Cross-ancestry genome-wide association studies of brain imaging phenotypes.

Genome-wide association studies of brain imaging phenotypes are mainly performed in European populations, but other populations are severely under-represented. Here, we conducted Chinese-alone and cross-ancestry genome-wide association studies of 3,414 brain imaging phenotypes in 7,058 Chinese Han and 33,224 white British participants. We identified 38 new associations in Chinese-alone analyses and 486 additional new associations in cross-ancestry meta-analyses at P < 1.46 × 10-11 for discovery and P < 0.05 for replication. We pooled significant autosomal associations identified by single- or cross-ancestry analyses into 6,443 independent associations, which showed uneven distribution in the genome and the phenotype subgroups. We further divided them into 44 associations with different effect sizes and 3,557 associations with similar effect sizes between ancestries. Loci of these associations were shared with 15 brain-related non-imaging traits including cognition and neuropsychiatric disorders. Our results provide a valuable catalog of genetic associations for brain imaging phenotypes in more diverse populations.

A study on the association between prefrontal functional connectivity and non-suicidal self-injury in adolescents with depression.

Objective: Among adolescents with depression, the occurrence of non-suicidal self-injury (NSSI) behavior is prevalent, constituting a high-risk factor for suicide. However, there has been limited research on the neuroimaging mechanisms underlying adolescent depression and NSSI behavior, and the potential association between the two remains unclear. Therefore, this study aims to investigate the alterations in functional connectivity (FC) of the regions in the prefrontal cortex with the whole brain, and elucidates the relationship between these alterations and NSSI behavior in adolescents with depression. Methods: A total of 68 participants were included in this study, including 35 adolescents with depression and 33 healthy controls. All participants underwent assessments using the 17-item Hamilton Depression Rating Scale (17-HAMD) and the Ottawa Self-Harm Inventory. In addition, functional magnetic resonance imaging (fMRI) data of the participants' brains were collected. Subsequently, the FCs of the regions in the prefrontal cortex with the whole brain was calculated. The FCs showing significant differences were then subjected to correlation analyses with 17-HAMD scores and NSSI behavior scores. Result: Compared to the healthy control group, the adolescent depression group exhibited decreased FCs in several regions, including the right frontal eye field, left dorsolateral prefrontal cortex, right orbitofrontal cortex, left insula and right anterior cingulate coetex. The 17-HAMD score was positively correlated with the frequency of NSSI behavior within 1 year (rs = 0.461, p = 0.005). The FC between the right anterior cingulate cortex and the right precuneus showed a negative correlation with the 17-HAMD scores (rs = -0.401, p = 0.023). Additionally, the FC between the right orbitofrontal cortex and the right insula, demonstrated a negative correlation with the frequency of NSSI behavior within 1 year (rs = -0.438, p = 0.012, respectively). Conclusion: Adolescents with depression showed decreased FCs of the prefrontal cortex with multiple brain regions, and some of these FCs were associated with the NSSI frequency within 1 year. This study provided neuroimaging evidence for the neurophysiological mechanisms underlying adolescent depression and its comorbidity with NSSI behavior.

Structural characteristics of amygdala subregions in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) patients often suffer from depressive symptoms, which seriously affect cooperation in treatment and nursing. The amygdala plays a significant role in depression. This study aims to explore the microstructural alterations of the amygdala in T2DM and to investigate the relationship between the alterations and depressive symptoms. Fifty T2DM and 50 healthy controls were included. Firstly, the volumes of subcortical regions and subregions of amygdala were calculated by FreeSurfer. Covariance analysis (ANCOVA) was conducted between the two groups with covariates of age, sex, and estimated total intracranial volume to explore the differences in volume of subcortical regions and subregions of amygdala. Furthermore, the structural covariance within the amygdala subregions was performed. Moreover, we investigate the correlation between depressive symptoms and the volume of subcortical regions and amygdala subregions in T2DM. We observed a reduction in the volume of the bilateral cortico-amygdaloid transition area, left basal nucleus, bilateral accessory basal nucleus, left anterior amygdaloid area of amygdala, the left thalamus and left hippocampus in T2DM. T2DM patients showed decreased structural covariance connectivity between left paralaminar nucleus and the right central nucleus. Moreover, there was a negative correlation between self-rating depression scale scores and the volume of the bilateral cortico-amygdaloid transition area in T2DM. This study reveals extensive structural alterations in the amygdala subregions of T2DM patients. The reduction in the volume of the bilateral cortico-amygdaloid transition area may be a promising imaging marker for early recognition of depressive symptoms in T2DM.

