Cortical excitation-inhibition ratio mediates the effect of pre-attentive auditory processing deficits on interpersonal difficulties

Abstract

Several lines of evidence identify aberrant excitatory-inhibitory neural processes across autism and schizophrenia spectrum disorders, particularly within the psychosocial domain. Such neural processes include increased excitatory glutamate and reduced inhibitory GABA concentrations, which may affect auditory pre-attentive processing as indexed by the mismatch negativity (MMN); thus, an excitation-inhibition imbalance might lead to aberrant MMN, which might in turn drive the relationship between the MMN and psychosocial difficulties. This research has the potential to enhance the neurochemical understanding of the relationship between electrophysiology (MMN) and behavioural/clinical measures (psychosocial difficulties). Thirty-eight adults (18 male, 18-40 years) completed the Schizotypal Personality Questionnaire (SPQ) and Autism-Spectrum Quotient (AQ). Glutamate and GABA concentrations in bilateral superior temporal cortex (STC) were quantified using proton magnetic resonance spectroscopy (1H-MRS) while auditory MMN to a duration deviant was measured with magnetoencephalography. Spearman correlations probed the relationships between STC glutamate/GABA ratios, MMN amplitude and latency, and AQ and SPQ dimensions. Mediation effects of glutamate/GABA ratios on the relationship between MMN and AQ-SPQ dimensions were probed using causal mediation analysis. Only SPQ-interpersonal and AQ-communication were significantly correlated with right hemisphere glutamate/GABA ratios and MMN latency (ps < 0.05), which were themselves correlated (p = .035). Two mediation models were investigated, with right MMN latency as predictor and SPQ-interpersonal and AQ-communication as outcome variables. Right STC glutamate/GABA ratios significantly mediated the relationship between MMN latency and SPQ-interpersonal scores, but only partially mediated the relationship between MMN latency and AQ-communication scores. These findings support the growing body of literature pointing toward an excitation-inhibition imbalance that is central to psychosocial functioning across multi-dimensional spectrum disorders, such as autism and schizophrenia, and provides neurochemical indicators of the processes that underlie psychosocial dysfunction.

Keywords: Autism; GABA; Glutamate; Mismatch negativity; Schizophrenia; Social cognition.