RESUMO
The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here, we generated a gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between the frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with interindividual variation in structural connectivity between the left-hemisphere frontal and temporal language cortex, and with the brain-related disorders dyslexia and schizophrenia which often involve affected language. These findings identify region-specific patterns of laminar gene expression as a feature of the brain's language network.
Assuntos
Idioma , Neocórtex , Humanos , Neocórtex/metabolismo , Lobo Temporal/metabolismo , Masculino , Feminino , Esquizofrenia/genética , Esquizofrenia/metabolismo , Neurônios/metabolismo , Lobo Frontal/metabolismo , Transcriptoma , AdultoRESUMO
Importance: Childhood is a crucial developmental phase for mental health and cognitive function, both of which are commonly affected in patients with psychiatric disorders. This neurodevelopmental trajectory is shaped by a complex interplay of genetic and environmental factors. While common genetic variants account for a large proportion of inherited genetic risk, rare genetic variations, particularly copy number variants (CNVs), play a significant role in the genetic architecture of neurodevelopmental disorders. Despite their importance, the relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored. Objective: Investigating CNV associations with dimensions of child psychopathology and cognitive functions. Design Setting and Participants: ABCD® study focuses on a cohort of over 11,875 youth aged 9 to 10, recruited from 21 sites in the US, aiming to investigate the role of various factors, including brain, environment, and genetic factors, in the etiology of mental and physical health from middle childhood through early adulthood. Data analysis occurred from April 2023 to April 2024. Main Outcomes and Measures: In this study, we utilized PennCNV and QuantiSNP algorithms to identify duplications and deletions larger than 50Kb across a cohort of 11,088 individuals from the Adolescent Brain Cognitive Development® study. CNVs meeting quality control standards were subjected to a genome-wide association scan to identify regions associated with quantitative measures of broad psychiatric symptom domains and cognitive outcomes. Additionally, a CNV risk score, reflecting the aggregated burden of genetic intolerance to inactivation and dosage sensitivity, was calculated to assess its impact on variability in overall and dimensional child psychiatric and cognitive phenotypes. Results: In a final sample of 8,564 individuals (mean age=9.9 years, 4,532 males) passing quality control, we identified 4,111 individuals carrying 5,760 autosomal CNVs. Our results revealed significant associations between specific CNVs and our phenotypes of interest, psychopathology and cognitive function. For instance, a duplication at 10q26.3 was associated with overall psychopathology, and somatic complaints in particular. Additionally, deletions at 1q12.1, along with duplications at 14q11.2 and 10q26.3, were linked to overall cognitive function, with particular contributions from fluid intelligence (14q11.2), working memory (10q26.3), and reading ability (14q11.2). Moreover, individuals carrying CNVs previously associated with neurodevelopmental disorders exhibited greater impairment in social functioning and cognitive performance across multiple domains, in particular working memory. Notably, a higher deletion CNV risk score was significantly correlated with increased overall psychopathology (especially in dimensions of social functioning, thought disorder, and attention) as well as cognitive impairment across various domains. Conclusions and Relevance: In summary, our findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology.
RESUMO
Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remains elusive. In this study, we employed pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area, and seven psychiatric disorders in approximately 700,000 individuals of European ancestry. Aggregating regional measures, we identified 50 genetic loci shared between psychiatric disorders and surface area, as well as 26 genetic loci shared with cortical thickness. Risk alleles exhibited bidirectional effects on both cortical thickness and surface area, such that some risk alleles for each disorder increased regional brain size while other risk alleles decreased regional brain size. Due to bidirectional effects, in many cases we observed extensive pleiotropy between an imaging phenotype and a psychiatric disorder even in the absence of a significant genetic correlation between them. The impact of genetic risk for psychiatric disorders on regional brain structure did exhibit a consistent pattern across highly comorbid psychiatric disorders, with 80% of the genetic loci shared across multiple disorders displaying consistent directions of effect. Cortical patterning of genetic overlap revealed a hierarchical genetic architecture, with the association cortex and sensorimotor cortex representing two extremes of shared genetic influence on psychiatric disorders and brain structural variation. Integrating multi-scale functional annotations and transcriptomic profiles, we observed that shared genetic loci were enriched in active genomic regions, converged on neurobiological and metabolic pathways, and showed differential expression in postmortem brain tissue from individuals with psychiatric disorders. Cumulatively, these findings provide a significant advance in our understanding of the overlapping polygenic architecture between psychopathology and cortical brain structure.