Construction of a Female Sterility Maintaining System Based on a Novel Mutation of the MEL2 Gene.

BACKGROUND: Hybrid rice has significant yield advantage and stress tolerance compared with inbred rice. However, production of hybrid rice seeds requires extensive manual labors. Currently, hybrid rice seeds are produced by crosspollination of male sterile lines by fertile paternal lines. Because seeds from paternal lines can contaminate the hybrid seeds, mechanized production by mixed-seeding and mixed-harvesting is difficult. This problem can be solved if the paternal line is female sterile. RESULTS: Here we identified a female infertile mutant named h569 carrying a novel mutation (A1106G) in the MEL2 gene that was previously reported to regulate meiosis entry both in male and female organs. h569 mutant is female infertile but male normal, suggesting that MEL2 regulates meiosis entry in male and female organs through distinct pathways. The MEL2 gene and h569 mutant gave us tools to construct female sterility maintaining systems that can be used for propagation of female sterile lines. We connected the wild-type MEL2 gene with pollen-killer gene ZmAA1 and seed-marker gene DsRed2 in one T-DNA cassette and transformed it into ZZH1607, a widely used restorer line. Transgenic line carrying a single transgene inserted in an intergenic region was selected to cross with h569 mutant. F2 progeny carrying homozygous A1106G mutation and hemizygous transgene displayed 1:1 segregation of fertile and infertile pollen grains and 1:1 segregation of fluorescent and non-fluorescent seeds upon self-fertilization. All of the non-fluorescent seeds generated female infertile plants, while the fluorescent seeds generated fertile plants that reproduced in the way as their previous generation. CONCLUSIONS: These results indicated that the female sterility maintaining system constructed in the study can be used to breed and propagate paternal lines that are female infertile. The application of this system will enable mechanized production of hybrid rice seed by using the mixed-seeding and mixed harvesting approach, which will significantly reduce the cost in hybrid rice seed production.

Use of Computed Tomography-Based Texture Analysis to Differentiate Benign From Malignant Salivary Gland Lesions.

OBJECTIVE: Salivary gland lesions show overlapping morphological findings and types of time/intensity curves. This research aimed to evaluate the role of 2-phase multislice spiral computed tomography (MSCT) texture analysis in differentiating between benign and malignant salivary gland lesions. METHODS: In this prospective study, MSCT was carried out on 90 patients. Each lesion was segmented on axial computed tomography (CT) images manually, and 33 texture features and morphological CT features were assessed. Logistic regression analysis was used to confirm predictors of malignancy ( P < 0.05 was considered to be statistically significant), followed by receiver operating characteristics analysis to assess the diagnostic performance. RESULTS: Univariate logistic regression analysis revealed that morphological CT features (shape, size, and invasion of adjacent tissues) and 17 CT texture parameters had significant differences between benign and malignant lesions ( P < 0.05). Multivariate binary logistic regression demonstrated that shape, invasion of adjacent tissues, entropy, and inverse difference moment were independent factors for malignant tumors. The diagnostic accuracy values of multivariate binary logistic models based on morphological parameters, CT texture features, and a combination of both were 87.8%, 90%, and 93.3%, respectively. CONCLUSIONS: Two-phase MSCT texture analysis was conducive to differentiating between malignant and benign neoplasms in the salivary gland, especially when combined with morphological CT features.

Aberrant dynamic functional network connectivity in type 2 diabetes mellitus individuals.

An increasing number of recent brain imaging studies are dedicated to understanding the neuro mechanism of cognitive impairment in type 2 diabetes mellitus (T2DM) individuals. In contrast to efforts to date that are limited to static functional connectivity, here we investigate abnormal connectivity in T2DM individuals by characterizing the time-varying properties of brain functional networks. Using group independent component analysis (GICA), sliding-window analysis, and k-means clustering, we extracted thirty-one intrinsic connectivity networks (ICNs) and estimated four recurring brain states. We observed significant group differences in fraction time (FT) and mean dwell time (MDT), and significant negative correlation between the Montreal Cognitive Assessment (MoCA) scores and FT/MDT. We found that in the T2DM group the inter- and intra-network connectivity decreases and increases respectively for the default mode network (DMN) and task-positive network (TPN). We also found alteration in the precuneus network (PCUN) and enhanced connectivity between the salience network (SN) and the TPN. Our study provides evidence of alterations of large-scale resting networks in T2DM individuals and shed light on the fundamental mechanisms of neurocognitive deficits in T2DM.

