Electrophysiological Markers of a Potential Excitatory:Inhibitory Imbalance in Children with Autism Spectrum Disorder

Background:  Sensory processing abnormalities are a core feature of Autism Spectrum Disorder (ASD). Emergent evidence suggests that hyper- or hypo-reactivity to sensory input(s) in ASD may be due to a neurochemical imbalance between excitatory glutamate (Glu) and inhibitory γ-aminobutyric acid (GABA) neurotransmission, also known as the excitatory:inhibitory (E:I) theory of ASD.

Objectives: To explore possible consequences of imbalanced GABA:Glu neurotransmission on the visual system, we investigated surround suppression in ASD using a visual motion processing task during electroencephalography (EEG) recording to derive the N1 event related potential (ERP). Behavioral studies have demonstrated that healthy adults have a directional impairment of discrimination in conditions of large/high-contrast visual stimuli, which is thought to reflect surround suppression of motion selective neurons and to be driven by GABA (Tadin et al., 2003; Aaen-Stockdale et al., 2009). Behaviorally, individuals with ASD have demonstrated weakened surround suppression, i.e. a selective enhancement of motion perception in conditions of large, high-contrast stimuli (Foss-Feig et al., 2013; Horder et al., 2014). To our knowledge, there have been no prior studies to investigate an ERP marker of surround suppression. To validate this paradigm, we demonstrated that healthy adults have delayed processing in conditions of large/high-contrast thought to reflect surround suppression as indexed by N1 ERP latency (p=0.013).

Methods:  In the pilot study, five high-functioning medication-free children with ASD based on DSM-5 criteria and four typically developing children from 7 – 12 years of age were recruited. ASD classification was confirmed using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) (Lord et al., 2012). All participants reported no history of neurological disorder and had normal or corrected-to-normal vision. Participants were screened for a contrast-sensitivity impairment using the Pelli-Robson Contrast Sensitivity Acuity Chart. During EEG recording participants completed a visual processing task. Stimuli were programmed using Psykinematix (Beaudot, 2009) and consisted of 1 cycle/degree drifting vertical sine wave gratings surrounded by two-dimensional Gaussian envelopes drifting either right or left at a consistent speed. Stimulus size (large vs. small) was either 5.0° or 0.7° and stimulus contrast (bright vs. faint) was either 92% or 2.8%. Recruitment is ongoing for the main study.

Results: In the high-contrast experiment, we demonstrated children with ASD have significantly enhanced processing of large stimuli compared to small stimuli thought to reflect weakened surround suppression (t(4) = 5.023, p=0.007) as indexed by N1 ERP latency. Typically developing children did not demonstrate N1 ERP latency differences in the high-contrast experiment (t(3) = -2.296, p=.105). Children with ASD had significantly shorter N1 ERP latencies to large/high contrast-stimuli than typically developing children (t(7) = -3.953, p=0.006). As expected, there were no processing differences between stimuli sizes in conditions of low contrast, since surround suppression is contrast-dependent.

Conclusions: Medication free children with ASD demonstrated weakened surround suppression. Shorter N1 latencies in conditions of large, high-contrast stimuli could lend support to the E:I imbalance theory of ASD. This paradigm may have potential for use as a clinical outcome measure in research trials to evaluate the effectiveness of investigational pharmaceuticals that act on GABAergic neurotransmission.