scholarly journals Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

2019 ◽  
Author(s):  
Clara Moreau ◽  
Sebastian Urchs ◽  
Kumar Kuldeep ◽  
Pierre Orban ◽  
Catherine Schramm ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Neuropsychiatric Symptoms ◽  
Critical Role ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Imaging Data ◽  
Genome Wide ◽  
Similar Range ◽  
Posterior Insula ◽  
Mirror Effects

Abstract16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear.We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify dimensions contributing to complex idiopathic conditions.CNVs had large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibited worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.

scholarly journals Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Clara A. Moreau ◽  
Sebastian G. W. Urchs ◽  
Kumar Kuldeep ◽  
Pierre Orban ◽  
Catherine Schramm ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Neuropsychiatric Symptoms ◽  
Critical Role ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Imaging Data ◽  
Genome Wide ◽  
Similar Range ◽  
Posterior Insula ◽  
Mirror Effects

Abstract 16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.

scholarly journals Genome-wide molecular effects of the neuropsychiatric 16p11 CNVs in an iPSC-to-iN neuronal model

2020 ◽  
Author(s):  
Thomas R. Ward ◽  
Xianglong Zhang ◽  
Louis C. Leung ◽  
Bo Zhou ◽  
Kristin Muench ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Model ◽  
Copy Number Variants ◽  
Induced Pluripotent Stem Cell ◽  
Neuronal Model ◽  
Autism Spectrum ◽  
Genome Wide ◽  
Induced Pluripotent ◽  
Methylation Patterns

AbstractCopy number variants (CNVs), either deletions or duplications, at the 16p11.2 locus in the human genome are known to increase the risk for autism spectrum disorders (ASD), schizophrenia, and for several other developmental conditions. Here, we investigate the global effects on gene expression and DNA methylation using a 16p11.2 CNV patient-derived induced pluripotent stem cell (iPSC) to induced neuron (iN) cell model system. This approach revealed genome-wide and cell-type specific alterations to both gene expression and DNA methylation patterns and also yielded specific leads on genes potentially contributing to some of the known 16p11.2 patient phenotypes. PCSK9 is identified as a possible contributing factor to the symptoms seen in carriers of the 16p11.2 CNVs. The protocadherin (PCDH) gene family is found to have altered DNA methylation patterns in the CNV patient samples. The iPSC lines used for this study are available through a repository as a resource for research into the molecular etiology of the clinical phenotypes of 16p11.2 CNVs and into that of neuropsychiatric and neurodevelopmental disorders in general.

scholarly journals An Autism Spectrum Disorder Adaptive Identification Based on the Elimination of Brain Connections: A Proof of Long-Range Underconnectivity

2021 ◽  
Author(s):  
Fatima zahra Benabdallah ◽  
Ahmed Drissi El Maliani ◽  
Dounia Lotfi ◽  
Rachid Jennane ◽  
Mohammed El hassouni
Keyword(s):  
Autism Spectrum Disorder ◽  
Functional Connectivity ◽  
Long Range ◽  
Data Exchange ◽  
Brain Connectivity ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Imaging Data ◽  
Brain Imaging Data

Abstract Autism spectrum disorder (ASD) is theoretically characterized by alterations in functional connectivity between brain regions. Many works presented approaches to determine informative patterns that help to predict autism from typical development. However, most of the proposed pipelines are not specifically designed for the autism problem, i.e they do not corroborate with autism theories about functional connectivity. In this paper, we propose a framework that takes into account the properties of local connectivity and long range under-connectivity in the autistic brain. The originality of the proposed approach is to adopt elimination as a technique in order to well emerge the autistic brain connectivity alterations, and show how they contribute to differentiate ASD from controls. Experimental results conducted on the large multi-site Autism Brain Imaging Data Exchange (ABIDE) show that our approach provides accurate prediction up to 70% and succeeds to prove the existence of deficits in the long-range connectivity in the ASD subjects brains.

scholarly journals The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs

2020 ◽  
Author(s):  
Clara Moreau ◽  
Guillaume Huguet ◽  
Sebastian Urchs ◽  
Elise Douard ◽  
Hanad Sharmarke ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Copy Number Variants ◽  
Neuropsychiatric Disorders ◽  
Pleiotropic Effect ◽  
Autism Spectrum ◽  
Hyperactivity Disorder ◽  
Severity Scores ◽  
Psychiatric Conditions ◽  
The Mean ◽  
Neutral Effect

AbstractCopy number variants (CNVs) are among the most highly penetrant genetic risk factors for neuropsychiatric disorders. Their impact on brain connectivity remains mostly unstudied. Because they confer risk for overlapping conditions, we hypothesized that they may converge on shared connectivity patterns.We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, 4 “neutral effect” CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity. The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. Individuals with idiopathic schizophrenia and ASD had similarities in connectivity with neuropsychiatric CNVs. We reported a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders.We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.One sentence summaryNeuropsychiatric CNVs across the genome reorganize brain connectivity architecture along dominant patterns contributing to complex idiopathic conditions.

scholarly journals A-24 Metacognition and behavioral regulation associated with distinct connectivity patterns in autism spectrum disorder

2019 ◽  
Vol 34 (6) ◽  
pp. 883-883
Author(s):  
H Bednarz ◽  
R Kana
Keyword(s):  
Autism Spectrum Disorder ◽  
Executive Function ◽  
Data Exchange ◽  
Brain Connectivity ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Parent Ratings ◽  
Behavioral Regulation ◽  
Imaging Data ◽  
Frontal Pole

