis was first conducted on 21 datasets, involving 1057 patients and 1186 healthy controls, to examine disrupted resting-state functional connectivity in schizophrenia, as measured by whole-brain voxel-wise functional network centrality (FNC). Subsequently, partial least squares regression analysis was employed to investigate the relationship between FNC changes and gene expression profiles obtained from the Allen Human Brain Atlas database. Finally, gene enrichment analysis was performed to unveil the biological significance of the altered FNC-related genes. Compared with healthy controls, patients with schizophrenia show consistently increased FNC in the right inferior parietal cortex extending to the supramarginal gyrus, angular gyrus, bilateral medial prefrontal cortex, and right dorsolateral prefrontal cortex, while decreased FNC in the bilateral insula, bilateral postcentral gyrus, and right inferior temporal gyrus. Meta-regression analysis revealed that increased FNC in the right inferior parietal cortex was positively correlated with clinical score. In addition, these observed functional connectivity changes were found to be spatially associated with the brain-wide expression of specific genes, which were enriched in diverse biological pathways and cell types. These findings highlight the aberrant functional connectivity observed in schizophrenia and its potential molecular underpinnings, providing valuable insights into the neuropathology of dysconnectivity associated with this disorder.

The impact of pre-adulthood urbanicity on hippocampal subfield volumes and neurocognitive abilities in young adults.

BACKGROUND: Urbanicity refers to the conditions that are particular to urban areas and is a growing environmental challenge that may affect hippocampus and neurocognition. This study aimed to investigate the effects of the average pre-adulthood urbanicity on hippocampal subfield volumes and neurocognitive abilities as well as the sensitive age windows of the urbanicity effects. PARTICIPANTS AND METHODS: We included 5,390 CHIMGEN participants (3,538 females; age: 23.69 ± 2.26 years, range: 18-30 years). Pre-adulthood urbanicity of each participant was defined as the average value of annual night-time light (NL) or built-up% from age 0-18, which were extracted from remote-sensing satellite data based on annual residential coordinates of the participants. The hippocampal subfield volumes were calculated based on structural MRI and eight neurocognitive measures were assessed. The linear regression was applied to investigate the associations of pre-adulthood NL with hippocampal subfield volumes and neurocognitive abilities, mediation models were used to find the underlying pathways among urbanicity, hippocampus and neurocognition, and distributed lag models were used to identify sensitive age windows of urbanicity effect. RESULTS: Higher pre-adulthood NL was associated with greater volumes in the left (ß = 0.100, 95%CI: [0.075, 0.125]) and right (0.078, [0.052, 0.103]) fimbria and left subiculum body (0.045, [0.020, 0.070]) and better neurocognitive abilities in information processing speed (-0.212, [-0.240, -0.183]), working memory (0.085, [0.057, 0.114]), episodic memory (0.107, [0.080, 0.135]), and immediate (0.094, [0.065, 0.123]) and delayed (0.087, [0.058, 0.116]) visuospatial recall, and hippocampal subfield volumes and visuospatial memory showed bilateral mediations for the urbanicity effects. Urbanicity effects were greatest on the fimbria in preschool and adolescence, on visuospatial memory and information processing from childhood to adolescence and on working memory after 14 years. CONCLUSION: These findings improve our understanding of the impact of urbanicity on hippocampus and neurocognitive abilities and will benefit for designing more targeted intervention for neurocognitive improvement.

Gene expression associated with human brain activations in facial expression recognition.

Previous studies identified some genetic loci of emotion, but few focused on human emotion-related gene expression. In this study, the facial expression recognition (FER) task-based high-resolution fMRI data of 203 subjects in the Human Connectome Project (HCP) and expression data of the six healthy human postmortem brain tissues in the Allen Human Brain Atlas (AHBA) were used to conduct a transcriptome-neuroimaging spatial association analysis. Finally, 371 genes were identified to be significantly associated with FER-related brain activations. Enrichment analyses revealed that FER-related genes were mainly expressed in the brain, especially neurons, and might be related to cell junction organization, synaptic functions, and nervous system development regulation, indicating that FER was a complex polygenetic biological process involving multiple pathways. Moreover, these genes exhibited higher enrichment for psychiatric diseases with heavy emotion impairments. This study provided new insight into understanding the FER-related biological mechanisms and might be helpful to explore treatment methods for emotion-related psychiatric disorders.

Abnormal Regional Spontaneous Brain Activities in White Matter in Patients with Autism Spectrum Disorder.

Previous studies have demonstrated patients with autism spectrum disorder (ASD) are accompanied by alterations of spontaneous brain activity in gray matter. However, whether the alterations of spontaneous brain activity exist in white matter remains largely unclear. In this study, 88 ASD patients and 87 typical controls (TCs) were included and regional homogeneity (ReHo) was calculated to characterize spontaneous brain activity in white matter. Voxel-wise two-sample t-tests were performed to investigate ReHo alterations, and cluster-level analyses were conducted to examine structural-functional coupling changes. Compared with TCs, the ASD group showed significantly decreased ReHo in the left superior corona radiata and left posterior limb of internal capsule, and decreased ReHo in the left anterior corona radiata with a trend level of significance. In addition, significantly weaker structural-functional coupling was observed in the left superior corona radiata and left posterior limb of internal capsule in ASD patients. Taken together, these findings highlighted abnormalities of white matter's regional spontaneous brain activity in ASD, which may provide new insights into the pathophysiological mechanisms of this disorder.

Disrupted local functional connectivity in schizophrenia: An updated and extended meta-analysis.

