Leanna M. Hernandez

Altered functional and structural brain network organization in autism

Structural and functional underconnectivity have been reported for multiple brain regions, functional systems, and white matter tracts in individuals with autism spectrum disorders (ASD). Although recent developments in complex network analysis have established that the brain is a modular network exhibiting small-world properties, network level organization has not been carefully examined in ASD. Here we used resting-state functional MRI (n = 42 ASD, n = 37 typically developing; TD) to show that children and adolescents with ASD display reduced short and long-range connectivity within functional systems (i.e., reduced functional integration) and stronger connectivity between functional systems (i.e., reduced functional segregation), particularly in default and higher-order visual regions. Using graph theoretical methods, we show that pairwise group differences in functional connectivity are reflected in network level reductions in modularity and clustering (local efficiency), but shorter characteristic path lengths (higher global efficiency). Structural networks, generated from diffusion tensor MRI derived fiber tracts (n = 51 ASD, n = 43 TD), displayed lower levels of white matter integrity yet higher numbers of fibers. TD and ASD individuals exhibited similar levels of correlation between raw measures of structural and functional connectivity (n = 35 ASD, n = 35 TD). However, a principal component analysis combining structural and functional network properties revealed that the balance of local and global efficiency between structural and functional networks was reduced in ASD, positively correlated with age, and inversely correlated with ASD symptom severity. Overall, our findings suggest that modeling the brain as a complex network will be highly informative in unraveling the biological basis of ASD and other neuropsychiatric disorders.

Reduced Functional Integration and Segregation of Distributed Neural Systems Underlying Social and Emotional Information Processing in Autism Spectrum Disorders

A growing body of evidence suggests that autism spectrum disorders (ASDs) are related to altered communication between brain regions. Here, we present findings showing that ASD is characterized by a pattern of reduced functional integration as well as reduced segregation of large-scale brain networks. Twenty-three children with ASD and 25 typically developing matched controls underwent functional magnetic resonance imaging while passively viewing emotional face expressions. We examined whole-brain functional connectivity of two brain structures previously implicated in emotional face processing in autism: the amygdala bilaterally and the right pars opercularis of the inferior frontal gyrus (rIFGpo). In the ASD group, we observed reduced functional integration (i.e., less long-range connectivity) between amygdala and secondary visual areas, as well as reduced segregation between amygdala and dorsolateral prefrontal cortex. For the rIFGpo seed, we observed reduced functional integration with parietal cortex and increased integration with right frontal cortex as well as right nucleus accumbens. Finally, we observed reduced segregation between rIFGpo and the ventromedial prefrontal cortex. We propose that a systems-level approach-whereby the integration and segregation of large-scale brain networks in ASD is examined in relation to typical development-may provide a more detailed characterization of the neural basis of ASD.

Autism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks

As genes that confer increased risk for autism spectrum disorder (ASD) are identified, a crucial next step is to determine how these risk factors impact brain structure and function and contribute to disorder heterogeneity. With three converging lines of evidence, we show that a common, functional ASD risk variant in the Met Receptor Tyrosine Kinase (MET) gene is a potent modulator of key social brain circuitry in children and adolescents with and without ASD. MET risk genotype predicted atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the default mode network. Notably, these effects were more pronounced in individuals with ASD. These findings highlight how genetic stratification may reduce heterogeneity and help elucidate the biological basis of complex neuropsychiatric disorders such as ASD.

The Power of the Like in Adolescence Effects of Peer Influence on Neural and Behavioral Responses to Social Media

We investigated a unique way in which adolescent peer influence occurs on social media. We developed a novel functional MRI (fMRI) paradigm to simulate Instagram, a popular social photo-sharing tool, and measured adolescents’ behavioral and neural responses to likes, a quantifiable form of social endorsement and potential source of peer influence. Adolescents underwent fMRI while viewing photos ostensibly submitted to Instagram. They were more likely to like photos depicted with many likes than photos with few likes; this finding showed the influence of virtual peer endorsement and held for both neutral photos and photos of risky behaviors (e.g., drinking, smoking). Viewing photos with many (compared with few) likes was associated with greater activity in neural regions implicated in reward processing, social cognition, imitation, and attention. Furthermore, when adolescents viewed risky photos (as opposed to neutral photos), activation in the cognitive-control network decreased. These findings highlight possible mechanisms underlying peer influence during adolescence.

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics

Neuroimaging investigations of autism spectrum disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD sub-populations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data.

