Content uploaded by Jeremy Cohen
Author content
All content in this area was uploaded by Jeremy Cohen on Aug 02, 2018
Content may be subject to copyright.
A preview of the PDF is not available
Annals of Behavioral Neuroscience Altered Anterior Insular Asymmetry in Pre-teen and Adolescent Youth with Autism Spectrum Disorder
Abstract and Figures
Autism Spectrum Disorder (ASD) is hallmarked by social-emotional reciprocity deficits. Social-emotional responding requires the clear recognition of social cues as well as the internal monitoring of emotional salience. Insular cortex is central to the salience network, and plays a key role in approach-avoidance emotional valuation. Consistent right anterior insular hypoactivity and variable volumetric differences of insular cortical volumes were shown previously. The current study analyzed anterior and posterior insular volume/asymmetry changes in ASD across age. Age was used as an additional grouping variable as previous studies indicated differential regional volume in ASD individuals before and after puberty onset. In the current sample, pre-teen ASD expressed left lateralized anterior insula, while adolescent ASD had right lateralization. Typically developing (TD) individuals expressed the opposite lateralization of anterior insula in both age-groups (right greater than left anterior insular volume among pre-teen TD and left greater than right anterior insular volume among adolescent TD). Social-emotional calibrated severity scores from the ADOS were positively correlated with leftward anterior insular asymmetry and negatively correlated with proportional right anterior insular volumes in ASD. Insular cortex has a lateralized role in autonomic nervous system regulation (parasympathetic control in the left, sympathetic control in the right). Atypical insular asymmetry in ASD may contribute to the development of networks with a diminished salience signal to human faces and voices, and may lead to more learned passive avoidant responses to such stimuli at younger ages, leading to more distressed responses in adolescence. Data here supports the use of early behavioral intervention to increase awareness of and reward for social-emotional cues.
Figures - uploaded by Jeremy Cohen
Author content
All figure content in this area was uploaded by Jeremy Cohen
Content may be subject to copyright.
... The right FG is believed to be involved in conscious processing of faces, while the left FG engages more broadly in visual perception and object recognition (64,65). Previous studies have shown that altered anterior insular asymmetry of ASD related to the scores of ADOS [ (66,67)]. Atypical insular asymmetry in ASD may contribute to the development of networks with a diminished salience signal to human faces and voices, and may lead to more learned passive avoidant responses to such stimuli (66). Our study adds evidence to support that atypical lateralization of special regions is related to symptom severity in ASD. ...
... Previous studies have shown that altered anterior insular asymmetry of ASD related to the scores of ADOS [ (66,67)]. Atypical insular asymmetry in ASD may contribute to the development of networks with a diminished salience signal to human faces and voices, and may lead to more learned passive avoidant responses to such stimuli (66). Our study adds evidence to support that atypical lateralization of special regions is related to symptom severity in ASD. ...
Background
Evidence suggests that there is a robust relationship between altered neuroanatomy and autistic symptoms in individuals with autism spectrum disorder (ASD). Social visual preference, which is regulated by specific brain regions, is also related to symptom severity. However, there were a few studies explored the potential relationships among brain structure, symptom severity, and social visual preference.
Methods
The current study investigated relationships among brain structure, social visual preference, and symptom severity in 43 children with ASD and 26 typically developing (TD) children (aged 2–6 years).
Results
Significant differences were found in social visual preference and cortical morphometry between the two groups. Decreased percentage of fixation time in digital social images (%DSI) was negatively related to not only the thickness of the left fusiform gyrus (FG) and right insula, but also the Calibrated Severity Scores for the Autism Diagnostic Observation Schedule-Social Affect (ADOS-SA-CSS). Mediation analysis showed that %DSI partially mediated the relationship between neuroanatomical alterations (specifically, thickness of the left FG and right insula) and symptom severity.
Conclusion
These findings offer initial evidence that atypical neuroanatomical alterations may not only result in direct effects on symptom severity but also lead to indirect effects on symptom severity through social visual preference. This finding enhances our understanding of the multiple neural mechanisms implicated in ASD.
