Altered brain structural covariance networks of the thalamic subfields in right chronic capsular stroke

Although extensive structural and functional abnormalities have been reported in schizophrenia, the gray matter volume (GMV) covariance of the amygdala remain unknown. The amygdala contains several subregions with different connection patterns and functions, but it is unclear whether the GMV covariance of these subregions are selectively affected in schizophrenia. To address this issue, we compared the GMV covariance of each amygdala subregion between 807 schizophrenia patients and 845 healthy controls from 11 centers. The amygdala was segmented into nine subregions using FreeSurfer (v7.1.1), including the lateral (La), basal (Ba), accessory-basal (AB), anterior-amygdaloid-area (AAA), central (Ce), medial (Me), cortical (Co), corticoamygdaloid-transition (CAT), and paralaminar (PL) nucleus. We developed an operational combat harmonization model for 11 centers, subsequently employing a voxel-wise general linear model to investigate the differences in GMV covariance between schizophrenia patients and healthy controls across these subregions and the entire brain, while adjusting for age, sex and TIV. Our findings revealed that five amygdala subregions of schizophrenia patients, including bilateral AAA, CAT, and right Ba, demonstrated significantly increased GMV covariance with the hippocampus, striatum, orbitofrontal cortex, and so on (permutation test, P< 0.05, corrected). These findings could be replicated in most centers. Rigorous correlation analysis failed to identify relationships between the altered GMV covariance with positive and negative symptom scale, duration of illness, and antipsychotic medication measure. Our research is the first to discover selectively impaired GMV covariance patterns of amygdala subregion in a large multicenter sample size of patients with schizophrenia.

Functional constipation (FCon) is a prevalent common functional gastrointestinal disorders (FGIDs) frequently linked to mental and psychological disorders. Although previous studies have demonstrated alterations in brain structure and function in FCon, there remains a lack of investigation into the network-level structural inter-relationships (e.g., structural covariance) within key regions such as the orbitofrontal cortex (OFC). This study aimed to investigate whether gray matter volume (GMV) covariance in OFC subregions is selectively disrupted in FCon patients. A cohort of 87 patients with FCon and 87 healthy controls (HC) underwent high-resolution structural MRI scans. The GMV covariance was analyzed using voxel-based morphometry, and the covariance patterns between OFC subregions and other brain regions were examined using a general linear model. FCon patients demonstrated selective alterations in GMV covariance, notably within the lateral and medial OFC subregions, which showed altered covariance with brain regions associated with sensory, motor, and cognitive control functions, including the olfactory cortex, supplementary motor area, insula, and superior frontal gyrus. Our findings indicate that FCon patients show specific GMV covariance alterations in the OFC subregions, suggesting that these structural changes may be associated with disrupted brain–gut interactions and gastrointestinal dysfunction in patients with functional constipation, though the complex and bidirectional nature of gut–brain communication warrants further investigation.

The human orbitofrontal cortex (OFC) is an enigmatic brain region that cannot be parcellated reliably using diffusional and functional magnetic resonance imaging (fMRI) because there is signal dropout that results from an inherent defect in imaging techniques. We hypothesise that the OFC can be reliably parcellated into subregions based on gray matter volume (GMV) covariance patterns that are derived from artefact-free structural images. A total of 321 healthy young subjects were examined by high-resolution structural MRI. The OFC was parcellated into subregions-based GMV covariance patterns; and then sex and laterality differences in GMV covariance pattern of each OFC subregion were compared. The human OFC was parcellated into the anterior (OFCa), medial (OFCm), posterior (OFCp), intermediate (OFCi), and lateral (OFCl) subregions. This parcellation scheme was validated by the same analyses of the left OFC and the bilateral OFCs in male and female subjects. Both visual observation and quantitative comparisons indicated a unique GMV covariance pattern for each OFC subregion. These OFC subregions mainly covaried with the prefrontal and temporal cortices, cingulate cortex and amygdala. In addition, GMV correlations of most OFC subregions were similar across sex and laterality except for significant laterality difference in the OFCl. The right OFCl had stronger GMV correlation with the right inferior frontal cortex. Using high-resolution structural images, we established a reliable parcellation scheme for the human OFC, which may provide an in vivo guide for subregion-level studies of this region and improve our understanding of the human OFC at subregional levels.