Neuroimaging studies have shown that schizophrenia is associated with disruption of resting-state local functional connectivity. However, these findings vary considerably, which hampers our understanding of the underlying pathophysiological mechanisms of schizophrenia. Here, we performed an updated and extended meta-analysis to identify the most consistent changes of local functional connectivity measured by regional homogeneity (ReHo) in schizophrenia. Specifically, a systematic search of ReHo studies in patients with schizophrenia in PubMed, Embase, and Web of Science identified 18 studies (20 datasets), including 652 patients and 596 healthy controls. In addition, we included three whole-brain statistical maps of ReHo differences calculated based on independent datasets (163 patients and 194 controls). A voxel-wise meta-analysis was then conducted to investigate ReHo alterations and their relationship with clinical characteristics using the newly developed seed-based d mapping with permutation of subject images (SDM-PSI) meta-analytic approach. Compared with healthy controls, patients with schizophrenia showed significantly higher ReHo in the bilateral medial superior frontal gyrus, while lower ReHo in the bilateral postcentral gyrus, right precentral gyrus, and right middle occipital gyrus. The following sensitivity analyses including jackknife analysis, subgroup analysis, heterogeneity test, and publication bias test demonstrated that our results were robust and highly reliable. Meta-regression analysis revealed that illness duration was negatively correlated with ReHo abnormalities in the right precentral/postcentral gyrus. This comprehensive meta-analysis not only identified consistent and reliably aberrant local functional connectivity in schizophrenia but also helped to further deepen our understanding of its pathophysiology.

Selective Aberrant Functional-Structural Coupling of Multiscale Brain Networks in Subcortical Vascular Mild Cognitive Impairment.

Subcortical vascular mild cognitive impairment (svMCI) is a common prodromal stage of vascular dementia. Although mounting evidence has suggested abnormalities in several single brain network metrics, few studies have explored the consistency between functional and structural connectivity networks in svMCI. Here, we constructed such networks using resting-state fMRI for functional connectivity and diffusion tensor imaging for structural connectivity in 30 patients with svMCI and 30 normal controls. The functional networks were then parcellated into topological modules, corresponding to several well-defined functional domains. The coupling between the functional and structural networks was finally estimated and compared at the multiscale network level (whole brain and modular level). We found no significant intergroup differences in the functional-structural coupling within the whole brain; however, there was significantly increased functional-structural coupling within the dorsal attention module and decreased functional-structural coupling within the ventral attention module in the svMCI group. In addition, the svMCI patients demonstrated decreased intramodular connectivity strength in the visual, somatomotor, and dorsal attention modules as well as decreased intermodular connectivity strength between several modules in the functional network, mainly linking the visual, somatomotor, dorsal attention, ventral attention, and frontoparietal control modules. There was no significant correlation between the altered module-level functional-structural coupling and cognitive performance in patients with svMCI. These findings demonstrate for the first time that svMCI is reflected in a selective aberrant topological organization in multiscale brain networks and may improve our understanding of the pathophysiological mechanisms underlying svMCI.

Dynamic Functional Connectivity Alterations and Their Associated Gene Expression Pattern in Autism Spectrum Disorders.

Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that are highly heritable and are associated with impaired dynamic functional connectivity (DFC). However, the molecular mechanisms behind DFC alterations remain largely unknown. Eighty-eight patients with ASDs and 87 demographically matched typical controls (TCs) from the Autism Brain Imaging Data Exchange II database were included in this study. A seed-based sliding window approach was then performed to investigate the DFC changes in each of the 29 seeds in 10 classic resting-state functional networks and the whole brain. Subsequently, the relationships between DFC alterations in patients with ASDs and their symptom severity were assessed. Finally, transcription-neuroimaging association analyses were conducted to explore the molecular mechanisms of DFC disruptions in patients with ASDs. Compared with TCs, patients with ASDs showed significantly increased DFC between the right dorsolateral prefrontal cortex (DLPFC) and left fusiform/lingual gyrus, between the DLPFC and the superior temporal gyrus, between the right frontal eye field (FEF) and left middle frontal gyrus, between the FEF and the right angular gyrus, and between the left intraparietal sulcus and the right middle temporal gyrus. Moreover, significant relationships between DFC alterations and symptom severity were observed. Furthermore, the genes associated with DFC changes in ASDs were identified by performing gene-wise across-sample spatial correlation analysis between gene expression extracted from six donors' brain of the Allen Human Brain Atlas and case-control DFC difference. In enrichment analysis, these genes were enriched for processes associated with synaptic signaling and voltage-gated ion channels and calcium pathways; also, these genes were highly expressed in autistic disorder, chronic alcoholic intoxication and several disorders related to depression. These results not only demonstrated higher DFC in patients with ASDs but also provided novel insight into the molecular mechanisms underlying these alterations.

Brain mRNA Expression Associated with Cortical Volume Alterations in Autism Spectrum Disorder.

Numerous studies report abnormal cerebral cortex volume (CCV) in autism spectrum disorder (ASD); however, genes related to CCV abnormalities in ASD remain largely unknown. Here, we identify genes associated with CCV alterations in ASD by performing spatial correlations between the gene expression of 6 donated brains and neuroimaging data from 1,404 ASD patients and 1,499 controls. Based on spatial correlations between gene expression and CCV differences from two independent meta-analyses and between gene expression and individual CCV distributions of 404 patients and 496 controls, we identify 417 genes associated with both CCV differences and individual CCV distributions. These genes are enriched for genetic association signals and genes downregulated in the ASD post-mortem brain. The expression patterns of these genes are correlated with brain activation patterns of language-related neural processes frequently impaired in ASD. These findings highlight a model whereby genetic risk impacts gene expression (downregulated), which leads to CCV alterations in ASD.