Genome-wide association study of hippocampal blood-oxygen-level-dependent-cerebral blood flow correlation in Chinese Han population.

Correlation between blood-oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) has been used as an index of neurovascular coupling. Hippocampal BOLD-CBF correlation is associated with neurocognition, and the reduced correlation is associated with neuropsychiatric disorders. We conducted the first genome-wide association study of the hippocampal BOLD-CBF correlation in 4,832 Chinese Han subjects. The hippocampal BOLD-CBF correlation had an estimated heritability of 16.2-23.9% and showed reliable genome-wide significant association with a locus at 3q28, in which many variants have been linked to neuroimaging and cerebrospinal fluid markers of Alzheimer's disease. Gene-based association analyses showed four significant genes (GMNC, CRTC2, DENND4B, and GATAD2B) and revealed enrichment for mast cell calcium mobilization, microglial cell proliferation, and ubiquitin-related proteolysis pathways that regulate different cellular components of the neurovascular unit. This is the first unbiased identification of the association of hippocampal BOLD-CBF correlation, providing fresh insights into the genetic architecture of hippocampal neurovascular coupling.

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.

Functional connectome through the human life span.

The functional connectome of the human brain represents the fundamental network architecture of functional interdependence in brain activity, but its normative growth trajectory across the life course remains unknown. Here, we aggregate the largest, quality-controlled multimodal neuroimaging dataset from 119 global sites, including 33,809 task-free fMRI and structural MRI scans from 32,328 individuals ranging in age from 32 postmenstrual weeks to 80 years. Lifespan growth charts of the connectome are quantified at the whole cortex, system, and regional levels using generalized additive models for location, scale, and shape. We report critical inflection points in the non-linear growth trajectories of the whole-brain functional connectome, particularly peaking in the fourth decade of life. Having established the first fine-grained, lifespan-spanning suite of system-level brain atlases, we generate person-specific parcellation maps and further show distinct maturation timelines for functional segregation within different subsystems. We identify a spatiotemporal gradient axis that governs the life-course growth of regional connectivity, transitioning from primary sensory cortices to higher-order association regions. Using the connectome-based normative model, we demonstrate substantial individual heterogeneities at the network level in patients with autism spectrum disorder and patients with major depressive disorder. Our findings shed light on the life-course evolution of the functional connectome and serve as a normative reference for quantifying individual variation in patients with neurological and psychiatric disorders.

Multimodal and multiscale evidence for network-based cortical thinning in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with widespread, irregular cortical thickness (CT) reductions across the brain. However, little is known regarding mechanisms that govern spatial distribution of the reductions. METHODS: We combined multimodal MRI and genetic, cytoarchitectonic and chemoarchitectonic data to examine structural covariance, functional synchronization, gene co-expression, cytoarchitectonic similarity and chemoarchitectonic covariance between regions atrophied in MDD. RESULTS: Regions atrophied in MDD were associated with significantly higher structural covariance, functional synchronization, gene co-expression and chemoarchitectonic covariance. These results were robust against methodological variations in brain parcellation and null model, reproducible in patients and controls, and independent of age at onset of MDD. Despite no significant differences in the cytoarchitectonic similarity, MDD-related CT reductions were susceptible to specific cytoarchitectonic class of association cortex. Further, we found that nodal shortest path lengths to disease epicenters derived from structural (right supramarginal gyrus) and chemoarchitectonic covariance (right sulcus intermedius primus) networks of healthy brains were correlated with the extent to which a region was atrophied in MDD, supporting the transneuronal spread hypothesis that regions closer to the epicenters are more susceptible to MDD. Finally, we showed that structural covariance and functional synchronization among regions atrophied in MDD were mainly related to genes enriched in metabolic and membrane-related processes, driven by genes in excitatory neurons, and associated with specific neurotransmitter transporters and receptors. CONCLUSIONS: Altogether, our findings provide empirical evidence for and genetic and molecular insights into connectivity-constrained CT thinning in MDD.

Abnormal cerebral blood flow and brain function in type 2 diabetes mellitus.

