Altered Brain Research Articles

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's disease (AD) is the fifth leading cause of death in older adults, and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a threefold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse [via a model of hindlimb immobilization (HLI)] on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-mo-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of amyloid precursor protein (APP) and tau protein in the hippocampus, 4) and reduced brain-derived neurotrophic factor (BDNF) expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.NEW & NOTEWORTHY Muscle disuse via hindlimb immobilization increased oxidative stress and insulin resistance in the hippocampus. These findings were in association with muscle iron overload in connection with iron dysregulation in the brain. Overall, our work identifies muscle disuse as a contributor to hippocampal dysfunction, potentially through an iron-based muscle-brain axis, highlighting iron dysregulation as a potential novel mechanism in the relationship between muscle health, cognitive function, and Alzheimer's disease risk.

Meningeal lymphatic function promotes oligodendrocyte survival and brain myelination

The precise neurophysiological changes prompted by meningeal lymphatic dysfunction remain unclear. Here, we showed that inducing meningeal lymphatic vessel ablation in adult mice led to gene expression changes in glial cells, followed by reductions in mature oligodendrocyte numbers and specific lipid species in the brain. These phenomena were accompanied by altered meningeal adaptive immunity and brain myeloid cell activation. During brain remyelination, meningeal lymphatic dysfunction provoked a state of immunosuppression that contributed to delayed spontaneous oligodendrocyte replenishment and axonal loss. The deficiencies in mature oligodendrocytes and neuroinflammation due to impaired meningeal lymphatic function were solely recapitulated in immunocompetent mice. Patients diagnosed with multiple sclerosis presented reduced vascular endothelial growth factor C in the cerebrospinal fluid, particularly shortly after clinical relapses, possibly indicative of poor meningeal lymphatic function. These data demonstrate that meningeal lymphatics regulate oligodendrocyte function and brain myelination, which might have implications for human demyelinating diseases.

Altered cingulate gyrus subregions functional connectivity in chronic insomnia disorder with anxiety

BackgroundChronic insomnia disorder (CID) is commonly associated with mood disorders. The cingulate gyrus (CG) plays a critical role in the pathophysiology of CID and anxiety. However, the specific characteristics of altered brain networks in the CG in CID with anxiety remain unclear. This study aimed to investigate the characteristics of CG functional connectivity (FC) in CID with and without anxiety. Methods: Resting-state functional magnetic resonance imaging was conducted on 92 CID and 36 healthy controls (HC). CID was divided into CID with anxiety (CID-A, N = 37) and CID without anxiety (CID-NA, N = 55) groups based on anxiety scores. Using the Human Brainnetome Atlas, the subregion CG FC network was constructed. ResultsCompared with HC, CID showed significantly decreased CG FC with the precuneus, middle frontal gyrus (MFG), and hippocampus, while showing significantly increased CG FC with the middle temporal gyrus (MTG)/superior temporal gyrus (STG). In contrast, CID-A showed significantly decreased CG FC with the salience network (insular, putamen) and default mode network (MTG/STG and inferior parietal lobule), while showing significantly increased CG FC with the thalamus and MFG compared to CID-NA. Further, CID-A and CID-NA could be classified with 84.21 % accuracy by using the CG FCs as features. Among these features, the CG FC with MFG, thalamus, and putamen had the highest contribution weights. ConclusionThis study revealed specific changes in the brain network of the CG subregion in CID-A. Understanding these CG FC alterations can help identify potential biomarkers specific to CID-A, which may be valuable for early detection and differentiation from other CID subtypes.

Schizophrenia and Neurodevelopment: Insights From Connectome Perspective.

Schizophrenia is conceptualized as a brain connectome disorder that can emerge as early as late childhood and adolescence. However, the underlying neurodevelopmental basis remains unclear. Recent interest has grown in children and adolescent patients who experience symptom onset during critical brain development periods. Inspired by advanced methodological theories and large patient cohorts, Chinese researchers have made significant original contributions to understanding altered brain connectome development in early-onset schizophrenia (EOS). We conducted a search of PubMed and Web of Science for studies on brain connectomes in schizophrenia and neurodevelopment. In this selective review, we first address the latest theories of brain structural and functional development. Subsequently, we synthesize Chinese findings regarding mechanisms of brain structural and functional abnormalities in EOS. Finally, we highlight several pivotal challenges and issues in this field. Typical neurodevelopment follows a trajectory characterized by gray matter volume pruning, enhanced structural and functional connectivity, improved structural connectome efficiency, and differentiated modules in the functional connectome during late childhood and adolescence. Conversely, EOS deviates with excessive gray matter volume decline, cortical thinning, reduced information processing efficiency in the structural brain network, and dysregulated maturation of the functional brain network. Additionally, common functional connectome disruptions of default mode regions were found in early- and adult-onset patients. Chinese research on brain connectomes of EOS provides crucial evidence for understanding pathological mechanisms. Further studies, utilizing standardized analyses based on large-sample multicenter datasets, have the potential to offer objective markers for early intervention and disease treatment.

