scholarly journals Default Mode and Fronto-Parietal Network Associations with IQ Development Across Childhood in Autism

2021 ◽  
Author(s):  
Joshua K Lee ◽  
An Chuen Billy Cho ◽  
Derek S Andrews ◽  
Sally Ozonoff ◽  
Sally J Rogers ◽  
...  
Keyword(s):  
Early Childhood ◽  
Intellectual Disability ◽  
Middle Childhood ◽  
Large Scale ◽  
Distance Matrix ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Compensatory Mechanisms ◽  
Default Mode ◽  
Low Iq

Abstract Background: Intellectual disability affects approximately one third of individuals with autism spectrum disorder (autism), yet a major unresolved question remains concerning the neurobiology that differentiates autistic individuals with and without intellectual disability. IQ is highly variable during childhood. We previously identified subgroups of autistic children with different trajectories of intellectual development from early childhood (2-3½ yeas) up to middle childhood (9-12 years): (a) Persistently-High: Individuals whose intelligence quotients (IQs) remained in the average or better range during this period, (b) Persistently-Low: Individuals whose IQs remained in the range of intellectual disability (IQ < 70) throughout development, and (c) Changers: Individuals whose IQs began in the range of intellectual disability but increased to the borderline or normal IQ range by middle childhood. In the present research, we sought to identify neurobiology that differentiates these trajectory-defined groups within our autism cohort in two brain networks with established links to intellectual functioning and its impairment in (1) the frontoparietal network (FPN), and (2) the default mode network (DMN). Methods: We conducted multivariate distance matrix regression (MDMR) and effect size analyses to examine the volumes of 22 brain regions (11 regions x 2 hemispheres) within the FPN and 24 (12 regions x 2 hemispheres) within the DMN in 48 Persistently-High (18 female), 108 Persistently-Low (32 female), and 109 Changers (39 female) using structural MRI that had been acquired at baseline, and IQ measurements from up to three time points spanning early to middle childhood (Mean Age Time 1: 3.2 years; Time 2: 5.4 years; Time 3: 11.3 years). FPN and DMN network regions of interest were defined on the basis of the large-scale networks defined in Smith et al., (2009).Results: Changers exhibited different DMN network structure from both Persistently-Low and Persistently-High trajectory groups at baseline, but the Persistently-High did not differ from the Persistently-Low group, suggesting that DMN structure may be an early predictor for change in IQ trajectory across childhood. In contrast, Persistently-High exhibited differences in the FPN from both Persistently-Low and Changers groups at baseline, suggesting a difference related more to concurrent IQ and the absence of intellectual disability. Conclusions: Within autism, DMN structure at baseline may differentiate individuals with persistently low IQ from those with more transitory low IQ that improves to the borderline range or better through early childhood, potentially indicating compensatory mechanisms which may be targeted by future interventions. The brain structure differences between these three IQ-based subgroups may be indicative of distinct neural underpinnings of autism phenotypic subtypes.

scholarly journals Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

2020 ◽  
Author(s):  
Kristen R. Maynard ◽  
Leonardo Collado-Torres ◽  
Lukas M. Weber ◽  
Cedric Uytingco ◽  
Brianna K. Barry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Web Application ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Sequencing Data ◽  
Dorsolateral Prefrontal ◽  
Transcriptomics Data

AbstractWe used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

scholarly journals Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Nasna Nassir ◽  
Asma Bankapur ◽  
Bisan Samara ◽  
Abdulrahman Ali ◽  
Awab Ahmed ◽  
...  
Keyword(s):  
Single Cell ◽  
Large Scale ◽  
De Novo ◽  
Cell Types ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
Variant Genes

Abstract Background In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of ‘brain to behaviour’ pathogenic mechanisms, remains largely unknown. Methods We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). Results We identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p < 5.23 × 10–11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 × 10–11, oligodendrocyte, p < 1.31 × 10–09). Conclusion Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.

scholarly journals Intellectual disability and cerebellar hypoplasia in autism reported by associative learning

2021 ◽  
Author(s):  
John P. Welsh ◽  
Jeffrey Munson ◽  
Tanya St. John ◽  
Christina N. Meehan ◽  
Elise N. Tran ◽  
...  
Keyword(s):  
Early Childhood ◽  
Intellectual Disability ◽  
Associative Learning ◽  
Early Onset ◽  
Autism Spectrum ◽  
Cerebellar Hypoplasia ◽  
Linear Discriminant ◽  
Motor Processing ◽  
Eye Blink ◽  
Children With Asd

ABSTRACTObjectiveTo determine how impairments in associative learning in autism spectrum disorder (ASD) relate to intellectual disability (ID) and early-childhood cerebellar hypoplasia.MethodsTrace and long-delay eye blink conditioning (EBC) were performed in 62 children age 11.2 years having: 1) ASD with ID (ASD+ID); 2) ASD without ID (ASD-noID); or 3) typical development (TD). The sub-second timing of conditioned eye-blink responses (CRs) acquired to a tone paired with a corneal air puff was related to brain structure at age 2 years and clinical measures across ages 2-12 years. Because CR timing is influenced strongly by cerebellar function, EBC was used to test hypotheses relating cerebellar hypoplasia to ASD.ResultsChildren with ASD+ID showed early-onset CRs during trace EBC that were related to early-childhood hypoplasia of the cerebellum but not of the cerebral cortex, hippocampus, or amygdala. Children with ASD-noID showed early-onset CRs only during long-delay EBC without cerebellar hypoplasia. Using EBC measures, logistic regression detected ASD with 81% sensitivity and 79% specificity while linear discriminant analysis separated ASD subgroups based on ID but not ASD severity. MRI of additional 2-year-olds with ASD indicated that early-onset CRs during trace EBC revealed ASD+ID more readily than cerebellar hypoplasia, per se.ConclusionsEarly-childhood cerebellar hypoplasia occurs in children with ASD+ID that demonstrate early-onset CRs during trace EBC. Trace EBC reveals the relationship between cerebellar hypoplasia and ASD+ID likely by engaging cerebro-cerebellar circuits involved in intellect. We emphasize that the cerebellum optimizes sensory-motor processing at sub-second intervals, impairments of which may contribute to ID.