... The reduced social score (i.e., lower symptom severity) provides preliminary proof that increased rightward asymmetry in Cluster A4 might have a compensatory effect in regulating social deficits. Although ASD patients have inactive responses to social stimuli, in some cases this low interaction may be improved by early intervention (Cohen et al., 2018). The data here suggest that The relationship between AIs and symptom severity. ...
... atypical rightward asymmetry of the thalamus may indeed be the anatomic basis of social interaction deficits in ASD, and timely and effective interventions may exert their effect through recombination and functional balance of social-cognitive brain networks (Cohen et al., 2018), including the thalamus. This effect may provide novel ideas and new targets for the future treatment of ASD. ...
Abnormal gray matter (GM) asymmetry has been verified in autism spectrum disorder (ASD), which is characterized by high heterogeneity. ASD is distinguished by three core symptom domains. Previous neuroimaging studies have offered support for divergent neural substrates of different core symptom domains in ASD. However, no previous study has explored GM asymmetry alterations underlying different core symptom domains. This study sought to clarify atypical GM asymmetry patterns underlying three core symptom domains in ASD with a large sample of 230 minors with ASD (ages 7–18 years) and 274 matched TD controls from the Autism Brain Imaging Data Exchange I (ABIDE I) repository. To this end, the scores of the revised autism diagnostic interview (ADI-R) subscales were normalized for grouping ASD into three core-symptom-defined subgroups: social interaction (SI), verbal communication (VA), and restricted repetitive behaviors (RRB). We investigated core-symptom-related GM asymmetry alterations in ASD resulting from advanced voxel-based morphometry (VBM) by general linear models. We also examined the relationship between GM asymmetry and age and between GM asymmetry and symptom severity assessed by the Autism Diagnostic Observation Schedule (ADOS). We found unique GM asymmetry alterations underlying three core-symptom-defined subgroups in ASD: more rightward asymmetry in the thalamus for SI, less rightward asymmetry in the superior temporal gyrus, anterior cingulate and caudate for VA, and less rightward asymmetry in the middle and inferior frontal gyrus for RRB. Furthermore, the asymmetry indexes in the thalamus were negatively associated with ADOS_SOCIAL scores in the general ASD group. We also showed significant correlations between GM asymmetry and age in ASD and TD individuals. Our results support the theory that each core symptom domain of ASD may have independent etiological and neurobiological underpinnings, which is essential for the interpretation of heterogeneity and the future diagnosis and treatment of ASD.
... The fact that we observed an association between right, not left, insular activation with health risk behaviors is not surprising as prior research in adults (Paulus et al., 2003) and adolescents (van have found similar lateralized results. Prior research suggests that the right and left insular cortex may be associated with lateralized autonomic nervous system functions (Montalbano and Shane Tubbs, 2018;Cohen et al., 2018;Craig, 2005). It is suggested that the left insular cortex is involved in activation of regulation and maintenance functions supported by the parasympathetic nervous system; whereas the right insular cortex is involved in the activation of the sympathetic nervous system which controls our responses to potential threats (Zhang et al., 1999). ...
Middle adolescence is the period of development during which youth begin to engage in health risk behaviors such as delinquent behavior and substance use. A promising mechanism for guiding adolescents away from risky choices is the extent to which adolescents are sensitive to the likelihood of receiving valued outcomes. Few studies have examined longitudinal change in adolescent risky decision making and its neural correlates. To this end, the present longitudinal three-wave study (Nw1 = 157, Mw1= 13.50 years; Nw2 = 148, Mw2= 14.52 years; Nw3 = 143, Mw3= 15.55 years) investigated the ontogeny of mid-adolescent behavioral and neural risk sensitivity, and their baseline relations to longitudinal self-reported health risk behaviors. Results showed that adolescents became more sensitive to risk both in behavior and the brain during middle adolescence. Across three years, we observed lower risk-taking and greater risk-related activation in the bilateral insular cortex. When examining how baseline levels of risk sensitivity were related to longitudinal changes in real-life health risk behaviors, we found that Wave 1 insular activity was related to increases in self-reported health risk behaviors over the three years. This research highlights the normative maturation of risk-related processes at the behavioral and neural levels during mid-adolescence.