Large-scale meta-analyses and network analyses of neural substrates underlying human escalated aggression

Escalated aggression represents a frequent and severe form of violence, sometimes manifesting as antisocial behavior. Driven by the pressures of modern life, escalated aggression is of particular concern due to its rising prevalence and its destructive impact on both individual well-being and socioeconomic stability. However, a consistent neural circuitry underpinning it remains to be definitively identified. Here, we addressed this issue by comparing brain alterations between individuals with escalated aggression and those without such behavioral manifestations. We first conducted a meta-analysis to synthesize previous neuroimaging studies on functional and structural alterations of escalated aggression (325 experiments, 2997 foci, 16,529 subjects). Following-up network and functional decoding analyses were conducted to provide quantitative characterizations of the identified brain regions. Our results revealed that brain regions constantly involved in escalated aggression were localized in the subcortical network (amygdala and lateral orbitofrontal cortex) associated with emotion processing, the default mode network (dorsal medial prefrontal cortex and middle temporal gyrus) associated with mentalizing, and the salience network (anterior cingulate cortex and anterior insula) associated with cognitive control. These findings were further supported by additional meta-analyses on emotion processing, mentalizing, and cognitive control, all of which showed conjunction with the brain regions identified in the escalated aggression. Together, these findings advance the understanding of the risk biomarkers of escalated aggressive populations and refine theoretical models of human aggression.

Thyroid Hormone and Alzheimer's: Bridging Epidemiology to Mechanism.

The identification of critical factors that can worsen the mechanisms contributing to the pathophysiology of Alzheimer's is paramount. Thyroid hormones (TH) fit this criterion. Epidemiological studies have identified an association between altered circulating TH levels and Alzheimer's. The study of human and animal models indicates that TH can affect all the main cellular, molecular, and genetic mechanisms known as hallmarks of Alzheimer's. This is true not only for the excessive production in the brain of protein aggregates leading to amyloid plaques and neurofibrillary tangles but also for the clearance of these molecules from the brain parenchyma via the blood-brain barrier and for the escalated process of neuroinflammation-and even for the effects of carrying Alzheimer's-associated genetic variants. Suboptimal TH levels result in a greater accumulation of protein aggregates in the brain. The direct TH regulation of critical genes involved in amyloid beta production and clearance is remarkable, affecting the expression of multiple genes, including APP (related to amyloid beta production), APOE, LRP1, TREM2, AQP4, and ABCB1 (related to amyloid beta clearance). TH also affects microglia by increasing their migration and function and directly regulating the immunosuppressor gene CD73, impacting the immune response of these cells. Studies aiming to understand the mechanisms that could explain how changes in TH levels can contribute to the brain alterations seen in patients with Alzheimer's are ongoing. These studies have potential implications for the management of patients with Alzheimer's and ultimately can contribute to devising new interventions for these conditions.

Olympic team rowers and team swimmers show altered functional brain activation during working memory and action inhibition

BackgroundHigh-level expertise in team-sports is associated with superior performance on executive functions (EFs) such as working memory (WM) and action inhibition, and with altered activation of brain areas related to these EFs. In most such studies, athletes were sampled from the domain of dynamic (i.e., open-skill) team-sports (e.g., soccer players). Whether static (i.e., closed-skill) team-sports athletes (e.g., rowers and synchronized swimmers) also show superior EFs performance and differential EF-related functional brain activation remains unknown. MethodsWe recruited 14 elite closed-skill athletes, all national champions, and internationally competitive in various rowing disciplines, as well as 14 controls matched on gender, age, and education, and had them perform working memory and action inhibition (stop-signal) tasks during fMRI scanning. ResultsGroup differences in performance in either task failed to obtain statistical significance, although athletes showed a numerical trend toward higher WM capacity than controls. Importantly, task-related BOLD responses suggested that Olympic closed-skill team athletes show stronger recruitment of brain areas that emphasize relatively stable task demands and weaker engagement of brain areas that emphasize rapidly changing demands imposed by extraneous stimulation. ConclusionFunctional brain imaging data suggest elite closed-skill athletes may employ different cognitive strategies.

