Electrophysiological Biomarkers of Sensory Processing Alterations in Idiopathic and Single-Gene Causes of ASD

Background: Studying syndromic ASD (sASD) represents a unique opportunity to uncover gene-specific neural response patterns and examine the extent of overlap with idiopathic ASD (iASD). Sensory symptoms are prominent features in patients with both sASD and iASD. Electroencephalography (EEG) represents one method to objectively examine sensory processing, and, more specifically, excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission.

Objectives: This study aims to characterize neural response patterns in iASD, ADNP syndrome, Phelan-McDermid syndrome (PMS), and FOXP1 syndrome with typically developing (TD) controls. We investigate whether sensory abnormalities observed behaviorally in iASD and sASD are also detectable using electrophysiological (EEG) measures.

Methods: EEG data were obtained from 19 individuals with Phelan-McDermid syndrome, 4 with FOXP1 syndrome, 3 with ADNP syndrome, 69 with iASD, and 26 TD controls between the ages of 4 and 16. Clinical genetic diagnoses were confirmed using chromosomal microarray or targeted sequencing. Transient visual evoked potentials (VEPs) were elicited using a contrast-reversing checkerboard stimulus. VEPs were extracted from ongoing EEG by signal averaging. Amplitudes for P60-N75 (reflecting excitatory activity) and N75-P100 (reflecting inhibitory activity) were calculated by measuring waveforms peak-to-trough. The magnitude squared coherence (MSC) statistic was used to calculate responses in four previously defined frequency bands: alpha (6-10 Hz), beta (12-28 Hz), low gamma (30-36 Hz), mid gamma (38-48 Hz). Auditory evoked potentials (AEP) during a four-tone habituation paradigm were also obtained from a subset of each group.

Results: The iASD group displayed significant attenuation compared to controls at P60-N75 (p<.001) and N75-P100 (p=.01) with no difference in latencies. The PMS group also displayed significantly attenuated amplitudes compared to controls at P60-N75 (p<.001) with no difference in latencies. The iASD group also displayed significant attenuation compared to controls at P60-N75 (p<.001) as well as N75-P100 (p=.01) with no difference in latencies. The ADNP group showed a similar pattern at P60-N75 (p=.027) and N75-P100 (p=.006), and significantly delayed latency at P100 (p=.048). There was significant individual variability in the FOXP1 group, corresponding to clinical phenotype. In the frequency domain, the iASD and PMS groups displayed significant differences in beta and both gamma bands (p values=.001 to .042 and <.001 to .012, respectively). The ADNP and FOXP1 groups also showed weaker responses in beta (p=.034; p=.032) and low gamma (p=.041; p=.016) bands. Preliminary results from AEPs demonstrate group specific differences in magnitude of response to initial tones and degree of habituation of response to subsequent tones.

Conclusions: Time-domain analyses revealed syndrome-specific phenotypes with excitatory deficits observed in iASD, PMS, and ADNP syndrome groups based on deficits in early negative VEP components (P60-N75). Greater variability in response amplitudes was observed in the FOXP1 syndrome group, although on average, longer latencies were observed in both ADNP syndrome and FOXP1 syndrome groups at P100. Frequency-domain analyses demonstrated differences in beta and low-gamma activity present across iASD and sASD groups. Future directions include collecting additional AEP data to determine whether brain-based sensory abnormalities exist across sensory modalities. This information could potentially be used to inform treatment approaches for individuals with both syndromic and idiopathic ASD.