scholarly journals Overt social interaction and resting state in young adult males with autism: core and contextual neural features

2018 ◽  
Author(s):  
Kyle Jasmin ◽  
Stephen J. Gotts ◽  
Y. Xu ◽  
S. Liu ◽  
Cameron Riddell ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Resting State ◽  
Temporal Correlation ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Adult Males ◽  
Language Abilities ◽  
Social Demand ◽  
Face To Face ◽  
Social Processing

AbstractConversation is an important and ubiquitous social behavior. Individuals with Autism Spectrum Disorder (autism) without intellectual disability often have normal structural language abilities but deficits in social aspects of communication like pragmatics, prosody, and eye contact. Previous studies of resting state activity suggest that intrinsic connections among neural circuits involved with social processing are disrupted in autism, but to date no neuroimaging study has examined neural activity during the most commonplace yet challenging social task: spontaneous conversation. Here we used functional MRI to scan autistic males (N=19) without intellectual disability and age- and IQ-matched typically developing controls (N=20) while they engaged in a total of 193 face-to-face interactions. Participants completed two kinds of tasks: Conversation, which had high social demand, and Repetition, which had low social demand. Autistic individuals showed abnormally increased task-driven inter-regional temporal correlation relative to controls, especially among social processing regions and during high social demand. Furthermore, these increased correlations were associated with parent ratings of participants’ social impairments. These results were then compared with previously-acquired resting-state data (56 Autism, 62 Control participants). While some inter-regional correlation levels varied by task or rest context, others were strikingly similar across both task and rest, namely increased correlation among the thalamus, dorsal and ventral striatum, somatomotor, temporal and prefrontal cortex in the autistic individuals, relative to the control groups. These results suggest a basic distinction. Autistic cortico-cortical interactions vary by context, tending to increase relative to controls during Task and decrease during Rest. In contrast, striato- and thalamocortical relationships with socially engaged brain regions are increased in both Task and Rest, and may be core to the condition of autism.

scholarly journals Single cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss of function mutation genes regulating glial cells

2021 ◽  
Author(s):  
Nasna Nassir ◽  
Asma Bankapur ◽  
Bisan Samara ◽  
Abdulrahman Ali ◽  
Awab Ahmed ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Single Cell ◽  
Large Scale ◽  
De Novo ◽  
Cell Types ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Abstract Background In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of ‘brain to behaviour’ pathogenic mechanisms, remains largely unknown. Methods We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single cell transcriptomes (> million cells) and de novo loss of function (LOF) ASD mutations (impacting 852 genes from 40122 cases). Results We identified multiple single cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high PLi genes. These clusters also showed significant enrichment with ASD loss of function mutation genes (p < 5.23 x 10− 11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF mutated genes into large scale human and mouse brain single cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 x 10− 11; oligodendrocyte, p < 1.31 x 10− 09). Conclusion Among the ASD genes enriched with pathogenic de novo LOF mutations (i.e., KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD, and the need to explore other biological pathways for this disorder.

scholarly journals A framework to identify modifier genes in patients with Phelan-McDermid syndrome

2017 ◽  
Author(s):  
Anne-Claude Tabet ◽  
Thomas Rolland ◽  
Marie Ducloy ◽  
Jonathan Lévy ◽  
Julien Buratti ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Features ◽  
Clinical Symptoms ◽  
Major Gene ◽  
Autism Spectrum ◽  
Speech Impairment ◽  
Compensatory Mechanisms ◽  
Genomic Regions ◽  
Relationship Of ◽  
Degrees Of Severity

ABSTRACTPhelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the first SHANK3 deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

scholarly journals Potential scalp stimulation targets for mental disorders: evidence from neuroimaging studies

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jin Cao ◽  
Thalia Celeste Chai-Zhang ◽  
Yiting Huang ◽  
Maya Nicole Eshel ◽  
Jian Kong
Keyword(s):  
Mental Disorders ◽  
Large Scale ◽  
Psychiatric Symptoms ◽  
Common Mental Disorders ◽  
Target Selection ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Transcranial Electrical Stimulation ◽  
Post Traumatic Stress ◽  
Compulsive Disorder

AbstractMental disorders widely contribute to the modern global disease burden, creating a significant need for improvement of treatments. Scalp stimulation methods (such as scalp acupuncture and transcranial electrical stimulation) have shown promising results in relieving psychiatric symptoms. However, neuroimaging findings haven’t been well-integrated into scalp stimulation treatments. Identifying surface brain regions associated with mental disorders would expand target selection and the potential for these interventions as treatments for mental disorders. In this study, we performed large-scale meta-analyses separately on eight common mental disorders: attention deficit hyperactivity disorder, anxiety disorder, autism spectrum disorder, bipolar disorder, compulsive disorder, major depression, post-traumatic stress disorder and schizophrenia; utilizing modern neuroimaging literature to summarize disorder-associated surface brain regions, and proposed neuroimaging-based target protocols. We found that the medial frontal gyrus, the supplementary motor area, and the dorsal lateral prefrontal cortex are commonly involved in the pathophysiology of mental disorders. The target protocols we proposed may provide new brain targets for scalp stimulation in the treatment of mental disorders, and facilitate its clinical application.

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