Maternal immune activation by toll-like receptor 7 agonist during mid-gestation increases susceptibility to blood-brain barrier leakage after puberty

Maternal immune activation (MIA), a maternal stressor, increases risk for neuropsychiatric diseases, such as Major Depressive Disorder in offspring. MIA of toll-like receptor 7 (TLR7) initiates an immune response in mother and fetuses in a sex-selective manner. The paraventricular nucleus of the hypothalamus (PVN), a brain region that is sexually dimorphic and regulates hypothalamic-pituitary-adrenal (HPA) stress responses, have been tied to stress-related behaviors (i.e., depression, anxiety, social impairments). The current study characterized the sex-selective impact of mid-gestational TLR7 activation on PVN vasculature of adult offspring based on a prior study of excess prenatal glucocorticoid stress. The PVN of offspring were evaluated to determine if fetal MIA impacted vascular leakage in the brains of adult mice with or without restraint stress. Timed-pregnant female mice were administered the TLR7 agonist Resiquimod (RQ) or saline vehicle on embryonic day (E) 12.5. Basal and restraint stress-induced corticosterone was measured to examine changes in stress response. Mice were perfused transcardially with fluorescein isothiocyanate (FITC) to assess blood vessel integrity. Sections with FITC-labeled blood vessels through the PVN of offspring were immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet) and IBA-1 (microglia). MIA with RQ led to elevated levels of plasma corticosterone 60-minutes after restraint in offspring, suggesting prenatal RQ impairs glucocorticoid negative feedback. Blood-brain barrier integrity was assessed. Adult offspring of RQ injected dams showed greater leakage in the PVN (greater in males than females). GFAP+ colocalization with FITC-labeled vessels was lower in the PVN of offspring from RQ treated dams, potentially contributing to the observed increased FITC leakage. Microglia were examined in relation to the vasculature as an indicator of a neuroimmune response. Data show IBA-1+ cells greater in size and number in the PVN with closer proximity to blood vessels after maternal injection of RQ in a male-selective manner. Microglia were unchanged in females from RQ-treated dams but were smaller in size after restraint. This study provides support for sex-selective influences of fetal immune antecedents for altered brain vascular and blood brain barrier development and adult neuroendocrine function that could indicate a PVN locus for increased susceptibility for adult disorders.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Comparative Pharmacokinetics of Δ9-Tetrahydrocannabinol in Adolescent and Adult Female Mice.

Introduction: Animal studies suggest that adolescent exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the intoxicating constituent of cannabis, causes lasting functional alterations in brain and other organs. Those studies often neglect the impact that age- and sex-dependent differences in the distribution and metabolism of the drug might exert on its pharmacological effects. Here, we provide a comparative analysis of Δ9-THC pharmacokinetics in adolescent and adult female mice, which identify significant dissimilarities in distribution and metabolism of Δ9-THC between females of these age groups. Materials and Methods: We administered Δ9-THC (5 mg/kg, intraperitoneal) to adolescent (37-day old) and young adult (70-day old) female mice and quantified Δ9-THC and its first-pass metabolites-11-hydroxy-Δ9-THC (11-OH-THC) and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC)-in plasma and brain tissue using liquid chromatography/tandem mass spectrometry. Results: Maximal plasma concentrations of Δ9-THC were 8 times higher in adolescent than adult female mice. Conversely, brain concentrations and brain-to-plasma ratios were 25-50% higher in adults than adolescents. Concentrations of Δ9-THC metabolites were higher in plasma but lower in brain of adolescent compared to adult female mice. Conclusions: The results identify multiple age-dependent differences in the pharmacokinetic properties of Δ9-THC in female mice, which might influence the pharmacological response to the drug.

Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration.

The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naïve, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.

