Phase-Amplitude Coupling in Autism Spectrum Disorder: Results from the Autism Biomarkers Consortium for Clinical Trials

Abstract

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.

Changes in Electroencephalography signals in a juvenile female Fragile X Syndrome mouse model

“…A recent EEG study comparing children with autism and typically developing controls, aged 6-11 years identified a notable increase in alpha-gamma and theta-gamma PAC strength in the autism group. Additionally, the study revealed significant correlations between whole-brain theta-gamma PAC strength with autism severity scores on social communication abilities, IQ and levels of restricted and repetitive behaviors across both cohorts (50). This is consistent with our results from FXS mouse model, where the strength of PAC, measured between the amplitude of the gamma band and the phase of lower frequency oscillations (4–12 Hz), is higher in KO female mouse models compared to WT controls.…”

“…Cross-frequency coupling has been developed as a method to assess moment-to-moment interaction between oscillations of different frequencies within EEG signals (50). PAC assesses how the amplitude of high-frequency activity is modulated by the phase of low-frequency oscillations.…”

“…It has been suggested that it functions as a mechanism for integrating large-scale neural networks by synchronizing neuronal firing time, which is necessary for efficient information processing (40)(41)(42). Furthermore, earlier research reported that children with autism have greater alpha to gamma PAC strength as compared to typically developing controls (43,50). Our analysis shows that in-home cage, as well as light-dark test and open-field test arenas, the strength of PAC, measured between the amplitude of gamma band (30-100 Hz) and the phase of lower frequency oscillations (4-12 Hz), is higher in KO female mouse models compared to WT controls (Figure 4: A, B, and C).…”

Lack of univariate, clinically-relevant biomarkers of autism in resting state EEG: a study of 776 participants

“…For MSE, scale was divided into four ranges: all (1-20), ne (1-7), medium (8-13), coarse (14)(15)(16)(17)(18)(19)(20). MSE within each channel was averaged across these scale ranges.…”

“…12 Peak alpha frequency has been reported to be higher in children with autism than in neurotypical children, 13 but also lower in autistic children than in neurotypical children. 14 Similarly, some autistic participants have exhibited greater PAC between theta phase and gamma power than neurotypical individuals, 15 other autistic participants have exhibited increased PAC between alpha and gamma oscillations, 13 but yet other autistic participants have exhibited speci c regional decreases as well as increases in PAC between alpha and gamma oscillations. 16 Autistic individuals generally exhibit decreases in low frequency connectivity, 17 but some studies have reported increases, 18 and complex patterns of changes in network connectivity topology have also been reported.…”