Inna Fishman

Atypical Cross Talk Between Mentalizing and Mirror Neuron Networks in Autism Spectrum Disorder

IMPORTANCE Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but it is unclear whether altered connectivity is especially prominent in brain networks that participate in social cognition. OBJECTIVE To investigate whether adolescents with ASD show altered functional connectivity in 2 brain networks putatively impaired in ASD and involved in social processing, theory of mind (ToM) and mirror neuron system (MNS). DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study using resting-state functional magnetic resonance imaging involving 25 adolescents with ASD between the ages of 11 and 18 years and 25 typically developing adolescents matched for age, handedness, and nonverbal IQ. MAIN OUTCOMES AND MEASURES Statistical parametric maps testing the degree of whole-brain functional connectivity and social functioning measures. RESULTS Relative to typically developing controls, participants with ASD showed a mixed pattern of both over- and underconnectivity in the ToM network, which was associated with greater social impairment. Increased connectivity in the ASD group was detected primarily between the regions of the MNS and ToM, and was correlated with sociocommunicative measures, suggesting that excessive ToM-MNS cross talk might be associated with social impairment. In a secondary analysis comparing a subset of the 15 participants with ASD with the most severe symptomology and a tightly matched subset of 15 typically developing controls, participants with ASD showed exclusive overconnectivity effects in both ToM and MNS networks, which were also associated with greater social dysfunction. CONCLUSIONS AND RELEVANCE Adolescents with ASD showed atypically increased functional connectivity involving the mentalizing and mirror neuron systems, largely reflecting greater cross talk between the 2. This finding is consistent with emerging evidence of reduced network segregation in ASD and challenges the prevailing theory of general long-distance underconnectivity in ASD. This excess ToM-MNS connectivity may reflect immature or aberrant developmental processes in 2 brain networks involved in understanding of others, a domain of impairment in ASD. Further, robust links with sociocommunicative symptoms of ASD implicate atypically increased ToM-MNS connectivity in social deficits observed in ASD.

Enhancing studies of the connectome in autism using the autism brain imaging data exchange II

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.

Regional specificity of aberrant thalamocortical connectivity in autism

Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region‐specific TC connectivity in ASD. Resting‐state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7–17 years) and 45 age, sex, and IQ‐matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions. Hum Brain Mapp 36:4497–4511, 2015.

Reduced integration and differentiation of the imitation network in autism: A combined functional connectivity magnetic resonance imaging and diffusion-weighted imaging study.

Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but few studies have integrated functional with structural connectivity measures. This multimodal investigation examined functional and structural connectivity of the imitation network in children and adolescents with ASD, and its links with clinical symptoms.

Reduced integration and differentiation of the imitation network in autism: A combined fcMRI and DWI study

Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but few studies have integrated functional with structural connectivity measures. This multimodal investigation examined functional and structural connectivity of the imitation network in children and adolescents with ASD, and its links with clinical symptoms.

Children with ASD show links between aberrant sound processing, social symptoms, and atypical auditory interhemispheric and thalamocortical functional connectivity

Highlights • Auditory processing deficits in ASD correlate with social and behavioral symptoms.• Reduced interhemispheric connectivity is found with more severe sensory symptoms.• Verbal IQ is lower in individuals with reduced interhemispheric connectivity.• Thalamocortical overconnectivity may compensate for sensory and social deficits.

Psychotropic Medication Use in Autism Spectrum Disorders May Affect Functional Brain Connectivity

Background Prescription of psychotropic medications is common in autism spectrum disorders (ASDs), either off-label or to treat comorbid conditions such as ADHD or depression. Psychotropic medications are intended to alter brain function. Yet, studies investigating the functional brain organization in ASDs rarely take medication usage into account. This could explain some of the inconsistent findings of atypical brain network connectivity reported in the autism literature. Methods The current study tested whether functional connectivity patterns, as assessed with functional magnetic resonance imaging (fMRI), differed in a cohort of 49 children and adolescents with ASDs based on psychotropic medication status, and in comparison with 50 matched typically developing (TD) participants. Twenty-five participants in the ASD group (51%) reported current psychotropic medication usage, including stimulants, antidepressants, antipsychotics, and anxiolytics. Age, IQ, head motion, and ASD symptom severity did not differ between groups. Whole-brain functional connectivity between 132 regions of interest was assessed. Results Different functional connectivity patterns were identified in the ASD group taking psychotropic medications (ASD-on), as compared to the TD group and the ASD subgroup not using psychotropic medications (ASD-none). The ASD-on group showed distinct underconnectivity between the cerebellum and basal ganglia but cortico-cortical overconnectivity compared to the TD group. Cortical underconnectivity relative to the TD pattern, on the other hand, was pronounced in the ASD-none group. Conclusions These results suggest that psychotropic medications may affect functional connectivity, and that medication status should be taken into consideration when studying brain function in autism.