RESUMO
Cortical asymmetry is a ubiquitous feature of brain organization that is subtly altered in some neurodevelopmental disorders, yet we lack knowledge of how its development proceeds across life in health. Achieving consensus on the precise cortical asymmetries in humans is necessary to uncover the developmental timing of asymmetry and the extent to which it arises through genetic and later influences in childhood. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in seven datasets and chart asymmetry trajectories longitudinally across life (4-89 years; observations = 3937; 70% longitudinal). We find replicable asymmetry interrelationships, heritability maps, and test asymmetry associations in large-scale data. Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in childhood and peaks in early adulthood. Areal asymmetry is low-moderately heritable (max h2SNP ~19%) and correlates phenotypically and genetically in specific regions, indicating coordinated development of asymmetries partly through genes. In contrast, thickness asymmetry is globally interrelated across the cortex in a pattern suggesting highly left-lateralized individuals tend towards left-lateralization also in population-level right-asymmetric regions (and vice versa), and exhibits low or absent heritability. We find less areal asymmetry in the most consistently lateralized region in humans associates with subtly lower cognitive ability, and confirm small handedness and sex effects. Results suggest areal asymmetry is developmentally stable and arises early in life through genetic but mainly subject-specific stochastic effects, whereas childhood developmental growth shapes thickness asymmetry and may lead to directional variability of global thickness lateralization in the population.
Assuntos
Longevidade , Imageamento por Ressonância Magnética , Adulto , Humanos , Encéfalo , Córtex Cerebral , Lateralidade Funcional , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , FemininoRESUMO
White matter tracts form the structural basis of large-scale brain networks. We applied brain-wide tractography to diffusion images from 30,810 adults (U.K. Biobank) and found significant heritability for 90 node-level and 851 edge-level network connectivity measures. Multivariate genome-wide association analyses identified 325 genetic loci, of which 80% had not been previously associated with brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia, and neurons. The multivariate association profiles implicated 31 loci in connectivity between core regions of the left-hemisphere language network. Polygenic scores for psychiatric, neurological, and behavioral traits also showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to variation in the structural connectome of the human brain.
Assuntos
Conectoma , Substância Branca , Adulto , Humanos , Estudo de Associação Genômica Ampla , Encéfalo , IdiomaRESUMO
Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.
Assuntos
Transtorno do Espectro Autista , Encéfalo , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Vias NeuraisRESUMO
BACKGROUND: Major depressive disorder (MDD) is accompanied by alterations in grey matter volume. However, the biological processes associated with regional structural perturbations remain elusive. METHODS: We applied integrative omics analysis to investigate specialized transcriptome signatures and translational determinants associated with regional grey matter variations in 2737 MDD patients relative to 3098 controls by summarizing the results from gene co-expression network analysis of Allen human brain transcriptome profiles in six donors, enrichment analysis of gene-sets and cellular structure from rodents and mediation analysis of BrainSpan proteome profile in six donors. RESULTS: We found convergent alterations of grey matter volume in MDD were associated with transcriptome profiles enriched for synaptic transmission, metabolism, immune processes and transmembrane transport. Genes with abnormal expression in post-mortem tissue in MDD were also associated with transcriptome signatures. Further gene co-expression network and enrichment analysis of MDD-related genes in these signatures revealed the modules with higher neuronal expression were enriched in the medial temporal cortex and temporo-parietal junction with genes differentially associated with neuronal development and metabolism. Also, the modules with higher non-neuronal (e.g. astrocyte and oligodendrocyte) expression were concentrated in the rostral and dorsal anterior cingulate cortex and were separately associated with immune response and transmembrane transport. Moreover, proteins as the gene expression products mediated the association between transcriptome signatures and brain volume changes in the visual and dorsolateral prefrontal cortex. CONCLUSIONS: Our multidimensional analyses offer a novel approach to detect specific biological pathways that capture regional structural variations in MDD, which suggests structural endophenotypes associated with MDD.
