Abnormalities in Subcortical Glutamate/Glutamine, but Not GABA, in Adults with an ASD: A [1H]MRS Study

Background: A major emerging hypothesis is that abnormalities in brain function in people with ASD are underpinned by abnormalities in the balance of inhibitory GABA and excitatory glutamate neurotransmission. This excitatory:inhibitory imbalance theory is indirectly supported by animal, postmortem and electrophysiological evidence - and we previously reported pilot evidence that adults with ASD have a significant reduction in glutamate/glutamine concentration in the basal ganglia. However, nobody has yet measured GABA in adults with ASD, or probed whether neurochemical abnormalities (in glutamate/GABA) are associated with abnormal patterns of neural function. 

Objectives: For the first time in adults with ASD, we used proton MEGAPRESS magnetic resonance spectroscopy ([1H]MRS) together with resting state fMRI to quantify (respectively) both GABA and glutamate, and the functional connectivity of left basal ganglia, in medication free adults with ASD.

Methods: We recruited 54 right-handed adult (age 18+) male participants: 24 individuals with ASD and 30 healthy controls who were well matched for age, gender and IQ. All participants had an IQ above 80. Participants in the ASD group met ICD-10 and ADOS-G/ADI-R criteria for autism spectrum disorder. The two groups did not differ in age (t-test, p=0.23) or full-scale IQ (p=0.33). Basal ganglia MEGAPRESS was acquired on a 3 Tesla General Electric MRI scanner using a single voxel centred on the left putamen. Absolute metabolite concentrations were determined using LCModel 6-3-0I software, with water scaling, and corrected for voxel CSF composition. We acquired resting state functional MRI (rsfMRI) in the same scanning session (EPI, TR=2 seconds, 256 volumes). rsfMRI data were analyzed using FSL software (v 4.1.8) Following preprocessing, we calculated seed-voxel connectivity maps for each participant using a seed ROI placed in the left putamen.

Results: Adults with ASD had a significant reduction in the Glx (glutamate and glutamine) signal (p=0.033) as compared to controls. However, there were no significant group differences in BG levels of GABA (two-tailed t-test: p=0.39) or in the glutamate:GABA ratio. Lower Glx was associated with more severe symptoms on the ADOS Social impairments domain. Further, we confirmed the functional relevance of the glutamate/glutamine reduction by integrating this finding with rsfMRI. We found that basal ganglia Glx was positively correlated with the degree of connectivity between the putamen and a network of cortical areas (p<0.05 whole brain cluster corrected). Further, the Glx-connectivity association was stronger (p<0.05 whole brain cluster corrected) for healthy controls than for ASD patients in medial frontal and superior temporal lobe.

Conclusions: This study replicates (in a different sample) previous findings from our laboratory (Horder et al 2013) that adults with ASD have a significant reduction in basal ganglia glutamate/glutamine. Further, we now demonstrate that these differences in glutamate/glutamine are associated with abnormal 'baseline' brain functional connectivity, and severity of clinical symptoms.