Patients recovering from COVID-19 who presented with anosmia during their acute episode have behavioral, functional, and structural brain alterations

Patients recovering from COVID-19 commonly exhibit cognitive and brain alterations, yet the specific neuropathological mechanisms and risk factors underlying these alterations remain elusive. Given the significant global incidence of COVID-19, identifying factors that can distinguish individuals at risk of developing brain alterations is crucial for prioritizing follow-up care. Here, we report findings from a sample of patients consisting of 73 adults with a mild to moderate SARS-CoV-2 infection without signs of respiratory failure and 27 with infections attributed to other agents and no history of COVID-19. The participants underwent cognitive screening, a decision-making task, and MRI evaluations. We assessed for the presence of anosmia and the requirement for hospitalization. Groups did not differ in age or cognitive performance. Patients who presented with anosmia exhibited more impulsive alternative changes after a shift in probabilities (r = − 0.26, p = 0.001), while patients who required hospitalization showed more perseverative choices (r = 0.25, p = 0.003). Anosmia correlated with brain measures, including decreased functional activity during the decision-making task, thinning of cortical thickness in parietal regions, and loss of white matter integrity. Hence, anosmia could be a factor to be considered when identifying at-risk populations for follow-up.

Gut microbiota-brain bile acid axis orchestrates aging-related neuroinflammation and behavior impairment in mice

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TβMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TβMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TβMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.

Local functional connectivity abnormalities in mild cognitive impairment and Alzheimer's disease: A meta-analytic investigation using minimum Bayes factor activation likelihood estimation

Functional magnetic resonance imaging research employing regional homogeneity (ReHo) analysis has uncovered aberrant local brain connectivity in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in comparison with healthy controls. However, the precise localization, extent, and possible overlap of these aberrations are still not fully understood. To bridge this gap, we applied a novel meta-analytic and Bayesian method (minimum Bayes Factor Activation Likelihood Estimation, mBF-ALE) for a systematic exploration of local functional connectivity alterations in MCI and AD brains. We extracted ReHo data via a standardized MEDLINE database search, which included 35 peer-reviewed experiments, 1,256 individuals with AD or MCI, 1,118 healthy controls, and 205 x-y-z coordinates of ReHo variation. We then separated the data into two distinct datasets: one for MCI and the other for AD. Two mBF-ALE analyses were conducted, thresholded at “very strong evidence” (mBF ≥ 150), with a minimum cluster size of 200 mm³. We also assessed the spatial consistency and sensitivity of our Bayesian results using the canonical version of the ALE algorithm. For MCI, we observed two clusters of ReHo decrease and one of ReHo increase. Decreased local connectivity was notable in the left precuneus (Brodmann area – BA 7) and left inferior temporal gyrus (BA 20), while increased connectivity was evident in the right parahippocampal gyrus (BA 36). The canonical ALE confirmed these locations, except for the inferior temporal gyrus. In AD, one cluster each of ReHo decrease and increase were found, with decreased connectivity in the right posterior cingulate cortex (BA 30 extending to BA 23) and increased connectivity in the left posterior cingulate cortex (BA 31). These locations were confirmed by the canonical ALE. The identification of these distinct functional connectivity patterns sheds new light on the complex pathophysiology of MCI and AD, offering promising directions for future neuroimaging-based interventions. Additionally, the use of a Bayesian framework for statistical thresholding enhances the robustness of neuroimaging meta-analyses, broadening its applicability to small datasets.

Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Regular cannabis use modulates gamma activity in brain regions serving motor control.

People who regularly use cannabis exhibit altered brain dynamics during cognitive control tasks, though the impact of regular cannabis use on the neural dynamics serving motor control remains less understood. We sought to investigate how regular cannabis use modulates the neural dynamics serving motor control. Thirty-four people who regularly use cannabis (cannabis+) and 33 nonusers (cannabis-) underwent structured interviews about their substance use history and performed the Eriksen flanker task to map the neural dynamics serving motor control during high-density magnetoencephalography (MEG). The resulting neural data were transformed into the time-frequency domain to examine oscillatory activity and were imaged using a beamforming approach. MEG sensor-level analyses revealed robust beta (16-24 Hz) and gamma oscillations (66-74 Hz) during motor planning and execution, which were imaged using a beamformer. Both responses peaked in the left primary motor cortex and voxel time series were extracted to evaluate the spontaneous and oscillatory dynamics. Our key findings indicated that the cannabis+ group exhibited weaker spontaneous gamma activity in the left primary motor cortex relative to the cannabis- group, which scaled with cannabis use and behavioral metrics. Interestingly, regular cannabis use was not associated with differences in oscillatory beta and gamma activity, and there were no group differences in spontaneous beta activity. Our findings suggest that regular cannabis use is associated with suppressed spontaneous gamma activity in the left primary motor cortex, which scales with the degree of cannabis use disorder symptomatology and is coupled to behavioral task performance.

