Glutamate and functional connectivity - support for the excitatory-inhibitory imbalance hypothesis in autism spectrum disorders

Psychiatry Res Neuroimaging. 2021 Jul 30;313:111302. doi: 10.1016/j.pscychresns.2021.111302. Epub 2021 May 12.


It has been proposed that the Glutamate (Glu) system is implicated in autism spectrum disorders (ASD) via an imbalance between excitatory and inhibitory brain circuits, which impacts on brain function. Here, we investigated the excitatory-inhibitory imbalance theory by measuring Glu-concentrations and the relationship with resting-state function. Nineteen adult males with ASD and 19 age and sex-matched healthy controls (HC) (23 - 58 years) underwent Proton Magnetic Resonance Spectroscopy of the dorsal anterior cingulate cortex (dACC) and resting-state functional Magnetic Resonance Imaging (fMRI). Glu and Glx concentrations were compared between groups. Seed-based functional connectivity was analyzed with a priori seeds of the right and left dACC. Finally, metabolite concentrations were related to functional connectivity coefficients and compared between both groups. Individuals with ASD showed significantly negative associations between increased Glx concentrations and reduced functional connectivity between the dACC and insular, limbic and parietal regions. In contrast, HC displayed a positive relationship between the same metabolite and connectivity measures. We provided new evidence to support the excitatory-inhibitory imbalance theory, where excitatory Glx concentrations were related to functional dysconnectivity in ASD. Future research is needed to investigate large-scale functional networks in association with both excitatory and inhibitory metabolites in subpopulations of ASD.

Keywords: Anterior cingulate cortex; Glutamate; Glutamate+Glutamine; Magnetic Resonance Imaging; Proton Magnetic Resonance Spectroscopy; Resting-state functional connectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autism Spectrum Disorder* / diagnostic imaging
  • Glutamic Acid*
  • Gyrus Cinguli / diagnostic imaging
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Proton Magnetic Resonance Spectroscopy


  • Glutamic Acid