Event-Related Functional Spectroscopy Reveals Distinct Glutamate and GABA Abnormalities in ASD and High-Risk Children

Background: Individuals with Autism Spectrum Disorder (ASD) often have impairments in social domains, such as difficulty decoding facial expressions and motor domains, including weakened grip strength. It is possible that a global imbalance of neural excitation and inhibition drives both of these behavioral atypicalities. In order to explore this potential relationship, we assessed grip response to perception of facial expressions using a motor-specific, event related, high-temporal resolution functional Magnetic Resonance Spectroscopy (ht-fMRS), which has the capacity to quantify second-by-second accumulation of the major excitatory and inhibitory neurotransmitters (i.e. glutamate and GABA) in specific regions of interest. Our ht-fMRS focused on the median pontine nuclei due to its implication in our prior DTI studies of ASD and the importance of these nuclei in integrating top-down emotion modulated startle circuits.

Objectives: 1) To use novel motor-specific ht-fMRS to characterize the neurochemical signature of perception of facial expression and initiation of grip response in the pons, and 2) to examine the motor-specific neurochemical signatures within the pons of children with ASD, at a high risk for ASD (ASD-Related), and with typical development (TD).

Methods: Data pertaining neurochemical accumulation during the perception of neutral and emotional faces and the subsequent grip response to those faces were gathered from 18 children with ASD, 12 children at a genetically higher risk for ASD (ASD-Related), and 13 children with TD, ages 6 -10 years. The ASD-Related group included children who had a genetic risk factor for ASD (i.e., having an ADHD diagnosis or a first-degree relative with ASD, major depressive disorder, bipolar disorder, or schizophrenia). Participants used bilateral MRI-compatible grip strength responders to indicate grip response (hard or light) in response to faces (emotional or neutral). A general linear model was constructed using the raw spectroscopic data to deconvolve the neurochemical signatures unique to grip in response to presentation of emotional and neutral faces.

Results: Baseline grip was associated with diagnostic group (p = 0.02), and latency to grip was significantly correlated with autism symptom severity (p=0.04). Neurochemical signatures of emotion modulation (emotion-neutral) of trial-by-trial grip intensity showed a blunted glutamate response in ASD compared to ASD-R and TD, but absent GABA in both ASD and ASD-R compared to TD (p =0.03).

Conclusions: Using a grip-strength and emotion task in ASD, we show a clearly impaired neurotransmitter response in ASD. Interestingly, we also find an intermediate phenotype in ASD-R: ASD-like GABA blunting but high-normal glutamate during emotion-modulated grip. Taken together these results provide evidence for altered neurochemical responses to sensory stimuli during a motor task in children with ASD as well as those with higher genetic risk for ASD.