Transient Visual Evoked Potentials in Monogenic and Idiopathic ASD

Background: There is a critical need to identify biomarkers of ASD that can be obtained from severely affected individuals. Visual evoked potentials (VEPs) offer a noninvasive technique to evaluate the functional integrity of visual pathways and are thought to primarily reflect the sum of excitatory and inhibitory postsynaptic potentials occurring on apical dendrites of pyramidal cells in superficial layers of the occipital cortex. The major positive and negative peaks in VEP waveforms reflect different cellular events (Creutzfeldt & Kuhnt 1973, Zemon et al 1986). The transient VEP (tVEP) waveform is well characterized with an initial peak (P0) at approximately 60 ms representing activation of the primary visual cortex from lateral geniculate nucleus (LGN) afferents (glutamatergic), a negative peak (N0) at approximately 80 ms representing excitatory (glutamatergic) postsynaptic activity, and a positive peak (P1) at approximately 100 ms reflecting inhibitory (GABAergic) activity. VEPs provide a novel method to answer questions about disease pathophysiology and may be useful as electrophysiological biomarkers reflecting neural mechanisms known to be associated with clinical disorders. Examining single-gene forms of ASD can inform our understanding of ASD more broadly.

Objectives: To use tVEPs to objectively measure the integrity of multiple frequency mechanisms in children with genetically-defined ASD subtypes relative to children with idiopathic ASD and to unaffected siblings.

Methods: VEPs were obtained from children with Phelan-McDermid syndrome (PMS), Fragile X syndrome (FXS), idiopathic ASD, unaffected siblings, and typically developing (TD) controls, extracted from ongoing EEG using a single electrophysiological channel. A contrast-reversing checkerboard stimulus (100% contrast) was displayed for 60 seconds to elicit a transient VEP, which enables the examination of multiple frequency mechanisms. All participants received genetic testing to confirm diagnoses. PMS was diagnosed using chromosomal microarray or targeted sequencing, and FXS was diagnosed by analyzing the FMR1 repeat. Standardized research diagnostic instruments (ADOS-2, ADI-R) and DSM-5 criteria were used to diagnose ASD.

Results: Children with PMS displayed distinct tVEP waveforms that reflect a deficit in glutamatergic activity and lack of a high frequency response as compared to children with FXS, idiopathic ASD, unaffected siblings, and TD controls. Children in all other samples displayed the expected tVEP waveform with peaks and troughs at P0, N0, and P1. Results from a measure of magnitude squared coherence (MSC) indicated that children with PMS only showed significant responses at the lowest frequency band (6-10 Hz), while all other groups showed responses at both low and high frequencies.

Conclusions: Our results support findings from animal models which indicated glutamatergic dysregulation in PMS (Yang  et al. 2012, Bozdagi et al. 2013) and the effects of SHANK3 deficiency on AMPA, NMDA, and metabotropic glutamate receptors. Fast acting ionotropic glutamate receptors are necessary to obtain a high frequency VEP response, which is absent in the data from children with PMS. This study is the first step towards identifying neural biomarkers in children with PMS. Future studies must assess electrophysiological functioning in larger samples and in other sensory modalities (e.g., auditory) to determine whether individuals with PMS have an underlying global sensory problem.