Exploring cognitive related microstructural alterations in normal appearing white matter and deep grey matter for small vessel disease: A quantitative susceptibility mapping study

Brain microstructural alterations possibly occur in the normal-appearing white matter (NAWM) and grey matter of small vessel disease (SVD) patients, and may contribute to cognitive impairment. The aim of this study was to explore cognitive related microstructural alterations in white matter and deep grey matter nuclei in SVD patients using magnetic resonance (MR) quantitative susceptibility mapping (QSM). 170 SVD patients, including 103 vascular mild cognitive impairment (VaMCI) and 67 no cognitive impairment (NCI), and 21 healthy control (HC) subjects were included, all underwent a whole-brain QSM scanning. Using a white matter and a deep grey matter atlas, subregion-based QSM analysis was conducted to identify and characterize microstructural alterations occurring within white matter and subcortical nuclei. Significantly different susceptibility values were revealed in NAWM and in several specific white matter tracts including anterior limb of internal capsule, corticospinal tract, medial lemniscus, middle frontal blade, superior corona radiata and tapetum among VaMCI, NCI and HC groups. However, no difference was found in white matter hyperintensities between VaMCI and NCI. A trend toward higher susceptibility in the caudate nucleus and globus pallidus of VaMCI patients compared to HC, indicating elevated iron deposition in these areas. Interestingly, some of these QSM parameters were closely correlated with both global and specific cognitive function scores, controlling age, gender and education level. Our study suggested that QSM may serve as a useful imaging tool for monitoring cognitive related microstructural alterations in brain. This is especially meaningful for white matter which previously lacks of attention.

Diagnostic value of structural, functional and effective connectivity in bipolar disorder.

The aim of this systematic review is to assess the functional magnetic resonance imaging (fMRI) studies of bipolar disorder (BD) patients that characterize differences in terms of structural, functional, and effective connectivity between the patients with BD, patients with other psychiatric disorders and healthy controls as possible biomarkers for diagnosing the disorder using neuroimaging. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), guidelines a systematic search for recent (since 2015) original studies on connectivity in bipolar disorder was conducted in PUBMED and SCOPUS. A total of 60 studies were included in this systematic review: 20 of the structural connectivity, 33 of the functional connectivity, and only 7 of the studies focused on effective connectivity complied with the inclusion and exclusion criteria. Despite the great heterogeneity in the findings, there are several trends that emerge. In structural connectivity studies, the main abnormalities in bipolar disorder patients were in the frontal gyrus, anterior, as well as posterior cingulate cortex and differences in emotion and reward-related networks. Cerebellum (vermis) to cerebrum functional connectivity was found to be the most common finding in BD. Moreover, prefrontal cortex and amygdala connectivity as part of the rich-club hubs were often reported to be disrupted. The most common findings based on effective connectivity were alterations in salience network, default mode network and executive control network. Although more studies with larger sample sizes are needed to ascertain altered brain connectivity as diagnostic biomarker, there is a perspective that the method could be used as a single marker of diagnosis in the future, and the process of adoption could be accelerated by using approaches such as semiunsupervised machine learning.

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

IBS stress reactivity phenotype is associated with blood transcriptome profiles and microstructural and functional brain changes.

Clinical evidence suggests significant interindividual differences in stress reactivity (SR), but biological mechanisms and therapeutic implications of these differences are poorly understood. We aimed to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of increased sympathetic nervous system (SNS) activation and brain imaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs). A cross-sectional observational study design, transcriptomics profiling, multimodal brain imaging, and psychosocial assessments were obtained in 291 female and male IBS participants and HCs. Prior to analyses, unsupervised clustering was applied to derive high and low SR subgroups across participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression. The high, compared to low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Brain imaging showed neuroplastic changes in the high SR group consistent with an upregulation of ascending arousal systems and sensory processing and integration regions, and functional connectivity changes in the central autonomic network. SR moderated the sex difference in extraintestinal symptoms. The findings support a model of tonically increased SNS activity as a plausible risk factor for increased autonomic reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater prevalence in IBS. These findings may have important implications for personalized treatment interventions in IBS.