Assuntos
Transtorno Depressivo Maior , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Substância Cinzenta/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7-mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.
Assuntos
Córtex Cerebral/fisiologia , Lateralidade Funcional/genética , Lateralidade Funcional/fisiologia , Idoso , Idoso de 80 Anos ou mais , Comportamento/fisiologia , Bancos de Espécimes Biológicos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Feminino , Mãos , Humanos , Idioma , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Occipital , Córtex Sensório-MotorRESUMO
Cortisol, the end product of the hypothalamic-pituitary-adrenal axis, regulates cognitive function and emotion processing. Cushing's disease, which is characterized by a unique excess of cortisol upon clinical diagnosis, serve as an excellent in vivo "hyperexpression" model to investigate the neurobiological mechanisms of cortisol in the human brain. Previous studies have shown the association between cortisol and functional connectivity within an a priori brain network. However, the whole-brain connectivity pattern that accompanies endogenous cortisol variation is still unclear, as are its associated genetic underpinnings. Here, using resting-state functional magnetic resonance imaging in 112 subjects (60 patients with Cushing's disease and 52 healthy subjects), we performed a voxel-level brain-wide association analysis to investigate the functional connectivity pattern associated with a wide variation in cortisol levels at 8 a.m. The results showed that the regions associated with cortisol as of 8 a.m. were primarily distributed in brain functional hubs involved in self-referential processing, such as the medial prefrontal cortex, anterior and posterior cingulate cortex, and caudate. We also found that regions in the middle temporal, inferior parietal and ventrolateral prefrontal cortex, which is important for social communication tasks, and in the visual and supplementary motor cortex, which is involved in primary sensorimotor perception, were adversely affected by excessive cortisol. The connectivity between these regions was also significantly correlated with neuropsychiatric profiles, such anxiety and depression. Finally, combined neuroimaging and transcriptome analysis showed that functional cortisol-sensitive brain variations were significantly coupled to regional expression of glucocorticoid and mineralocorticoid receptors. These findings reveal cortisol-biased functional signatures in the human brain and shed light on the transcriptional regulation constraints on the cortisol-related brain network.
RESUMO
Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing vs. empathizing cognitive styles, with resemblances to male vs. female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness, and subcortical volume measures in 32,256 participants from the UK Biobank. Polygenic risks for the two disorders were positively correlated (r = 0.08, p = 7.13 × 10-50) and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each polygenic risk score was associated with multivariate brain asymmetry after adjusting for sex, ASD r = 0.03, p = 2.17 × 10-9, and schizophrenia r = 0.04, p = 2.61 × 10-11, but the multivariate patterns were mostly distinct for the two polygenic risks and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both polygenic risks were associated with asymmetries of regions important for language and executive functions, consistent with behavioral associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risks for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Esquizofrenia , Transtorno Autístico/complicações , Encéfalo , Função Executiva , Feminino , Humanos , Idioma , Imageamento por Ressonância Magnética , Masculino , Esquizofrenia/complicações , Esquizofrenia/genéticaRESUMO
Left-right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain's left-right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left-right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits.