... Altogether, these findings suggest an early developmental failure to establish appropriate epigenomic landscapes requisite for transcriptional programing of neurogenesis and development, likely impacting the neuronal stem cell (NSC) compartment in the SVZ. A related structure in the brain that has also been connected to ASD is the insular cortex (Caria and de Falco, 2015;Jd et al., 2018;Nomi et al., 2019). Most neurons in the insular cortex are derived from the SVZ during development, particularly by the pallial-subpallial boundary, and atypical patterns of activation of the insula have been observed in ASD (González-Arnay et al., 2017). ...
Introduction
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.
Methods
We used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.
Results
Through MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.
Conclusion
These findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.
Introduction
The number of insular gyri is elevated in patients with schizophrenia. Thus, it has potential as a marker of early neurodevelopmental abnormalities. However, currently it remains unclear whether patients with other neuropsychiatric disorders, such as affective disorders, also have this gross brain anatomical feature.
Materials and methods
The macroscopic features of the insular cortex in 26 patients with bipolar disorder (BD), 56 with major depressive disorder (MDD), and control subjects for each clinical group (24 for BD and 33 for MDD) were assessed using magnetic resonance imaging.
Results
The number of short insular gyri was higher in BD patients than in matched controls bilaterally with well-developed accessory and middle short gyri. Furthermore, the left middle short gyrus was more developed in MDD patients than in matched controls, and was weakly associated with the severity of depressive symptoms.
Discussion
The present results indicate that changes in the gross morphology of the insular cortex in BD and MDD is a potential vulnerability factor associated with their neurodevelopmental pathologies, and may also contribute to the severity of symptoms in MDD.
Background
The insular cortex comprises multiple functionally differentiated sub-regions, each of which has different patterns of connectivity with other brain regions. Such diverse connectivity patterns are thought to underlie a wide range of insular functions, including cognitive, affective, and sensorimotor processing, many of which are abnormal in autism spectrum disorder (ASD). Although past neuroimaging studies of ASD have shown structural and functional abnormalities in the insula, possible alterations in the sub-regional organization of the insula and the functional characteristics of each sub-region have not been examined in the ASD brain. Methods
Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 36 adult males with ASD and 38 matched typically developed (TD) controls. A data-driven clustering analysis was applied to rs-fMRI data of voxels in the left and right insula to automatically group voxels with similar intrinsic connectivity pattern into a cluster. After determining the optimal number of clusters based on information theoretic measures of variation of information and mutual information, functional parcellation patterns in both the left and the right insula were compared between the TD and ASD groups. Furthermore, functional profiles of each sub-region were meta-analytically decoded using Neurosynth and were compared between the groups. ResultsWe observed notable alterations in the anterior sector of the left insula and the middle ventral sub-region of the right insula in the ASD brain. Meta-analytic decoding revealed that whereas the anterior sector of the left insula contained two functionally differentiated sub-regions for cognitive, sensorimotor, and emotional/affective functions in TD brain, only a single functional cluster for cognitive and sensorimotor functions was identified in the anterior sector in the ASD brain. In the right insula, the middle ventral sub-region, which is primarily specialized for sensory- and auditory-related functions, showed a significant volumetric increase in the ASD brain compared with the TD brain. Conclusions
The results indicate an altered organization of sub-regions in specific parts of the left and right insula of the ASD brain. The alterations in the left and right insula may constitute neural substrates underlying abnormalities in emotional/affective and sensory functions in ASD.
Autism spectrum disorders (ASDs) comprise a heterogeneous set of neurodevelopmental disorders characterized by dramatic impairments of interpersonal behavior, communication, and empathy. Recent neuroimaging studies suggested that ASD are disorders characterized by widespread abnormalities involving distributed brain network, though clear evidence of differences in large-scale brain network interactions underlying the cognitive and behavioral symptoms of ASD are still lacking. Consistent findings of anterior insula cortex hypoactivation and dysconnectivity during tasks related to emotional and social processing indicates its dysfunctional role in ASD. In parallel, increasing evidence showed that successful control of anterior insula activity can be attained using real-time fMRI paradigms. More importantly, successful regulation of this region was associated with changes in behavior and brain connectivity in both healthy individuals and psychiatric patients. Building on these results we here propose and discuss the use of real-time fMRI neurofeedback in ASD aiming at improving emotional and social behavior.