Repetitive behaviors in autism are linked to imbalance of corticostriatal connectivity: a functional connectivity MRI study

Abstract The neural underpinnings of repetitive behaviors (RBs) in autism spectrum disorders (ASDs), ranging from cognitive to motor characteristics, remain unknown. We assessed RB symptomatology in 50 ASD and 52 typically developing (TD) children and adolescents (ages 8–17 years), examining intrinsic functional connectivity (iFC) of corticostriatal circuitry, which is important for reward-based learning and integration of emotional, cognitive and motor processing, and considered impaired in ASDs. Connectivity analyses were performed for three functionally distinct striatal seeds (limbic, frontoparietal and motor). Functional connectivity with cortical regions of interest was assessed for corticostriatal circuit connectivity indices and ratios, testing the balance of connectivity between circuits. Results showed corticostriatal overconnectivity of limbic and frontoparietal seeds, but underconnectivity of motor seeds. Correlations with RBs were found for connectivity between the striatal motor seeds and cortical motor clusters from the whole-brain analysis, and for frontoparietal/limbic and motor/limbic connectivity ratios. Division of ASD participants into high (n = 17) and low RB subgroups (n = 19) showed reduced frontoparietal/limbic and motor/limbic circuit ratios for high RB compared to low RB and TD groups in the right hemisphere. Results suggest an association between RBs and an imbalance of corticostriatal iFC in ASD, being increased for limbic, but reduced for frontoparietal and motor circuits.

Frontal asymmetry index in Williams syndrome: Evidence for altered emotional brain circuitry?

Asymmetrical frontal electroencephalography (EEG) activity is associated with motivational neural systems of approach/withdrawal behaviors. Greater left frontal EEG has been linked to increased appetitive tendencies whereas increased right frontal activity is related to the activation of avoidance mechanisms. Williams syndrome (WS) is a genetic condition characterized by a highly sociable personality manifested by a propensity to approach strangers and decreased social fear. Consequently, the current study was designed to investigate the frontal cortical activity during resting state, indexed by relative alpha power, in adults with WS as compared to typically developing (TD) controls, and a subgroup of TD extraverts. Results indicated that participants with WS produced attenuated left frontal activity relative to TD peers, or TD extraverts in particular; yet, no groups differed in their degree of right frontal activity. Finally, while both TD group and the extravert subset showed trends of greater left over right frontal activity, the WS participants demonstrated opposing effect of increased right over left frontal EEG. Importantly, individuals with WS produced deviating frontal activity patterns compared to TD extraverts despite exhibiting common social-affiliative tendencies, underscoring that neural mechanisms that give rise to extraversion in WS may not function similarly to those subserving this personality trait expressed in TD.

Atypical Functional Connectivity of Amygdala Related to Reduced Symptom Severity in Children With Autism

OBJECTIVE Converging evidence indicates that brain abnormalities in autism spectrum disorders (ASDs) involve atypical network connectivity. Given the central role of social deficits in the ASD phenotype, this investigation examined functional connectivity of the amygdala-a brain structure critically involved in processing of social information-in children and adolescents with ASDs, as well as age-dependent changes and links with clinical symptoms. METHOD Resting-state functional magnetic resonance imaging (rs-fMRI) data from 55 participants with ASDs and 50 typically developing (TD) controls, aged 7 to 17 years, were included. Groups were matched for age, gender, IQ, and head motion. Functional connectivity MRI (fcMRI) analysis was applied to examine intrinsic functional connectivity (iFC) of the amygdala, including cross-sectional tests of age-related changes. RESULTS Direct between-group comparisons revealed reduced functional connectivity between bilateral amygdalae and left inferior occipital cortex, accompanied by greater connectivity between right amygdala and right sensorimotor cortex in the ASD group. This atypical pattern of amygdala connectivity was associated with decreased symptom severity and better overall functioning, as specifically seen in an ASD subgroup with the most atypical amygdala iFC but the least impaired social functioning. Age-related strengthening of amygdala-prefrontal connectivity, as observed in the TD group, was not detected in children with ASDs. CONCLUSION Findings support aberrant network sculpting in ASDs, specifically atypical integration between amygdala and primary sensorimotor circuits. Paradoxical links between atypical iFC and behavioral measures suggest that abnormal amygdala functional connections may be compensatory in some individuals with ASDs.