Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [¹H]MRS study

Abstract

Dysfunctional glutamatergic neurotransmission has been implicated in autism spectrum disorder (ASD). However, relatively few studies have directly measured brain glutamate in ASD adults, or related variation in glutamate to clinical phenotype. We therefore set out to investigate brain glutamate levels in adults with an ASD, comparing these to healthy controls and also comparing results between individuals at different points on the spectrum of symptom severity. We recruited 28 adults with ASD and 14 matched healthy controls. Of those with ASD, 15 fulfilled the 'narrowly' defined criteria for typical autism, whereas 13 met the 'broader phenotype'. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD--the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex--as well as in a parietal cortex 'control' region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the 'narrow' and 'broader' phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not. There were no detectable differences in Glx, or any other metabolite, in the parietal lobe control region. There were no significant between-group differences in age, gender, IQ, voxel composition or data quality. In conclusion, individuals across the spectrum of ASD have regionally specific abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development.

Figure 1

Examples of the location of proton magnetic resonance spectroscopy ([¹H]MRS) voxels. Three voxels were positioned in (a) left basal ganglia (20 × 20 × 15 mm³) to include the head of the caudate, putamen and internal capsule, (b) left dorsolateral prefrontal cortex (16 × 24 × 20 mm³) and (c) left medial parietal lobe (20 × 20 × 20 mm³).

Figure 2

Example of a proton magnetic resonance spectroscopy ([¹H]MRS) spectrum showing LCModel 6-1-0 fit.

Figure 3

Individual participant data showing basal ganglia glutamate and glutamine (Glx) by group. ASD, autism spectrum disorder.

Figure 4

Association between basal ganglia glutamate and glutamine (Glx) and Autism Diagnostic Interview—Revised (ADI-R) Communication Subscale Score in individuals with autism spectrum disorder (ASD).