PURPOSE: Type 2 diabetes mellitus (T2DM) lead to impaired cerebral blood perfusion, which leads to changes in brain function and affects the cognitive function of patients. In this study, cerebral blood flow (CBF) was used to evaluate the effect of T2DM on cerebral perfusion, and functional connectivity (FC) analysis was further used to explore whether the FC between the abnormal CBF region and the whole brain was changed. In addition, amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were used to investigate the changes in spontaneous activity and connectivity strength of the brain network. METHODS: We recruited 40 T2DM patients and 55 healthy controls (HCs). They underwent 3D-T1WI, rs-fMRI, arterial spin labeling (ASL) sequence scans and a series of cognitive tests. Cognitive test scores and brain imaging indicators were compared between the two groups, and the relationships among laboratory indicators, cognitive test scores, and brain imaging indicators were explored in the T2DM group. RESULTS: Compared to HCs, The CBF values of Calcarine_L and Precuneus_R in the T2DM group were lower. The DC value of Paracentral_Lobule_L and Precuneus_L, and the ALFF value of Hippocampus_L in the T2DM group were higher. In addition, the CBF values of Calcarine_L was negatively correlated with fasting insulin and HOMA_IR. CONCLUSION: This study found that there were regions of cerebral hypoperfusion in T2DM patients, which are associated with insulin resistance. In addition, we found abnormally elevated brain activity and enhanced functional connectivity in T2DM patients, which we speculated was the compensatory mechanism of brain neural activity.

Cross-ancestry genome-wide association meta-analyses of hippocampal and subfield volumes.

The hippocampus is critical for memory and cognition and neuropsychiatric disorders, and its subfields differ in architecture and function. Genome-wide association studies on hippocampal and subfield volumes are mainly conducted in European populations; however, other ancestral populations are under-represented. Here we conduct cross-ancestry genome-wide association meta-analyses in 65,791 individuals for hippocampal volume and 38,977 for subfield volumes, including 7,009 individuals of East Asian ancestry. We identify 339 variant-trait associations at P < 1.13 × 10-9 for 44 hippocampal traits, including 23 new associations. Common genetic variants have similar effects on hippocampal traits across ancestries, although ancestry-specific associations exist. Cross-ancestry analysis improves the fine-mapping precision and the prediction performance of polygenic scores in under-represented populations. These genetic variants are enriched for Wnt signaling and neuron differentiation and affect cognition, emotion and neuropsychiatric disorders. These findings may provide insight into the genetic architectures of hippocampal and subfield volumes.

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking. METHODS: Leveraging resting-state functional magnetic resonance imaging data from 1148 patients with MDD and 1079 healthy control participants (ages 11-93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. First, we characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among patients with MDD. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity. RESULTS: Our findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among patients with MDD, which inspired the identification of 2 reproducible neurophysiological subtypes. Subtype 1 showed severe deviations, with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and the predictive ability of baseline deviations for antidepressant treatment outcomes. CONCLUSIONS: These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.

Abnormal dynamic functional connectivity of thalamic subregions in patients with first-episode, drug-naïve major depressive disorder.

Background: Recent studies have shown that major depressive disorder (MDD) is associated with altered intrinsic functional connectivity (FC) of the thalamus; however, investigations of these alterations at a finer time scale and the level of thalamic subregions are still lacking. Methods: We collected resting-state functional MRI data from 100 treatment-naïve, first-episode MDD patients and 99 age-, gender- and education-matched healthy controls (HCs). Seed-based whole-brain sliding window-based dFC analyses were performed for 16 thalamic subregions. Between-group differences in the mean and variance of dFC were determined using threshold-free cluster enhancement algorithm. For significant alterations, there relationships with clinical and neuropsychological variables were further examined via bivariate and multivariate correlation analyses. Results: Of all thalamic subregions, only the left sensory thalamus (Stha) showed altered variance of dFC in the patients characterized by increases with the left inferior parietal lobule, left superior frontal gyrus, left inferior temporal gyrus, and left precuneus, and decreases with multiple frontal, temporal, parietal, and subcortical regions. These alterations accounted for, to a great extent, clinical, and neuropsychological characteristics of the patients as revealed by the multivariate correlation analysis. In addition, the bivariate correlation analysis revealed a positive correlation between the variance of dFC between the left Stha and right inferior temporal gurus/fusiform and childhood trauma questionnaires scores (r = 0.562, P < 0.001). Conclusion: These findings suggest that the left Stha is the most vulnerable thalamic subregion to MDD, whose dFC alterations may serve as potential biomarkers for the diagnosis of the disease.

