The morphometric co-atrophy networking of schizophrenia, autistic and obsessive spectrum disorders.
ABSTRACT: By means of a novel methodology that can statistically derive patterns of co-alterations distribution from voxel-based morphological data, this study analyzes the patterns of brain alterations of three important psychiatric spectra-that is, schizophrenia spectrum disorder (SCZD), autistic spectrum disorder (ASD), and obsessive-compulsive spectrum disorder (OCSD). Our analysis provides five important results. First, in SCZD, ASD, and OCSD brain alterations do not distribute randomly but, rather, follow network-like patterns of co-alteration. Second, the clusters of co-altered areas form a net of alterations that can be defined as morphometric co-alteration network or co-atrophy network (in the case of gray matter decreases). Third, within this network certain cerebral areas can be identified as pathoconnectivity hubs, the alteration of which is supposed to enhance the development of neuronal abnormalities. Fourth, within the morphometric co-atrophy network of SCZD, ASD, and OCSD, a subnetwork composed of eleven highly connected nodes can be distinguished. This subnetwork encompasses the anterior insulae, inferior frontal areas, left superior temporal areas, left parahippocampal regions, left thalamus and right precentral gyri. Fifth, the co-altered areas also exhibit a normal structural covariance pattern which overlaps, for some of these areas (like the insulae), the co-alteration pattern. These findings reveal that, similarly to neurodegenerative diseases, psychiatric disorders are characterized by anatomical alterations that distribute according to connectivity constraints so as to form identifiable morphometric co-atrophy patterns.
Project description:<h4>Background</h4>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by atypical brain anatomy and connectivity. Graph-theoretical methods have mainly been applied to detect altered patterns of white matter tracts and functional brain activation in individuals with ASD. The network topology of gray matter (GM) abnormalities in ASD remains relatively unexplored.<h4>Methods</h4>An innovative meta-connectomic analysis on voxel-based morphometry data (45 experiments, 1,786 subjects with ASD) was performed in order to investigate whether GM variations can develop in a distinct pattern of co-alteration across the brain. This pattern was then compared with normative profiles of structural and genetic co-expression maps. Graph measures of centrality and clustering were also applied to identify brain areas with the highest topological hierarchy and core sub-graph components within the co-alteration network observed in ASD.<h4>Results</h4>Individuals with ASD exhibit a distinctive and topologically defined pattern of GM co-alteration that moderately follows the structural connectivity constraints. This was not observed with respect to the pattern of genetic co-expression. Hub regions of the co-alteration network were mainly left-lateralized, encompassing the precuneus, ventral anterior cingulate, and middle occipital gyrus. Regions of the default mode network appear to be central in the topology of co-alterations.<h4>Conclusion</h4>These findings shed new light on the pathobiology of ASD, suggesting a network-level dysfunction among spatially distributed GM regions. At the same time, this study supports pathoconnectomics as an insightful approach to better understand neuropsychiatric disorders.
Project description:One quarter of veterans returning from the 1990-1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task ("see a letter, push a button") performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia-anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction.
Project description:It is becoming clearer that the impact of brain diseases is more convincingly represented in terms of co-alterations rather than in terms of localization of alterations. In this context, areas characterized by a long mean distance of co-alteration may be considered as hubs with a crucial role in the pathology. We calculated meta-analytic transdiagnostic networks of co-alteration for the gray matter decreases and increases, and we evaluated the mean Euclidean, fiber-length, and topological distance of its nodes. We also examined the proportion of co-alterations between canonical networks, and the transdiagnostic variance of the Euclidean distance. Furthermore, disease-specific analyses were conducted on schizophrenia and Alzheimer's disease. The anterodorsal prefrontal cortices appeared to be a transdiagnostic hub of long-distance co-alterations. Also, the disease-specific analyses showed that long-distance co-alterations are more able than classic meta-analyses to identify areas involved in pathology and symptomatology. Moreover, the distance maps were correlated with the normative connectivity. Our findings substantiate the network degeneration hypothesis in brain pathology. At the same time, they suggest that the concept of co-alteration might be a useful tool for clinical neuroscience.
Project description:Asymmetries in gray matter alterations raise important issues regarding the pathological co-alteration between hemispheres. Since homotopic areas are the most functionally connected sites between hemispheres and gray matter co-alterations depend on connectivity patterns, it is likely that this relationship might be mirrored in homologous interhemispheric co-altered areas. To explore this issue, we analyzed data of patients with Alzheimer's disease, schizophrenia, bipolar disorder and depressive disorder from the BrainMap voxel-based morphometry database. We calculated a map showing the pathological homotopic anatomical co-alteration between homologous brain areas. This map was compared with the meta-analytic homotopic connectivity map obtained from the BrainMap functional database, so as to have a meta-analytic connectivity modeling map between homologous areas. We applied an empirical Bayesian technique so as to determine a directional pathological co-alteration on the basis of the possible tendencies in the conditional probability of being co-altered of homologous brain areas. Our analysis provides evidence that: the hemispheric homologous areas appear to be anatomically co-altered; this pathological co-alteration is similar to the pattern of connectivity exhibited by the couples of homologues; the probability to find alterations in the areas of the left hemisphere seems to be greater when their right homologues are also altered than vice versa, an intriguing asymmetry that deserves to be further investigated and explained.
