Dorsal anterior cingulate cortex glutamate concentrations and their relationships in adults with autism spectrum disorder
Siegel-Ramsay, Jennifer Eileen
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Previous studies have reported altered glutamate (Glu) concentrations in the blood and brain of individuals with autism spectrum disorder (ASD) compared to neurotypical controls (NC), but the direction (increased or decreased) of metabolite differences is still unclear. Moreover, the relationship between Glu and both brain function and clinical manifestations of the disorder require further investigation. Within this study, we investigated metabolite concentrations within the dorsal anterior cingulate cortex (dACC), a brain region functionally associated with inhibitory executive control tasks and also part of the salience network. There were 19 participants with ASD and 20 NCs between the ages of 23 and 58 years who participated in this study. A study clinician administered the Autism Diagnostic Observation Schedule (ADOS) to individuals with ASD to further confirm their diagnosis. In addition, all participants in this study completed assessments of general intelligence and attention, which included an inhibitory executive control task. Researchers also acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H-MRS) in the dACC to quantify both Glu and combined Glu and glutamine (Glx) concentrations. We hypothesised that these metabolite concentrations would be altered (decreased or increased) in adult participants with ASD compared to NCs and would correlate with inhibitory performance and ASD severity in individuals with ASD. Participants also underwent a resting-state functional magnetic resonance imaging (fMRI) scan to assess the relationship between functional connectivity and Glu and Glx concentrations. We also hypothesised that there would be an altered relationship between local Glu and Glx concentrations and seed-based functional connectivity in adults with ASD compared to NCs. There were no significant group differences in Glu or Glx concentrations between individuals with ASD and NCs. Furthermore, we did not find any relationship between metabolite concentrations and either inhibitory performance or clinical symptoms of the disorder. This evidence suggests that increased or decreased Glu and Glx concentrations were not a core marker of altered brain function in the dACC in this group of adult individuals with ASD. When individuals taking psychotropic medications were excluded from the analysis, there was a significant interaction between age and group for Glx concentrations. This evidence weakly suggests disease-specific variations in Glx concentrations over the lifespan of an individual with ASD. Nevertheless, this result did not survive correction for multiple comparisons and requires further replication. In our final experiment, we reported that Glu concentrations were negatively correlated with right and left dACC seed-based resting-state functional connectivity to the left medial temporal lobe only in individuals with ASD. We also reported an interaction between groups in the association between Glx concentrations and both left and right dACC functional connectivity to other salience network regions including the insular cortex. This evidence suggests that local Glu and Glx concentrations were incongruent with long-distance functional connectivity in individuals with ASD. This analysis was largely exploratory, but further investigation and replication of these relationships may further explain the pathophysiology of the disorder as well as provide a useful marker for therapeutic intervention.