This past year we have continued to evaluate the neural characteristics and associated behavioral consequences of Autism Spectrum Disorders (ASD). Prevailing theories suggest that ASD results from impaired brain communication due to aberrant timing or coordination of neuronal firing patterns (impaired synchrony). However, it remains debated whether synchrony abnormalities in ASD are among local and/or long-range circuits, are circuit-specific or are generalized, reflect increased (hyper-) synchrony and/or decreased (hypo-) synchrony, and whether they are frequency band specific or are distributed across the frequency spectrum. In previous studies, we used data driven techniques in conjunction with both fMRI and structural data to show that the abnormalities in ASD brain networks are most prominent within brain regions that support social functions. To provide an additional test of this hypothesis we used MEG to record spontaneously oscillating neural signals from high functioning adolescents and adults with ASD and typically developing control subjects. We used a method recently developed in our lab to look at all-to-all synchronization across the brain in conjunction with data driven analyses to compare local and long-distance synchrony in a frequency-specific manner. We found that individuals with ASD showed local increased or hypersynchrony in the theta band (4-7 Hz) in lateral occipitotemporal cortex. We also observed long-range decreased or hyposynchronous activity in the alpha band (10-13 Hz) that was most prominent in neural circuitry underpinning social processing. The magnitude of this alpha band hyposynchrony was correlated with social symptom severity. These results suggest that while ASD is associated with both decreased long-range synchrony and increased posterior local synchrony - with each effect limited to a specific frequency band - impairments in social functioning may be most related to decreased alpha synchronization between critical nodes of the social processing network (Ghuman et al., 2017). In the past year we have now begun to turn our attention to determining whether it is possible to modify these aberrant networks, and if so, whether this modification will be clinically relevant. To address these questions we developed a novel covert neurofeedback procedure that may potentially expand the treatment and training options for individuals suffering from a variety of neuropsychiatric conditions. Our study utilized an fMRI-based training technique in which positive feedback is provided based on correlations of brain activity between different regions of a brain network known to exhibit abnormal connectivity (weak signal correlation) in ASD patients (based on an independent analysis of over 60 high- functioning ASD and 60 control subjects studied in our lab). As opposed to traditional training techniques, this approach grants direct access to the aberrant networks themselves. Using this form of covert neurofeedback, we observed significantly stronger correlations in the networks being trained after four, two-hour neurofeedback sessions. Moreover, the resulting change was long-term, and was mostly maintained for as long as a year later, including transfer to the resting state. In addition, and perhaps most importantly, this brain network change was correlated with a change in behavior, as measured by parent questionnaires (Ramot et al., eLife, 2017). These results have important implications for any neuropsychiatric disorder in which there are underlying network connectivity issues, as well as for many basic science questions. Indeed, we are currently using a similar approach to determine if we can modify the neural circuits associated with developmental prosopagnosia (abnormally poor memory for faces), and whether any observed changed in network structure will impact real-world face recognition ability. During the past year we have also continued our investigations of the neural underpinnings of social communicative difficulties (Crutcher et al., Human Brain Mapping, 2018) and sensory deficits in ASD (specifcally in gustatory processing, Avery et al., Neuroimage Clinical, 2018). Picky eating and other poor eating habits are common among adolescents with ASD and are often related to aberrant sensory experience, including heightened reactivity to food taste and texture. However, little is known about the neural mechanisms that underlie eating difficulties in ASD. To address this issue, we evaluated neural responses to gustatory stimuli using fMRI and its relation to self-reported eating habits. We found that eating-related problems were associated with abnormally strong brain responses in gustatory cortex to pictures of foods, as well as with atypical functional connectivity of gustatory cortex with other regions of the brain. These brain-based differences may predispose these individuals to maladaptive and unhealthy patterns of selective eating behavior. Continued effort has also been directed towards evaluating differences and commonalities in the clinical profiles of adolescent ASD girls and boys (Ratto et al., Journal of Autism & Developmental Disorders, 2018; White et al., Autism Research, 2017). Of particular interest, our large-scale study of age- and IQ-matched ASD adolescents (n = 228) revealed that, although females and males were rated similarly on gold-standard diagnostic measures overall (ADOS and ADI-R), females with higher IQs were less likely to meet criteria on the ADI-R. Females were also found to be signicantly more impaired on parent reported autistic traits and adaptive skills. Overall, these findings suggest that some autistic females may be missed by current diagnostic procedures, thereby providing evidence for the need for clinical instruments specificaly designed for the evaluating ASD in females.

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Ratto, Allison B; Kenworthy, Lauren; Yerys, Benjamin E et al. (2018) What About the Girls? Sex-Based Differences in Autistic Traits and Adaptive Skills. J Autism Dev Disord 48:1698-1711
Crutcher, Jason; Martin, Alex; Wallace, Gregory L (2018) Dissociations in the neural substrates of language and social functioning in autism spectrum disorder. Autism Res 11:1175-1186
Power, Jonathan D; Plitt, Mark; Gotts, Stephen J et al. (2018) Ridding fMRI data of motion-related influences: Removal of signals with distinct spatial and physical bases in multiecho data. Proc Natl Acad Sci U S A 115:E2105-E2114
Avery, Jason A; Ingeholm, John E; Wohltjen, Sophie et al. (2018) Neural correlates of taste reactivity in autism spectrum disorder. Neuroimage Clin 19:38-46
Ghuman, Avniel Singh; van den Honert, Rebecca N; Huppert, Theodore J et al. (2017) Aberrant Oscillatory Synchrony Is Biased Toward Specific Frequencies and Processing Domains in the Autistic Brain. Biol Psychiatry Cogn Neurosci Neuroimaging 2:245-252
Power, Jonathan D (2017) A simple but useful way to assess fMRI scan qualities. Neuroimage 154:150-158
Wallace, Gregory L; Dudley, Katerina; Anthony, Laura et al. (2017) Divergence of Age-Related Differences in Social-Communication: Improvements for Typically Developing Youth but Declines for Youth with Autism Spectrum Disorder. J Autism Dev Disord 47:472-479
Power, Jonathan D; Plitt, Mark; Laumann, Timothy O et al. (2017) Sources and implications of whole-brain fMRI signals in humans. Neuroimage 146:609-625
Ramot, Michal; Kimmich, Sara; Gonzalez-Castillo, Javier et al. (2017) Direct modulation of aberrant brain network connectivity through real-time NeuroFeedback. Elife 6:
White, Emily I; Wallace, Gregory L; Bascom, Julia et al. (2017) Sex differences in parent-reported executive functioning and adaptive behavior in children and young adults with autism spectrum disorder. Autism Res 10:1653-1662

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