Project description:<b>Purpose:</b> This study aimed to explore alterations in functional connectivity (FC) within and between default mode network (DMN), central executive network, and salience network in autism spectrum disorder (ASD) with co-occurring attention deficit hyperactivity disorder (ADHD). <b>Method:</b> A total of 135 individuals' date of the Autism Brain Imaging Data Exchange II was used to compare the ASD+ADHD group with the ASD group in relation to the abnormal within-network and between-network connectivity of the ASD group relative to the TD group; consequently, the correlation analysis between abnormal FC and behavior was performed. <b>Results:</b> The ASD+ADHD group exhibited decreased within-network connectivity in the precuneus of the ventral DMN compared with the ASD group. Among the three groups, the ASD+ADHD group showed lower connectivity, whereas the ASD group had higher connectivity than the TD group, although the effect of the separate <i>post hoc</i> test was not significant. Meanwhile, the ASD+ADHD group showed increased between-network connectivity between the ventral DMN and dorsal DMN and between the ventral DMN and left executive control network, compared with the ASD and TD groups. <b>Conclusion:</b> Dysfunction of DMN in the "triple-network model" is the core evidence for ASD with co-occurring ADHD.
Project description:The pathological brain is characterized by distributed morphological or structural alterations in the grey matter, which tend to follow identifiable network-like patterns. We analysed the patterns formed by these alterations (increased and decreased grey matter values detected with the voxel-based morphometry technique) conducting an extensive transdiagnostic search of voxel-based morphometry studies in a large variety of brain disorders. We devised an innovative method to construct the networks formed by the structurally co-altered brain areas, which can be considered as pathological structural co-alteration patterns, and to compare these patterns with three associated types of connectivity profiles (functional, anatomical, and genetic). Our study provides transdiagnostical evidence that structural co-alterations are influenced by connectivity constraints rather than being randomly distributed. Analyses show that although all the three types of connectivity taken together can account for and predict with good statistical accuracy, the shape and temporal development of the co-alteration patterns, functional connectivity offers the better account of the structural co-alteration, followed by anatomic and genetic connectivity. These results shed new light on the possible mechanisms at the root of neuropathological processes and open exciting prospects in the quest for a better understanding of brain disorders.
Project description:The availability of human pluripotent stem cells (hPSCs) offers the opportunity to generate lineage-specific cells to investigate mechanisms of human diseases specific to brain regions. Here, we report a differentiation paradigm for hPSCs that enriches for hippocampal dentate gyrus (DG) granule neurons. This differentiation paradigm recapitulates the expression patterns of key developmental genes during hippocampal neurogenesis, exhibits characteristics of neuronal network maturation, and produces PROX1+ neurons that functionally integrate into the DG. Because hippocampal neurogenesis has been implicated in schizophrenia (SCZD), we applied our protocol to SCZD patient-derived human induced pluripotent stem cells (hiPSCs). We found deficits in the generation of DG granule neurons from SCZD hiPSC-derived hippocampal NPCs with lowered levels of NEUROD1, PROX1, and TBR1, reduced neuronal activity, and reduced levels of spontaneous neurotransmitter release. Our approach offers important insights into the neurodevelopmental aspects of SCZD and may be a promising tool for drug screening and personalized medicine.
Project description:There are at least two fundamental unanswered questions in the literature on autism spectrum disorders (ASD): Are abnormalities in white (WM) and gray matter (GM) consistent with one another? Are WM morphometric alterations consistent with alterations in the GM of regions connected by these abnormal WM bundles and vice versa? The aim of this work is to bridge this gap. After selecting voxel-based morphometry and diffusion tensor imaging studies comparing autistic and normally developing groups of subjects, we conducted an activation likelihood estimation (ALE) meta-analysis to estimate consistent brain alterations in ASD. Multidimensional scaling was used to test the similarity of the results. The ALE results were then analyzed to identify the regions of concordance between GM and WM areas. We found statistically significant topological relationships between GM and WM abnormalities in ASD. The most numerous were negative concordances, found bilaterally but with a higher prevalence in the right hemisphere. Positive concordances were found in the left hemisphere. Discordances reflected the spatial distribution of negative concordances. Thus, a different hemispheric contribution emerged, possibly related to pathogenetic factors affecting the right hemisphere during early developmental stages. Besides, WM fiber tracts linking the brain structures involved in social cognition showed abnormalities, and most of them had a negative concordance with the connected GM regions. We interpreted the results in terms of altered brain networks and their role in the pervasive symptoms dramatically impairing communication and social skills in ASD patients.
Project description:Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.