Abstract Objective Executive function (EF) deficits are well documented in children with autism spectrum disorder (ASD)1-2 and are commonly measured clinically using parent ratings3. No studies have investigated whether parent ratings of EF predict brain connectivity in ASD. Aim Examine whether the Behavior Rating Inventory of Executive Function (BRIEF) predicts functional brain connectivity in ASD. Method Resting-state fMRI and behavioral data were obtained from the Autism Brain Imaging Data Exchange (ABIDE-II) database6 (n = 106 ASD, ages 5-13). ROI-to-ROI (Region of Interest) connectivity was computed for 132 ROIs spanning the whole brain, defined using Conn Toolbox. Multiple regression analyses examined the effect of BRIEF metacognition on connectivity while controlling for BRIEF behavioral regulation, and vice versa. Age, sex, and full-scale IQ were included as covariates. FDR correction was used (p < 0.05). Results More severe deficits in metacognition were associated with stronger connectivity between the left hippocampus and several ROIs, including the cerebellum and planum temporale. More severe deficits in metacognition were associated with weaker right hippocampus – right frontal pole connectivity. More severe deficits in behavioral regulation were associated with stronger connectivity between subcortical regions (i.e., thalamus, putamen, and caudate) and regions involved in motor (superior frontal gyrus) and limbic systems (cingulate gyrus). More severe behavioral regulation deficits were associated with weaker cerebellar-cerebellar connectivity. Conclusions Findings suggest that parent-ratings of metacognitive abilities in children with ASD are associated with hippocampal connectivity, while behavioral regulation abilities are associated with thalamic and striatum connections. These results build upon previous studies of metacognition and behavioral regulation 5,6.

scholarly journals Structure–Function Connectomics Reveals Aberrant Developmental Trajectory Occurring at Preadolescence in the Autistic Brain

2020 ◽  
Vol 30 (9) ◽  
pp. 5028-5037
Author(s):  
Changchun He ◽  
Huafu Chen ◽  
Lucina Q Uddin ◽  
Asier Erramuzpe ◽  
Paolo Bonifazi ◽  
...  
Keyword(s):  
Structure Function ◽  
Diffusion Tensor ◽  
Critical Role ◽  
Autism Spectrum ◽  
Developmental Trajectory ◽  
Brain Maturation ◽  
Support Vector ◽  
Imaging Data ◽  
Brain Connectome ◽  
Brain Connectomics

Abstract Accumulating neuroimaging evidence shows that age estimation obtained from brain connectomics reflects the level of brain maturation along with neural development. It is well known that autism spectrum disorder (ASD) alters neurodevelopmental trajectories of brain connectomics, but the precise relationship between chronological age (ChA) and brain connectome age (BCA) during development in ASD has not been addressed. This study uses neuroimaging data collected from 50 individuals with ASD and 47 age- and gender-matched typically developing controls (TDCs; age range: 5–18 years). Both functional and structural connectomics were assessed using resting-state functional magnetic resonance imaging and diffusion tensor imaging data from the Autism Brain Imaging Data Exchange repository. For each participant, BCA was estimated from structure–function connectomics through linear support vector regression. We found that BCA matched well with ChA in TDC children and adolescents, but not in ASD. In particular, our findings revealed that individuals with ASD exhibited accelerated brain maturation in youth, followed by a delay of brain development starting at preadolescence. Our results highlight the critical role of BCA in understanding aberrant developmental trajectories in ASD and provide the new insights into the pathophysiological mechanisms of this disorder.

scholarly journals Altered neocortical gene expression, brain overgrowth and functional over-connectivity in Chd8 haploinsufficient mice

2017 ◽  
Author(s):  
Philipp Suetterlin ◽  
Shaun Hurley ◽  
Conor Mohan ◽  
Kimberley L. H. Riegman ◽  
Marco Pagani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Brain Size ◽  
Brain Connectivity ◽  
Neuropsychiatric Symptoms ◽  
Autism Spectrum ◽  
Social Stimuli ◽  
Motor Delay ◽  
Behavioural Phenotypes ◽  
Spectrum Disorders

ABSTRACTTruncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at mid-gestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the down-regulated transcripts. Resting-state functional MRI identified increased synchronised activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioural phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8+/- mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.

scholarly journals Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders

2021 ◽  
Author(s):  
Daniel Roelfs ◽  
Dennis van der Meer ◽  
Dag Alnæs ◽  
Oleksandr Frei ◽  
Robert Loughnan ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Brain Connectivity ◽  
Autism Spectrum ◽  
Genetic Determinants ◽  
Functional Brain ◽  
Hyperactivity Disorder ◽  
Genome Wide ◽  
Genetic Overlap ◽  
The Uk ◽  
Shared Genetic

Psychiatric disorders are complex, heritable, and highly polygenic. Supported by findings of abnormalities in functional magnetic resonance imaging (fMRI) based measures of brain connectivity, current theoretical and empirical accounts have conceptualized them as disorders of brain connectivity and dysfunctional integration of brain signaling, however, the extent to which these findings reflect common genetic factors remains unclear. Here, we performed a multivariate genome-wide association analysis of fMRI-based functional brain connectivity in a sample of 30,701 individuals from the UK Biobank and investigated the shared genetic determinants with seven major psychiatric disorders. The analysis revealed significant genetic overlap between functional brain connectivity and schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety, and major depression, adding further genetic support for the dysconnectivity hypothesis of psychiatric disorders and identifying potential genetic and functional targets for future studies.

The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

2008 ◽  
Vol 15 (2) ◽  
pp. 50-59 ◽  
Author(s):  
Amy Philofsky
Keyword(s):  
Language Development ◽  
Critical Role ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Prevalence Estimates ◽  
Notable Increase ◽  
Screening Assessment ◽  
Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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