Background: Autism spectrum disorder (ASD) is defined behaviorally, but measures that probe underlying neural mechanisms may provide clues to biomarker discovery and brain-based patient stratification with clinical utility. Phase-amplitude coupling (PAC) has been posited as a measure of the balance between top-down and bottom-up processing in cortex, as well as a marker for sensory processing and predictive coding difficulties in ASD. We evaluate differences in PAC metrics of resting-state brain dynamics between children with and without ASD and relate PAC measures to age and behavioral assessments. Methods: We analyzed electroencephalography data collected by the Autism Biomarkers Consortium for Clinical Trials, including 225 (192 male) ASD and 116 (81 male) typically-developing children aged 6-11 years. We evaluated the strength and phase preference of PAC and the test-retest reliability of PAC across sessions. Results: There was significantly increased alpha-gamma and theta-gamma PAC strength in ASD. When considering all participants together, we found significant associations of whole brain theta-gamma PAC strength with measures of social communication (Beta = 0.185; p = 0.006) and repetitive behaviors (Beta = 0.166; p = 0.009) as well as age (Beta = 0.233; p < 0.0001); however, these associations did not persist when considering the ASD group alone. There are also group differences in theta-gamma phase preference. Conclusions: This large, rigorously collected sample indicated altered PAC strength and phase bias in ASD. These findings suggest opportunities for back-translation into animal models as well as clinical potential for stratification of brain-based subgroups in ASD.

SJW has served as a consultant for Janssen Research and Development. GD has served on the scientific advisory boards of Akili Interactive, Hoffmann-La Roche, Janssen Research and Development, LabCorp, Tris Pharma, and Zynerba; she has served as a consultant for Apple, Axial Ventures, Gerson Lehrman Group, Guidepoint Global, and Teva Pharmaceutical; she serves as CEO of DASIO, LLC; she has received book royalties from Guilford, Oxford University Press, and Springer Nature Press; she has developed technology, data, and/or products that have been licensed to Apple or Cryo-Cell International, from which she and Duke University have benefited financially; and she holds a patent (10,912,801) and has patent applications (62,757,234, 25,628,402, and 62,757,226). FS has served as a consultant for BlackThorn Therapeutics, Janssen Research and Development, and Hoffmann-La Roche. JCM has received funding from Janssen Research and Development; he has served as consultant for Blackthorn Therapeutics, BridgeBio, Customer Value Partners, and Determined Health; he has served on the scientific advisory boards of Modern Clinics and Pastorus; and he receives royalties from Guilford, Lambert Press, and Springer. The other authors report no financial relationships with commercial interests.

Support for this project was provided by the National Institute of Mental Health (U19 MH108206; JCM and R01 MH122428; DŞ).

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A central Institutional Review Board of Yale University gave ethical approval for this work.

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