Magnetoencephalography Studies of the Envelope Following Response During Amplitude-Modulated Sweeps: Diminished Phase Synchrony in Autism Spectrum Disorder

Abstract

Prevailing theories of the neural basis of at least a subset of individuals with autism spectrum disorder (ASD) include an imbalance of excitatory and inhibitory neurotransmission. These circuitry imbalances are commonly probed in adults using auditory steady-state responses (ASSR, driven at 40 Hz) to elicit coherent electrophysiological responses (EEG/MEG) from intact circuitry. Challenges to the ASSR methodology occur during development, where the optimal ASSR driving frequency may be unknown. An alternative approach (more agnostic to driving frequency) is the amplitude-modulated (AM) sweep in which the amplitude of a tone (with carrier frequency 500 Hz) is modulated as a sweep from 10 to 100 Hz over the course of ∼15 s. Phase synchrony of evoked responses, measured via intra-trial coherence, is recorded (by EEG or MEG) as a function of frequency. We applied such AM sweep stimuli bilaterally to 40 typically developing and 80 children with ASD, aged 6–18 years. Diagnoses were confirmed by DSM-5 criteria as well as autism diagnostic observation schedule (ADOS) observational assessment. Stimuli were presented binaurally during MEG recording and consisted of 20 AM swept stimuli (500 Hz carrier; sweep 10–100 Hz up and down) with a duration of ∼30 s each. Peak intra-trial coherence values and peak response frequencies of source modeled responses (auditory cortex) were examined. First, the phase synchrony or inter-trial coherence (ITC) of the ASSR is diminished in ASD; second, hemispheric bias in the ASSR, observed in typical development (TD), is maintained in ASD, and third, that the frequency at which the peak response is obtained varies on an individual basis, in part dependent on age, and with altered developmental trajectories in ASD vs. TD. Finally, there appears an association between auditory steady-state phase synchrony (taken as a proxy of neuronal circuitry integrity) and clinical assessment of language ability/impairment. We concluded that (1) the AM sweep stimulus provides a mechanism for probing ASSR in an unbiased fashion, during developmental maturation of peak response frequency, (2) peak frequencies vary, in part due to developmental age, and importantly, (3) ITC at this peak frequency is diminished in ASD, with the degree of ITC disturbance related to clinically assessed language impairment.

Characteristics of auditory steady-state responses to different click frequencies in awake intact macaques

“…The above results (higher sensitivity to a higher stimulus repetition rate in macaques) might be ascribed to differences in sources of ASSRs between macaques and humans: ASSRs might more strongly reflect the activity of the subcortical sources of ASSRs in macaques while the activity of the cortical sources is dominant in human ASSRs. However, ASSR amplitudes are maximal at 40 Hz in the subcortical as well as cortical responses in humans [9,48] although there is some individual variation in peak response frequencies ranging from 30 to 50 Hz in humans [49,50]. These findings support the idea that the difference in the maximal frequencies between macaques (83.3 Hz) and humans (40 Hz) may be attributed to species differences rather than differences in the ASSR sources.…”

Autism Spectrum Disorder and auditory sensory alterations: a systematic review on the integrity of cognitive and neuronal functions related to auditory processing

“…Reduced 40 Hz power was also found in adolescents with ASD at both right and left primary auditory cortex, with no difference in gamma-band responses (Seymour et al 2021 ). Diminished auditory gamma-band responses were found in ASD children, indicating that peak frequencies likely vary with developmental age (Roberts et al 2021 ).…”

Modern Biomarkers for Autism Spectrum Disorder: Future Directions

“…A recent meta-analysis found evidence for prolonged M50 and M100 latencies to pure tone stimuli [66] and a recent study suggested that the M50 latencies might be used to predict treatment response to GABA-B agonists [67]. Others have studied gamma-band coherence with various auditory stimuli [68][69][70].…”