The hippocampus is a key brain region that participates in a range of cognitive and affective functions, and is involved in the etiopathogenesis of numerous neuropsychiatric disorders. The structural complexity and functional diversity of the hippocampus suggest the existence of structural and functional subdivisions within this structure. For the first time, we parcellated the human hippocampus with two independent data sets, each of which consisted of 198 T1-weighted structural magnetic resonance imaging (sMRI) images of healthy young subjects. The method was based on gray matter volume (GMV) covariance, which was quantified by a bivariate voxel-to-voxel linear correlation approach, as well as a multivariate masked independent component analysis approach. We subsequently interrogated the relationship between the GMV covariance patterns and the functional connectivity patterns of the hippocampal subregions using sMRI and resting-state functional MRI (fMRI) data from the same participants. Seven distinct GMV covariance-based subregions were identified for bilateral hippocampi, with robust reproducibility across the two data sets. We further demonstrated that the structural covariance patterns of the hippocampal subregions had a correspondence with the intrinsic functional connectivity patterns of these subregions. Together, our results provide a topographical configuration of the hippocampus with converging structural and functional support. The resulting subregions may improve our understanding of the hippocampal connectivity and functions at a subregional level, which provides useful parcellations and masks for future neuroscience and clinical research on the structural and/or functional connectivity of the hippocampus.

Recent studies examining electroconvulsive therapy (ECT) have reported that early sessions can induce rapid antidepressant and antipsychotic effects, and the early termination of ECT was reported to increase the risk of relapse. We hypothesized that different neural mechanisms associated with the therapeutic effects of ECT may be involved in the different responses observed during the early and late periods of ECT treatment. We investigated whether these antidepressant and antipsychotic effects were associated with temporally and spatially different regional gray matter volume (GMV) changes during ECT. Fourteen patients with major depressive disorder, with or without psychotic features, underwent 3-Tesla structural magnetic resonance imaging scans before (time point [Tp] 1), after the fifth or sixth ECT session (Tp2), and after ECT completion (Tp3). We investigated the regions in which GMV changed between Tp1 and Tp2, Tp2 and Tp3, and Tp1 and Tp3 using voxel-based morphometry. In addition, we investigated the association between regional GMV changes and improvement in depressive or psychotic symptoms. GMV increase in the left superior and inferior temporal gyrus during Tp1–Tp2 was associated with improvement in psychotic symptoms (P < 0.025). GMV increase in the left hippocampus was associated with improvement of depressive symptoms in Tp2–Tp3 (P < 0.05). Our findings suggest that different temporal lobe structures are associated with early antipsychotic and late antidepressant effects of ECT.

Evidence highlights that dopamine (DA) system dysregulation and prefrontal cortex (PFC) dysfunction may underlie the pathophysiology of schizophrenia. However, the associations among DA genes, PFC morphometry, and schizophrenia have not yet been fully clarified. Based on the brain gene expression dataset from Allen Human Brain Atlas and structural magnetic resonance imaging data (NDIS = 1727, NREP = 408), we first identified 10 out of 22 PFC subregions whose gray matter volume (GMV) covariance profiles were reliably associated with their DA genes coexpression profiles, then four out of the identified 10 PFC subregions demonstrated abnormally increased GMV covariance with the hippocampus, insula, and medial frontal areas in schizophrenia patients (NCASE = 100; NCONTROL=102). Moreover, based on a schizophrenia postmortem expression dataset, we found that the DA genes coexpression of schizophrenia was significantly reduced between the middle frontal gyrus and hippocampus, in which 21 DA genes showed significantly unsynchronized expression changes, and the 21 genes' brain expression were enriched in brain activity invoked by working memory, reward, speech production, and episodic memory. Our findings indicate the DA genes selectively regulate the structural covariance of PFC subregions by their coexpression profiles, which may underlie the disrupted GMV covariance and impaired cognitive functions in schizophrenia.