Alterations of peripheral cytokines, BDNF, and surface-based morphometry indices in T2DM patients without cognitive impairment.

Purpose: This study aimed to investigate potential biological mechanisms underlying cognitive function alterations in Type 2 diabetes mellitus (T2DM) patients by integrating cortical morphology with peripheral cytokine levels and brain-derived neurotrophic factor (BDNF) levels, and to offer potential insights for the early detection of T2DM-related cognitive impairment. Methods: This study included 16 T2DM patients with a Montreal Cognitive Assessment (MoCA) score of at least 26 points, as well as 16 healthy controls with normal cognitive function. The participants also completed the digit span test and digit symbol substitution test. Participants' serum levels of Interleukin 4 (IL-4), IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and BDNF were also examined. Each subject underwent a high-resolution 3T structural brain MRI scan. Based on the aparc. a2009s atlas, we calculated the cortical thickness, sulcus depth, gyrification index, and fractal dimension for each participant using surface-based morphometry (SBM). Correlation analysis between cognitive measures, serum levels of cytokines and BDNF, and SBM indices were further performed. Results: The levels of IL-4 and BDNF showed significant group differences. In the T2DM group, the sulcus depth exhibited a significant decrease in the left transverse frontopolar gyri and sulci, as well as in the right pole-occipital; the fractal dimension showed a significant increase in the right posterior-dorsal part of the cingulate gyrus; and the gyrification index significantly increased in the left inferior part of the precentral sulcus and right triangular part of the inferior frontal gyrus. Correlation analysis revealed a significant positive correlation between IL-10 levels and the sulcus depth of left transverse frontopolar gyri and sulci; a significant positive correlation between the sulcus depth of the right pole-occipital and the digit span test-forward scores, and a significant negative correlation between the gyrification index of the left inferior part of the precentral sulcus and the digit span test-backward scores among T2DM participants. Conclusion: T2DM patients without cognitive impairment displayed reductions in IL 4 and BDNF levels, as well as significant alterations in their SBM indices, indicating that prior to the emergence of cognitive impairment, the SBM indices, peripheral cytokines, and BDNF may have altered in T2DM patients. IL-10 may lessen inflammation-related brain edema and preserve sulcus depth in T2DM patients through its anti-inflammatory activity.

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.

Transarterial chemoembolization (TACE) plus tyrosine kinase inhibitors versus TACE in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

PURPOSE: Transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) has been increasingly used to treat unresectable hepatocellular carcinoma (uHCC). However, the superiority of combination therapy to TACE monotherapy remains controversial. Therefore, here we performed a meta-analysis to evaluate the efficacy and safety of TACE plus TKIs in patients with uHCC. METHODS: We searched four databases for eligible studies. The primary outcome was time to progression (TTP), while the secondary outcomes were overall survival (OS), tumor response rates, and adverse events (AEs). Pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) were collected for TTP and OS, and the data were analyzed using random-effects meta-analysis models in STATA software. OR and 95% CIs were used to estimate dichotomous variables (complete remission[CR], partial remission[PR], stable disease[SD], progressive disease[PD], objective response rate[ORR], disease control rate[DCR], and AEs) using RStudio's random-effects model. Quality assessments were performed using the Newcastle-Ottawa scale (NOS) for observational studies and the Cochrane risk of bias tool for randomized controlled trials (RCTs). RESULTS: The meta-analysis included 30 studies (9 RCTs, 21 observational studies) with 8246 patients. We judged the risk of bias as low in 44.4% (4/9) of the RCTs and high in 55.6% (5/9) of the RCTs. All observational studies were considered of high quality, with a NOS score of at least 6. Compared with TACE alone or TACE plus placebo, TACE combined with TKIs was superior in prolonging TTP (combined HR 0.72, 95% CI 0.65-0.80), OS (combined HR 0.57, 95% CI 0.49-0.67), and objective response rate (OR 2.13, 95% CI 1.23-3.67) in patients with uHCC. However, TACE plus TKIs caused a higher incidence of AEs, especially hand-foot skin reactions (OR 87.17%, 95%CI 42.88-177.23), diarrhea (OR 18.13%, 95%CI 9.32-35.27), and hypertension (OR 12.24%, 95%CI 5.89-25.42). CONCLUSIONS: Our meta-analysis found that TACE plus TKIs may be beneficial for patients with uHCC in terms of TTP, OS, and tumor response rates. However, combination therapy is also associated with a significantly increased risk of adverse reactions. Therefore, we must evaluate the clinical benefits and risks of combination therapy. Further well-designed RCTs are needed to confirm our findings. TRIAL REGISTRATION: PROSPERO registration number: CRD42022298003.