Assuntos
Córtex Cerebral/diagnóstico por imagem , Lateralidade Funcional/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Cortisol has long been considered to play a crucial role in the pathogenesis of stress-related disorders. Cushing's disease (CD) provides an excellent "hyperexpression model" to investigate the chronic effects of cortisol on brain physiology and cognition. Previous studies have shown that cortisol is associated with neurophysiological alterations in animal models, which has also been examined by neural activity and cerebral blood flow (CBF) in human studies. However, the manner in which cortisol affects the coupling between brain activity and metabolic demand remains largely unknown. METHODS: Here we used functional magnetic resonance imaging and arterial-spin-labeling imaging to investigate neurophysiological coupling by examining the ratio of CBF and functional connectivity strength (FCS) in 100 participants (47 CD patients and 53 healthy controls). RESULTS: The results showed that CD was associated with lower CBF-FCS coupling predominantly in regions involving cognitive processing, such as the left dorsolateral prefrontal cortex and precuneus, as well as greater CBF-FCS coupling in subcortical structures, including the bilateral thalamus, right putamen, and hippocampus (P < 0.05, false discovery rate corrected). Moreover, regions with disrupted CBF-FCS coupling were associated with cortisol dosage and cognitive decline in CD patients. CONCLUSIONS: Together, these findings elucidate the effect of cortisol excess on cerebral microenvironment regulation and associated cognitive disturbances in the human brain.
Assuntos
Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Hidrocortisona/sangue , Hipersecreção Hipofisária de ACTH/diagnóstico por imagem , Adulto , Encéfalo/metabolismo , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/metabolismo , Marcadores de Spin , Adulto JovemRESUMO
Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. While a cortico-striatal-limbic network has been implicated in the pathophysiology of OCD, the neural correlates of this network in OCD are not well understood. In this study, we examined resting state functional connectivity among regions within the cortico-striatal-limbic OCD neural network, including the rostral anterior cingulate cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, thalamus and caudate, in 44 OCD and 43 healthy participants. We then examined relationships between OCD neural network connectivity and OCD symptom severity in OCD participants. OCD relative to healthy participants showed significantly greater connectivity between the left caudate and bilateral dorsolateral prefrontal cortex. We also found a positive correlation between left caudate-bilateral dorsolateral prefrontal cortex connectivity and depression scores in OCD participants, such that greater positive connectivity was associated with more severe symptoms. This study makes a significant contribution to our understanding of functional networks and their relationship with depression in OCD.
Assuntos
Imageamento por Ressonância Magnética , Rede Nervosa/fisiopatologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Índice de Gravidade de Doença , Adulto , Tonsila do Cerebelo/fisiopatologia , Estudos de Casos e Controles , Córtex Cerebral/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Feminino , Giro do Cíngulo/fisiopatologia , Humanos , Masculino , Rede Nervosa/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Tálamo/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. Neuroimaging studies have implicated altered connectivity among the functional networks of the cerebral cortex in the pathophysiology of OCD. However, there has been no comprehensive investigation of the cross-talk between the cerebellum and functional networks in the cerebral cortex. METHODS: This functional neuroimaging study was completed by 44 adult participants with OCD and 43 healthy control participants. We performed large-scale data-driven brain network analysis to identify functional connectivity patterns using resting-state functional magnetic resonance imaging data. RESULTS: Participants with OCD showed lower functional connectivity within the somatomotor network and greater functional connectivity among the somatomotor network, cerebellum, and subcortical network (e.g., thalamus and pallidum; all p < .005). Network-based statistics analyses demonstrated one component comprising connectivity within the somatomotor network that showed lower connectivity and a second component comprising connectivity among the somatomotor network, and motor regions in particular, and the cerebellum that showed greater connectivity in participants with OCD relative to healthy control participants. In participants with OCD, abnormal connectivity across both network-based statistics-derived components positively correlated with OCD symptom severity (p = .006). CONCLUSIONS: To our knowledge, this study is the first comprehensive investigation of large-scale network alteration across the cerebral cortex, subcortical regions, and cerebellum in OCD. Our findings highlight a critical role of the cerebellum in the pathophysiology of OCD.