Increasing neuroimaging studies have attempted to identify biomarkers of Huntington's disease (HD) progression. Here, we conducted voxel-based meta-analyses of voxel-based morphometry (VBM) studies on HD to investigate the evolution of gray matter volume (GMV) alterations and explore the effects of genetic and clinical features on GMV changes. A systematic review was performed to identify the relevant studies. Meta-analyses of whole-brain VBM studies were performed to assess the regional GMV changes in all HD mutation carriers, in presymptomatic HD (pre-HD), and in symptomatic HD (sym-HD). A quantitative comparison was performed between pre-HD and sym-HD. Meta-regression analyses were used to explore the effects of genetic and clinical features on GMV changes. Twenty-eight studies were included, comparing a total of 1811 HD mutation carriers [including 1150 pre-HD and 560 sym-HD] and 969 healthy controls (HCs). Pre-HD showed decreased GMV in the bilateral caudate nuclei, putamen, insula, anterior cingulate/paracingulate gyri, middle temporal gyri, and left dorsolateral superior frontal gyrus compared with HCs. Compared with pre-HD, GMV decrease in sym-HD extended to the bilateral median cingulate/paracingulate gyri, Rolandic operculum and middle occipital gyri, left amygdala, and superior temporal gyrus. Meta-regression analyses found that age, mean lengths of CAG repeats, and disease burden were negatively associated with GMV atrophy of the bilateral caudate and right insula in all HD mutation carriers. This meta-analysis revealed the pattern of GMV changes from pre-HD to sym-HD, prompting the understanding of HD progression. The pattern of GMV changes may be biomarkers for disease progression in HD.

FIGURE 1. Changes in cortical thickness provide one measure of brain maturation. A large longitudinal study found that for most areas of cortex, children with attention deficit hyperactivity disorder (ADHD) reach peak cortical thickness several years later than typically developing children, supporting presence of developmental delay. The rate of cortical thinning also differed between the group who continued to meet diagnostic criteria into adulthood (persistent ADHD) and those who did not (remitted ADHD). Areas of cortex in which the rate of thinning correlated with adult symptom level (green, more symptoms associated with more thinning) are approximated on medial and lateral simplified representations of cortex. An earlier study also identified multiple areas in which cortex was thinner in adults with persistent ADHD compared with controls (orange). In addition, this study noted some areas of thicker cortex in remitted ADHD when compared with persistent ADHD (blue).

Objective: It is common that major depressive disorder (MDD) is accompanied by gastrointestinal (GI) symptoms. However, few studies have focused on the clinical characteristics and its possible mechanism, while brain gray matter (GM) structure is important in the pathogenesis of GI symptoms. In this study, we aimed to investigate the basic clinical characteristics and regional GM volume changes in MDD accompanied by GI symptoms.Method: Patients with MDD (n=49) and age, gender, and educational level-matched healthy controls (n=30) were recruited. Patients with MDD were divided into two groups based on the GI status: MDD with (n=27) and without (n=22) GI symptoms. The 24-item Hamilton Depression Rating Scale (HAMD) was administered. T1-weighted anatomical images were obtained and analyzed. Correlation analysis was used to identify the possible associations between changed regional GM volume and GI symptoms and depressive symptoms.Results: The HAMD reductive ratio for 2 weeks of treatment in the GI symptoms group was significantly higher than the non-GI symptoms group (P<0.05). The regional GM volume showed significant differences among the three groups (Gaussian Random Field [GRF] correction, voxel-P<0.01, cluster-P <0.05). Compared with non-GI symptoms group, GI symptoms group exhibited significantly increased GM volume in the left hippocampus, left parahippocampal gyrus, right parahippocampal gyrus; and decreased GM volume in the right middle frontal gyrus, right precentral gyrus, right cuneus, right precuneus, right superior occipital gyrus (GRF correction, voxel-P <0.01, cluster-P <0.05). These altered brain areas were correlated with the GI symptoms, not depressive symptoms.Conclusion: The changed regional brain GM volume in GI-MDD group may be the pathogenesis for the GI symptoms. In addition, the GI symptoms may predict the prognosis of MDD.