Resting-state functional connectivity of the raphe nuclei in major depressive Disorder: A Multi-site study.

Accumulating evidence showed that major depressive disorder (MDD) is characterized by a dysfunction of serotonin neurotransmission. Raphe nuclei are the sources of most serotonergic neurons that project throughout the brain. Incorporating measurements of activity within the raphe nuclei into the analysis of connectivity characteristics may contribute to understanding how neurotransmitter synthesized centers are involved in thepathogenesisof MDD. Here, we analyzed the resting-state functional magnetic resonance imaging (RS-fMRI) dataset from 1,148 MDD patients and 1,079 healthy individuals recruited across nine centers. A seed-based analysis with the dorsal raphe and median raphe nuclei was performed to explore the functional connectivity (FC) alterations. Compared to controls, for dorsal raphe, the significantly decreased FC linking with the right precuneus and median cingulate cortex were found; for median raphe, the increased FC linking with right superior cerebellum (lobules V/VI) was found in MDD patients. In further exploratory analyzes, MDD-related connectivity alterations in dorsal and median raphe nuclei in different clinical factors remained highly similar to the main findings, indicating these abnormal connectivities are a disease-related alteration. Our study highlights a functional dysconnection pattern of raphe nuclei in MDD with multi-site big data. These findings help improve our understanding of the pathophysiology of depression and provide evidence of the theoretical foundation for the development of novel pharmacotherapies.

Detecting type 2 diabetes mellitus cognitive impairment using whole-brain functional connectivity.

Type 2 diabetes mellitus (T2DM) is closely linked to cognitive decline and alterations in brain structure and function. Resting-state functional magnetic resonance imaging (rs-fMRI) is used to diagnose neurodegenerative diseases, such as cognitive impairment (CI), Alzheimer's disease (AD), and vascular dementia (VaD). However, whether the functional connectivity (FC) of patients with T2DM and mild cognitive impairment (T2DM-MCI) is conducive to early diagnosis remains unclear. To answer this question, we analyzed the rs-fMRI data of 37 patients with T2DM and mild cognitive impairment (T2DM-MCI), 93 patients with T2DM but no cognitive impairment (T2DM-NCI), and 69 normal controls (NC). We achieved an accuracy of 87.91% in T2DM-MCI versus T2DM-NCI classification and 80% in T2DM-NCI versus NC classification using the XGBoost model. The thalamus, angular, caudate nucleus, and paracentral lobule contributed most to the classification outcome. Our findings provide valuable knowledge to classify and predict T2DM-related CI, can help with early clinical diagnosis of T2DM-MCI, and provide a basis for future studies.

Frequency-resolved connectome alterations in major depressive disorder: A multisite resting fMRI study.

BACKGROUND: Functional connectome studies have revealed widespread connectivity alterations in major depressive disorder (MDD). However, the low frequency bandpass filtering (0.01-0.08 Hz or 0.01-0.1 Hz) in most studies have impeded our understanding on whether and how these alterations are affected by frequency of interest. METHODS: Here, we performed frequency-resolved (0.01-0.06 Hz, 0.06-0.16 Hz and 0.16-0.24 Hz) connectome analyses using a large-sample resting-state functional MRI dataset of 1002 MDD patients and 924 healthy controls from seven independent centers. RESULTS: We reported significant frequency-dependent connectome alterations in MDD in left inferior parietal, inferior temporal, precentral, and fusiform cortices and bilateral precuneus. These frequency-dependent connectome alterations are mainly derived by abnormalities of medium- and long-distance connections and are brain network-dependent. Moreover, the connectome alteration of left precuneus in high frequency band (0.16-0.24 Hz) is significantly associated with illness duration. LIMITATIONS: Multisite harmonization model only removed linear site effects. Neurobiological underpinning of alterations in higher frequency (0.16-0.24 Hz) should be further examined by combining fMRI data with respiration, heartbeat and blood flow recordings in future studies. CONCLUSIONS: These results highlight the frequency-dependency of connectome alterations in MDD and the benefit of examining connectome alteration in MDD under a wider frequency band.