Typical Cortical Concentration of GABA and Glutamate in Young Adults with Autism Spectrum Disorder

Background: An imbalance of excitation and inhibition (E/I) in neural circuits has been postulated as a key neurobiological characteristic of autism spectrum disorder (ASD). Various evidence from genetics, animal models and post-mortem analyses point to a central role of the inhibitory transmitter GABA, yet evidence in humans is lacking. Magnetic resonance spectroscopy (MRS) provides a non-invasive technique to measure concentrations of GABA and other neurometabolites in vivo. Several recent MRS studies have found reduced GABA concentration in children with ASD, lending support to the E/I imbalance model. However, results are inconsistent across experimental procedures, regions of interest, and sample characteristics, including the potential confounding effects of psychotropic medication use.

Objectives: Since developmental changes may underlie the mixed results of GABA in cross-sectional studies in children, we aimed to test GABA levels in young adults with ASD, at the end point of the developmental trajectory, while controlling for effects of sex and medication use.

Methods: Participants included 30 adults with ASD (19 male) with diagnoses confirmed through ADOS, ADI and clinical judgment using DSM-5 criteria, and included 39 age-, sex- , and IQ- matched neurotypical controls (22 male). MRS scans were acquired with a 3T scanner using MEGA-PRESS editing, in 5 different volumes of interest (VOIs; Figure 1A): medial occipital cortex, left temporal cortex, parietal cortex opposite to the participant’s dominant hand, and in right and left lateral occipital cortex (functionally-defined human MT complex). GABA+ (GABA plus co-edited macromolecules) and Glx (glutamate plus glutamine) concentrations were quantified in each VOI using the Gannet GABA Analysis Toolkit, and scaled to water (Figure 1B). Measurements in the occipital VOI were repeated in two separate scanning sessions to assess test-retest reliability.

Results: There were no differences in GABA+ levels (Figure 2A), Glx levels (Figure 2B), or their ratio, between individuals with ASD and neurotypicals, in any of the VOIs (all t’s<1.55). The same pattern of results was obtained when excluding participants treated with selective serotonin reuptake inhibitor drugs (SSRIs; NT: n=1; ASD: n=8), and when excluding participants treated with any psychotropic medications (NT: n=2; ASD: n=14). There were no sex differences in any of the MRS measures and no correlations with age. GABA+ and Glx concentrations did not correlate with ADOS, SRS, or Sensory Scale scores. Likewise, GABA+ and Glx did not correlate with behavioral measures of visual perception (motion discrimination thresholds or contrast detection thresholds, measured with psychophysical tasks). Test-retest repeatability analysis of the occipital VOI measurements revealed low coefficients of variation across sessions (GABA+: CV=4%; Glx: CV=6%) but poor intraclass correlations (GABA+: ICC=.24; Glx: ICC=.35; Figure 2C-D).

Conclusions: The current study provides a comprehensive set of measurements in 5 different VOIs in adults with ASD and found typical levels of both GABA+ and Glx concentrations in ASD, yielding no support for brain-wide alteration of E/I imbalance. We suggest that low test-retest reliability might limit the power to detect small group differences, and that better signal-to-noise is required in future studies.