Defining a subgroup within autism leads to potential enrichment criteria in investigational therapeutic development: Comparing resting state gamma band power to a fragile X syndrome reference sample

Background Elevated resting gamma power is a reproducible, robust neurophysiology marker across species in fragile X syndrome (FXS), a major known cause of autism spectrum disorders (ASD). In FXS, this neurophysiological phenotype is well described and particularly prominent in males harboring fully methylated full CGG repeat expansions. However, gamma power evaluations in idiopathic ASD have yielded variable results. As a single-gene model of ASD, FXS hold promise to biologically model some of the autism spectrum. Exaggerated gamma power in FXS is thought to reflect increased cortical excitability, a common feature of ASD, and has been shown to correlate with symptoms in both human FXS individuals and the Fmr1 knockout mouse model of FXS. A recent clinical trial of the BK channel positive modulator, Codabakalner, provided encouraging signs that normalization of gamma power in FXS may provide therapeutic benefit [14]. Interventional and biomarker studies in ASD provide support that this may also be the case in ASD. We utilized gamma band power to evaluate neurophysiological overlap between ASD and FXS seeking to determine the prevalence and clinical characteristics of those with ASD who exhibit a FXS-like elevated resting state gamma phenotype. Methods This cross-sectional resting EEG analysis included 159 individuals with non-syndromic ASD and 41 males with fully methylated full mutation FXS. Relative gamma power was calculated as 30-100 Hz power divided by 1-100 Hz power across 10-20-equivalent electrodes, excluding 55-65 Hz. We defined the cutoff for elevated resting gamma band power in ASD as relative gamma power of greater than or equal to the median minus one standard deviation of gamma power in our FXS male sample. Results A FXS-derived relative-gamma threshold of 0.185 or greater was met by 22% of participants with ASD (n=35). As expected, the mean ASD group resting state gamma was lower than the male FXS sample (p < 0.001). ASD participant threshold proportions by age group were 3/37 (8.1%) below 13 years, 9/50 (18.0%) age 13-18 years, and 23/72 (31.9%) in the 18+ years group. Within the ASD group, there were no observable clinical characteristics that readily differentiated participants with an elevated gamma phenotype from those without this phenotype. Conclusions Approximately one fifth of all participants and slightly over 30 percent of adults with ASD met the FXS-derived elevated resting gamma band power criterion. This represents the first investigation using a translational brain neurophysiology marker in a syndromic form of autism to parse a clinical idiopathic ASD sample to identify potential overlapping brain features. The results will work to support potential targeting of ASD subgroups in the future utilizing therapeutic approaches initially established in a single-gene form of developmental disability.