17344
Abnormalities in Subcortical Glutamate/Glutamine, but Not GABA, in Adults with an ASD: A [1H]MRS Study

Saturday, May 17, 2014: 10:42 AM
Marquis A (Marriott Marquis Atlanta)
M. A. Mendez1, J. Horder1, N. Gillan2, S. Coghlan1 and D. G. Murphy2,3, (1)Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King's College London, London, United Kingdom, (2)Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King's College London, London, United Kingdom, (3)The Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, King’s College London, London, United Kingdom
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.