The goal of early autism screening is earlier treatment. We pilot-tested a 12-week, low-intensity treatment with seven symptomatic infants ages 7-15 months. Parents mastered the intervention and maintained skills after treatment ended. Four comparison groups were matched from a study of infant siblings. The treated group of infants was significantly more symptomatic than most of the comparison groups at 9 months of age but was significantly less symptomatic than the two most affected groups between 18 and 36 months. At 36 months, the treated group had much lower rates of both ASD and DQs under 70 than a similarly symptomatic group who did not enroll in the treatment study. It appears feasible to identify and enroll symptomatic infants in parent-implemented intervention before 12 months, and the pilot study outcomes are promising, but testing the treatment's efficacy awaits a randomized trial.
Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.
Background
Autonomic dysregulation has been recently reported as a feature of autism spectrum disorder (ASD). However, the nature of autonomic atypicalities in ASD remain largely unknown. The goal of this study was to characterize the cardiac autonomic profile of children with ASD across four domains affected in ASD (anxiety, attention, response inhibition, and social cognition), and suggested to be affected by autonomic dysregulation.
Methods
We compared measures of autonomic cardiac regulation in typically developing children (n = 34) and those with ASD (n = 40) as the children performed tasks eliciting anxiety, attention, response inhibition, and social cognition. Heart rate was used to quantify overall autonomic arousal, and respiratory sinus arrhythmia (RSA) was used as an index of vagal influences. Associations between atypical autonomic findings and intellectual functioning (Weschler scale), ASD symptomatology (Social Communication Questionnaire score), and co-morbid anxiety (Revised Children’s Anxiety and Depression Scale) were also investigated.
Results
The ASD group had marginally elevated basal heart rate, and showed decreased heart rate reactivity to social anxiety and increased RSA reactivity to the social cognition task. In this group, heart rate reactivity to the social anxiety task was positively correlated with IQ and task performance, and negatively correlated with generalized anxiety. RSA reactivity in the social cognition task was positively correlated with IQ.
Conclusions
Our data suggest overall autonomic hyperarousal in ASD and selective atypical reactivity to social tasks.
We prospectively examined evidence for the sustained effects of early intervention based on a follow-up study of 39 children with ASD who began participation in a randomized clinical trial testing the effectiveness of the Early Start Denver Model (ESDM) at age 18 to 30 months. The intervention, conducted at a high level of intensity in-home for 2 years, showed evidence of efficacy immediately posttreatment.
This group of children was assessed at age 6 years, 2 years after the intervention ended, across multiple domains of functioning by clinicians naive to previous intervention group status.
The ESDM group, on average, maintained gains made in early intervention during the 2-year follow-up period in overall intellectual ability, adaptive behavior, symptom severity, and challenging behavior. No group differences in core autism symptoms were found immediately posttreatment; however, 2 years later, the ESDM group demonstrated improved core autism symptoms and adaptive behavior as compared with the community-intervention-as-usual (COM) group. The 2 groups were not significantly different in terms of intellectual functioning at age 6 years. Both groups received equivalent intervention hours during the original study, but the ESDM group received fewer hours during the follow-up period.
These results provide evidence that gains from early intensive intervention are maintained 2 years later. Notably, core autism symptoms improved in the ESDM group over the follow-up period relative to the COM group. This improvement occurred at the same time that the ESDM group received significantly fewer services. This is the first study to examine the role of early ESDM behavioral intervention initiated at less than 30 months of age in altering the longer-term developmental course of autism.
Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
The recently published Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) includes revised diagnostic algorithms and standardized severity scores for modules used to assess younger children. A revised algorithm and severity scores are not yet available for Module 4, used with verbally fluent adults. The current study revises the Module 4 algorithm and calibrates raw overall and domain totals to provide metrics of autism spectrum disorder (ASD) symptom severity. Sensitivity and specificity of the revised Module 4 algorithm exceeded 80 % in the overall sample. Module 4 calibrated severity scores provide quantitative estimates of ASD symptom severity that are relatively independent of participant characteristics. These efforts increase comparability of ADOS scores across modules and should facilitate efforts to examine symptom trajectories from toddler to adulthood.