Alterations in gray matter (GM) are commonly observed in schizophrenia. Accumulating studies suggest that the brain changes associated with schizophrenia are distributed rather than focal, involving interconnected networks of areas as opposed to single regions. In the current study we aimed to explore GM volume (GMV) changes in a relatively large sample of treatment-naive first-episode schizophrenia (FES) patients using optimized voxel-based morphometry (VBM) and covariation analysis. High-resolution T1-weighted images were obtained using 3.0-T magnetic resonance imaging (MRI) from 86 first-episode drug-naive patients with schizophrenia and 86 age- and gender-matched healthy volunteers. Symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS). GMV was assessed using optimized VBM and in 16 regions of interest (ROIs), selected on the basis of a previous meta-analysis. The relationships between GMVs in the ROIs were examined using an analysis of covariance (ANCOVA). The VBM analysis revealed that first-episode patients showed reduced GMV in the hippocampus bilaterally. The ROI analysis identified reductions in GMV in the left inferior frontal gyrus, bilateral hippocampus and right thalamus. The ANCOVA revealed different patterns of regional GMV correlations in patients and controls, including of inter- and intra-insula, inter-amygdala and insula-postcentral gyrus connections. Schizophrenia involves regional reductions in GMV and changes in GMV covariance in the insula, amygdala and postcentral gyrus. These findings were evident at the onset of the disorder, before treatment, and therefore cannot be attributable to the effects of chronic illness progression or medication.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Neurodegenerative change in the central nervous system has been suggested as one of the pathophysiological mechanisms of autonomic nervous system dysfunction in Parkinson’s disease (PD). We analyzed gray matter (GM) volume changes and clinical parameters in patients with PD to investigate any involvement in the brain structures responsible for autonomic control in patients with PD having orthostatic hypotension (OH). Voxel-based morphometry was applied to compare regional GM volumes between PD patients with and without OH. Multivariate logistic regression analysis using a hierarchical model was carried out to identify clinical factors independently contributing to the regional GM volume changes in PD patients with OH. The Sobel test was used to analyze mediation effects between the independent contributing factors to the GM volume changes. PD patients with OH had more severe autonomic dysfunction and reduction in volume in the right inferior temporal cortex than those without OH. The right inferior temporal volume was positively correlated with the Qualitative Scoring MMSE Pentagon Test (QSPT) score, reflecting visuospatial/visuoperceptual function, and negatively correlated with the Composite Autonomic Severity Score (CASS). The CASS and QSPT scores were found to be factors independently contributing to regional volume changes in the right inferior temporal cortex. The QSPT score was identified as a mediator in which regional GM volume predicts the CASS. Our findings suggest that a decrease in the visuospatial/visuoperceptual process may be involved in the presentation of autonomic nervous system dysfunction in PD patients.

