Abnormalities in Subcortical Glutamate/Glutamine, But Not GABA, In Adults With An ASD – A [1H]MRS Study

TY - CHAP

T1 - Abnormalities in Subcortical Glutamate/Glutamine, But Not GABA, In Adults With An ASD – A [1H]MRS Study

AU - Horder, Jamie

PY - 2014

Y1 - 2014

N2 - 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 concentration in basal ganglia. However, nobody has yet measured GABA in adults with ASD, or related differences in glutamate/GABA to those in neural functional connectivity. 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. 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 worse symptoms on the ADOS Social impairments domain. Further, we confirmed the functional relevance of the Glx 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 relationship with connectivity 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 BG Glx. Further, we now demonstrate that these differences in glutamate are associated with abnormal brain functional connectivity and severity of clinical symptoms.

AB - 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 concentration in basal ganglia. However, nobody has yet measured GABA in adults with ASD, or related differences in glutamate/GABA to those in neural functional connectivity. 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. 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 worse symptoms on the ADOS Social impairments domain. Further, we confirmed the functional relevance of the Glx 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 relationship with connectivity 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 BG Glx. Further, we now demonstrate that these differences in glutamate are associated with abnormal brain functional connectivity and severity of clinical symptoms.

KW - ASD

KW - autism

KW - GABA

KW - Glx

KW - MRS

KW - [1H]MRS

M3 - Meeting abstract

BT - 13th International Meeting for Autism Research (IMFAR) 2014

ER -