Atypical Neural Processing of Ironic and Sincere Remarks in Children and Adolescents with Autism Spectrum Disorders

Individuals with ASD show consistent impairment in processing pragmatic language when attention to multiple social cues (e.g., facial expression, tone of voice) is often needed to navigate social interactions. Building upon prior fMRI work examining how facial affect and prosodic cues are used to infer a speakers communicative intent, the authors examined whether children and adolescents with ASD differ from typically developing (TD) controls in their processing of sincere versus ironic remarks. At the behavioral level, children and adolescents with ASD and matched TD controls were able to determine whether a speakers remark was sincere or ironic equally well, with both groups showing longer response times for ironic remarks. At the neural level, for both sincere and ironic scenarios, an extended cortical network—including canonical language areas in the left hemisphere and their right hemisphere counterparts—was activated in both groups, albeit to a lesser degree in the ASD sample. Despite overall similar patterns of activity observed for the two conditions in both groups, significant modulation of activity was detected when directly comparing sincere and ironic scenarios within and between groups. While both TD and ASD groups showed significantly greater activity in several nodes of this extended network when processing ironic versus sincere remarks, increased activity was largely confined to left language areas in TD controls, whereas the ASD sample showed a more bilateral activation profile which included both language and “theory of mind” areas (i.e., ventromedial prefrontal cortex). These findings suggest that, for high-functioning individuals with ASD, increased activity in right hemisphere homologues of language areas in the left hemisphere, as well as regions involved in social cognition, may reflect compensatory mechanisms supporting normative behavioral task performance.

Neural and Behavioral Responses During Self-Evaluative Processes Differ in Youth With and Without Autism

This fMRI study investigated neural responses while making appraisals of self and other, across the social and academic domains, in children and adolescents with and without autism spectrum disorders (ASD). Compared to neurotypical youth, those with ASD exhibited hypoactivation of ventromedial prefrontal cortex during self-appraisals. Responses in middle cingulate cortex (MCC) and anterior insula (AI) also distinguished between groups. Stronger activity in MCC and AI during self-appraisals was associated with better social functioning in the ASD group. Although self-appraisals were significantly more positive in the neurotypical group, positivity was unrelated to brain activity in these regions. Together, these results suggest that multiple brain regions support making self-appraisals in neurotypical development, and function atypically in youth with ASD.

Altered resting perfusion and functional connectivity of default mode network in youth with autism spectrum disorder.

Neuroimaging studies can shed light on the neurobiological underpinnings of autism spectrum disorders (ASD). Studies of the resting brain have shown both altered baseline metabolism from PET/SPECT and altered functional connectivity (FC) of intrinsic brain networks based on resting‐state fMRI. To date, however, no study has investigated these two physiological parameters of resting brain function jointly, or explored the relationship between these measures and ASD symptom severity.

Salience Network Connectivity in Autism Is Related to Brain and Behavioral Markers of Sensory Overresponsivity

OBJECTIVE The salience network, an intrinsic brain network thought to modulate attention to internal versus external stimuli, has been consistently found to be atypical in autism spectrum disorders (ASD). However, little is known about how this altered resting-state connectivity relates to brain activity during information processing, which has important implications for understanding sensory overresponsivity (SOR), a common and impairing condition in ASD related to difficulty downregulating brain responses to sensory stimuli. This study examined how SOR in youth with ASD relates to atypical salience network connectivity and whether these atypicalities are associated with abnormal brain response to basic sensory information. METHOD Functional magnetic resonance imaging was used to examine how parent-rated SOR symptoms related to salience network connectivity in 61 youth (aged 8-17 years; 28 with ASD and 33 IQ-matched typically developing youth). Correlations between resting-state salience network connectivity and brain response to mildly aversive tactile and auditory stimuli were examined. RESULTS SOR in youth with ASD was related to increased resting-state functional connectivity between salience network nodes and brain regions implicated in primary sensory processing and attention. Furthermore, the strength of this connectivity at rest was related to the extent of brain activity in response to auditory and tactile stimuli. CONCLUSION Results support an association between intrinsic brain connectivity and specific atypical brain responses during information processing. In addition, findings suggest that basic sensory information is overly salient to individuals with SOR, leading to overattribution of attention to this information. Implications for intervention include incorporating sensory coping strategies into social interventions for individuals with SOR.

Reduced modulation of thalamocortical connectivity during exposure to sensory stimuli in ASD

Recent evidence for abnormal thalamic connectivity in autism spectrum disorders (ASD) and sensory processing disorders suggests the thalamus may play a role in sensory over‐responsivity (SOR), an extreme negative response to sensory stimuli, which is common in ASD. However, there is yet little understanding of changes in thalamic connectivity during exposure to aversive sensory inputs in individuals with ASD. In particular, the pulvinar nucleus of the thalamus is implicated in atypical sensory processing given its role in selective attention, regulation, and sensory integration. This study aimed to examine the role of pulvinar connectivity in ASD during mildly aversive sensory input. Functional magnetic resonance imaging was used to examine connectivity with the pulvinar during exposure to mildly aversive auditory and tactile stimuli in 38 youth (age 9–17; 19 ASD, 19 IQ‐matched typically developing (TD)). Parents rated childrens SOR severity on two standard scales. Compared to TD, ASD participants displayed aberrant modulation of connectivity between pulvinar and cortex (including sensory‐motor and prefrontal regions) during sensory stimulation. In ASD participants, pulvinar‐amygdala connectivity was correlated with severity of SOR symptoms. Deficits in modulation of thalamocortical connectivity in youth with ASD may reflect reduced thalamo‐cortical inhibition in response to sensory stimulation, which could lead to difficulty filtering out and/or integrating sensory information. An increase in amygdala connectivity with the pulvinar might be partially responsible for deficits in selective attention as the amygdala signals the brain to attend to distracting sensory stimuli. Autism Res 2017, 10: 801–809.