This study aimed to explore gray matter volume (GMV) changes in patients undergoing hemodialysis and assess the clinical risk factors associated with GMV changes and the relationship between GMV changes and neuropsychologic test results. Eighty-eight hemodialysis patients and 76 healthy controls (HCs) were recruited in this study. Fifty patients underwent follow-up examinations (follow-up duration: 1.75 ± 0.55 years), including magnetic resonance imaging, blood biochemical, and neuropsychologic testing. Changes in GMV between the patients and HCs were assessed. Longitudinal GMV changes were also explored in the patients. The clinical risk factors associated with longitudinal GMV changes and the correlations between longitudinal GMV changes and neuropsychologic test results were analyzed in the patients. Patients undergoing hemodialysis had diffusely decreased GMV compared with HCs (with age, sex, and total intracranial volume [TIV] as covariates, P<0.001, voxel-wise threshold false discovery rate [FDR] corrected). Compared with patients at baseline, regional decreased GMV were found in patients at follow-up (with age and TIV as covariates, P<0.05, voxel-wise threshold FDR corrected). Increased serum urea concentrations, parathyroid hormone levels, and hemodialysis duration were independent risk factors for decreased GMV in patients undergoing hemodialysis (all P<0.05, FDR corrected). Patients undergoing hemodialysis had lower mini-mental state examination (MMSE) (27[26, 29]) and Montreal cognitive assessment (MoCA) (22[19.5, 24.0]) scores than those of the HCs (30[29, 30] and 28[26.9, 29]) (all P<0.05). The MMSE scores of the patients at follow-up (26[25, 28.5]) were lower than those of patients at baseline (28[25, 29.5]) (P=0.02). The decreased left caudate volumes were positively correlated with reduced MMSE scores in hemodialysis patients (rs=0.437, P=0.033). Patients undergoing hemodialysis had noticeable GM atrophy over time, related to cognitive impairments.

Ulcerative colitis (UC) and Crohn's disease (CD) are 2 subtypes of inflammatory bowel disease (IBD). Several studies have reported brain abnormalities in IBD patients. This study aims to identify differences of gray matter volume (GMV) between patients with UC and healthy controls (HCs). Fifty-seven patients with UC and 40 HCs underwent structural magnetic resonance imaging. Voxel-based morphometry method was used to detect GMV differences. Receiver operating characteristic (ROC) curve was applied to investigate reliable biomarkers for identifying patients with UC from HCs. Regression analysis was used to examine relationships between the structure alternations and clinical symptoms. Compared with HCs, patients with UC showed decreased GMV in the insula, thalamus, pregenual anterior cingulate cortex, hippocampus/parahippocampus, amygdala, and temporal pole; they showed increased GMV in the putamen, supplementary motor area, periaqueductal gray, hypothalamus, and precentral gyrus. Receiver operating characteristic analysis showed the highest classification power of thalamus. The inclusion of anxiety and depression as covariates eliminated the differences in the right insula, pregenual anterior cingulate cortex, supplementary motor area, and precentral gyrus. Most of the GMV changes were found in active patients with UC, with few changes in patients with UC in remission. We also found significantly negative correlation between UC duration and GMV in several regions. The current neuroimaging findings were involved in visceral sensory pathways and were partially associated with the levels of anxiety and depression and clinical stage of patients with UC. This study might provide evidence for possible neuromechanisms of UC.

Post-COVID-19 olfactory dysfunction (PCOD) has been associated with structural brain changes, but the underlying molecular mechanisms and their relationship to gray matter volume (GMV) changes remain unclear. We included 36 patients with PCOD and 40 healthy controls. All patients underwent olfactory psychophysical testing (Sniffin' Sticks) and a visual analogue scale (VAS) assessment for olfactory function. GMV values for 34 brain regions were extracted, and Spearman's correlation analysis was performed with olfactory psychophysical testing scores. Partial least squares regression (PLS) was applied to explore the relationship between regional GMV differences and gene expression patterns. Gene set enrichment analysis was performed to identify relevant biological processes and cell types. PCOD patients showed increased GMV in the entorhinal cortex (t = 3.065, p = 0.003), positively correlated with the VAS score for olfactory function (r = 0.37, p = 0.028) and Sniffin' Sticks Test total score (r = 0.37, p = 0.026). PLS analysis identified gene expression patterns that were significantly associated with regional GMV changes. Enrichment analysis revealed that genes linked to GMV changes were enriched for biological processes related to "inorganic ion transmembrane transport" and "regulation of protein transport". Additionally, these genes were highly expressed in GABAergic neurons. These findings provide mechanistic insights into the relationship between altered brain structure and gene expression in PCOD, highlighting the involvement of specific biological pathways and cell types in the pathophysiology of olfactory dysfunction following COVID-19.