Early Electrophysiological Biomarkers of Risk for ASD: Insights Gained from Studies of Infant Siblings and Tuberous Sclerosis Complex

 

Background: A variety of genetic and environmental factors contribute to the heterogeneity of autism spectrum disorders (ASD). However, across etiologies, the underlying neurobiology of ASD converges on the regulation of fundamental processes of brain development such as cortical organization, synapse structure and function, and intra-cortical connectivity. These processes can be measured through methods such as electroencephalography (EEG) before behavioral signs of atypical development emerge. The investigation of infants at heightened genetic risk for ASD affords us an opportunity to examine early biomarkers of risk. Such investigations can shed light on mechanisms underlying atypical development.

Objectives: We present data from two studies of biomarkers of risk for ASD: (1) a study of infants with an older sibling with ASD (“infant siblings”) and (2) a multisite study of infants with Tuberous Sclerosis Complex (TSC). We asked whether there were common and distinct biomarkers of risk across and within groups.

Methods: Infants in each study were tested longitudinally, the infant siblings (n=35 LR, n=47 HR) beginning at age 3 months and the infants with TSC (n=18 LR, n=40 TSC) beginning at age 6 months. Each group was compared to a cohort of “low risk” infants without a known genetic susceptibility for ASD. High density spontaneous EEG was recorded while infants watched abstract, non-social images on a screen. Variables of interest included EEG oscillatory power as a marker of baseline neural synchrony, and frequency variance and whole brain coherence as measures of connectivity and network formation. Cognition and social communication were measured beginning at 6 months of age, with ASD diagnosis made at age 36 months using the Autism Diagnostic Observation Schedule (ADOS) and clinical best estimate.

Results: Distinct trajectories were identified based on risk grouping in spontaneous EEG power, frequency variance, and coherence. More specifically, in the first year of life infants at high risk demonstrated (1) reduced power in alpha (8-11 Hz) [LR: relative power 0.15-0.20 across first year of life, HR: 0.08-0.10, p<0.01 at each age] and gamma (35-50 Hz) bands [LR:relative power 0.05-0.06, HR: 0.03-0.04, p<0.01 at age 9 and 12 months], with the greatest reduction in alpha power found in infants with TSC who developed ASD [p=0.003 at 18 and 24 months] and (2) differences in frequency variance (specifically, greater rate of change in FV in LR infants, p<0.01), alpha band coherence (modularity at 3 months lower in HR infants, 0.035 vs 0.040, p=0.03) that reflected differences in connectivity and signal complexity. Biomarkers of risk were detectable as early as 3 months in the infant siblings and 6 months in infants with TSC in EEG power and coherence.

Conclusions: The putative neurobiological processes that underlie the development of ASD unfold early in life and precede behavioral signs of atypical development. EEG holds particular promise as a biomarker of risk for both scientific and practical reasons. We consider the methodological, clinical, and ethical implications of pre-behavioral biomarkers of risk and discuss the potential for studies to inform the initiation of early developmental interventions before behavioral signs of ASD emerge.