Assuntos
Córtex Cerebral , Transtorno Obsessivo-Compulsivo , Adulto , Encéfalo , Cerebelo , Córtex Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Cognitive dysfunction is one of the most prominent characteristics of psychiatric disorders. Currently, the neural correlates of cognitive dysfunction across psychiatric disorders are poorly understood. The aim of this study was to investigate functional connectivity and structural perturbations across psychiatric diagnoses in three neurocognitive networks of interest: the default mode network (DMN), the frontoparietal network (FPN), and the salience network (SN). METHODS: We performed meta-analyses of resting-state functional magnetic resonance imaging whole-brain seed-based functional connectivity in 8298 patients (involving eight disorders) and 8165 healthy control subjects and a voxel-based morphometry analysis of structural magnetic resonance imaging data in 14,027 patients (involving eight disorders) and 14,504 healthy control subjects. To aid the interpretation of the results, we examined neurocognitive function in 776 healthy participants from the Human Connectome Project. RESULTS: We found that the three neurocognitive networks of interest were characterized by shared alterations of functional connectivity architecture across psychiatric disorders. More specifically, hypoconnectivity was expressed between the DMN and ventral SN and between the SN and FPN, whereas hyperconnectivity was evident between the DMN and FPN and between the DMN and dorsal SN. This pattern of network alterations was associated with gray matter reductions in patients and was localized in regions that subserve general cognitive performance. CONCLUSIONS: This study is the first to provide meta-analytic evidence of common alterations of functional connectivity within and between neurocognitive networks. The findings suggest a shared mechanism of network interactions that may associate with the generalized cognitive deficits observed in psychiatric disorders.
Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Transtornos Mentais/fisiopatologia , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Adulto , Estudos de Casos e Controles , Transtornos Cognitivos/complicações , Conectoma , Feminino , Neuroimagem Funcional , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos Mentais/complicações , Adulto JovemRESUMO
Neuropsychiatric disorders are increasingly conceptualized as disconnection syndromes that are associated with abnormal network integrity in the brain. However, whether different neuropsychiatric disorders show commonly dysfunctional connectivity architectures in large-scale brain networks remains largely unknown. Here, we performed a meta-connectomic study to identify disorder-related functional modules and brain regions by combining meta-analyses of 182 published resting-state functional MRI studies in 11 neuropsychiatric disorders and graph-theoretical analyses of 3 independent resting-state functional MRI datasets with healthy and diseased populations (Alzheimer's disease and major depressive disorder [MDD]). Three major functional modules, the default mode, frontoparietal, and sensorimotor networks were commonly abnormal across disorders. Moreover, most of the disorders preferred to target the network connector nodes that were primarily involved in intermodule communications and multiple cognitive components. Apart from these common dysfunctions, different brain disorders were associated with specific alterations in network modules and connector regions. Finally, these meta-connectomic findings were confirmed by two empirical example cases of Alzheimer's disease and MDD. Collectively, our findings shed light on the shared biological mechanisms of network dysfunctions of diverse disorders and have implications for clinical diagnosis and treatment from a network perspective.
Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Conectoma/métodos , Transtorno Depressivo Maior/fisiopatologia , Adulto , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Adulto JovemRESUMO
AIMS: Deep brain stimulation of the subthalamic nucleus (STN-DBS) has become an effective treatment strategy for patients with Parkinson's disease. However, the biological mechanism underlying DBS treatment remains poorly understood. METHOD: In this study, we investigated how STN-DBS modulated the brain network using a bimodal positron emission tomography (PET)/functional magnetic resonance imaging (fMRI) dataset. We first performed an activation likelihood estimation meta-analysis of 13 PET/SPECT studies concerning STN-DBS effects on resting-state brain activity in Parkinson's disease. Additionally, using a functional connectivity analysis in resting-state fMRI, we investigated whether these STN-DBS-affected regions were functionally connected to constitute an effective network. RESULTS: The results revealed that STN-DBS reduced brain activity in the right thalamus, bilateral caudal supplementary area, and the left primary motor cortex, and it increased brain activity in the left thalamus during rest. Second, these STN-DBS-affected areas were functionally connected within an STN-DBS effective network. CONCLUSION: Deep brain stimulation of the subthalamic nucleus (STN-DBS) may deactivate the motor cortex as a remote and network effect, affecting the target and the neighboring subcortical areas. These areas may constitute an effective network of STN-DBS modulation. Our results shed light on the mechanisms of STN-DBS treatment from a network perspective and highlight the potential therapeutic benefits of targeted network modulation.
Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Núcleo Subtalâmico/diagnóstico por imagem , Núcleo Subtalâmico/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Imagem Multimodal , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , DescansoRESUMO
Objective To explore the temporal and spatial distribution of CCAAT/enhancer-binding protein homologous protein (CHOP) and calnexin (CNX) in the dentate gyrus of mesial temporal lobe epilepsy (mTLE) mouse model. Methods We used kainic acid (KA) to induce acute phase (12 h and 24 h) mTLE mouse models and performed Western blotting and immunofluorescence to detect the different expressions and distribution pattern of CHOP and CNX in CA3 of the hippocampus. Results Compared with the controls,the expressions of CHOP(F=1.136,P=0.4069) and CNX (F=2.378,P=0.2087) did not increase in CA3 of hippocampus 12 h following KA injection in the acute phase of mTLE mouse models,whereas the expressions in CA1 and CA3 of hippocampus 24 h after injection were significantly higher (F=8.510,P=0.0362;F=6.968,P=0.0497,respectively). As shown by immunofluorescence analysis,CHOP was expressed mainly in CA3 of hippocampus 12 h after KA injection,and increased in CA1 and CA3 24 h after KA administration. Compared with the controls,the expressions of CHOP(F=24.480,P=0.0057) and CNX (F=7.149,P=0.0478) were significantly higher 24 h after KA injection.Conclusions The expression of CHOP increases along with the progression of seizures,indicating the increased level of endoplasmic reticulum stress. An increasing number of CNX,which serves as molecular chaperone,may be needed to facilitate the unfolded protein to complete the folding process.
Assuntos
Giro Denteado/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Fator de Transcrição CHOP/metabolismo , Animais , Calnexina/metabolismo , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Ácido Caínico , Camundongos , Convulsões/induzido quimicamente , Convulsões/metabolismoRESUMO
Mesial temporal lobe epilepsy (mTLE) is the main type and most common medically intractable form of epilepsy. Severity of disease-based stratified samples may help identify new disease-associated mutant genes. We analyzed mRNA expression profiles from patient hippocampal tissue. Three of the seven patients had severe mTLE with generalized-onset convulsions and consciousness loss that occurred over many years. We found that compared with other groups, patients with severe mTLE were classified into a distinct group. Whole-exome sequencing and Sanger sequencing validation in all seven patients identified three novel SUN domain-containing ossification factor (SUCO) mutations in severely affected patients. Furthermore, SUCO knock down significantly reduced dendritic length in vitro. Our results indicate that mTLE defects may affect neuronal development, and suggest that neurons have abnormal development due to lack of SUCO, which may be a generalized-onset epilepsy-related gene.
Assuntos
Epilepsia do Lobo Temporal/genética , Exoma , Proteínas de Membrana/genética , Adulto , Idoso , Sequência de Aminoácidos , Animais , Estudos de Casos e Controles , Células Cultivadas , Córtex Cerebral/citologia , Dendritos/ultraestrutura , Epilepsia do Lobo Temporal/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Neurônios/metabolismo , Neurônios/ultraestrutura , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Adulto JovemRESUMO
Notch signaling in the nervous system is often regarded as a developmental pathway. However, recent studies have suggested that Notch is associated with neuronal discharges. Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues. Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity. In contrast, pretreatment with exogenous Jagged1 to elevate Notch signaling before KA application had proconvulsant effects. In vivo, we demonstrated that the impacts of activated Notch signaling on seizures can in part be attributed to the regulatory role of Notch signaling on excitatory synaptic activity in CA1 pyramidal neurons. In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons. Taken together, our findings suggest a correlation between aberrant Notch signaling and epileptic seizures. Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures.