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

Jennifer E. Siegel-Ramsay, Liana Romaniuk, Heather C. Whalley, Neil Roberts, Holly Branigan, Andrew C. Stanfield, Stephen M. Lawrie, Maria R. Dauvermann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number111302
JournalPsychiatry Research - Neuroimaging
Early online date12 May 2021
Publication statusPublished - 30 Jul 2021

Bibliographical note

Funding Information:
We sincerely thank all participants who took part in the study. The scans were acquired at the Edinburgh Imaging Facility in the Queen's Medical Research Institute (EIF-QMRI). We would like to thank Dr. Scott Semple (MRI physicist), Annette Cooper, and her team of radiographers at EIF-QMRI for help in organizing the study and acquiring the scans. The investigators also acknowledge the support of the Scottish Mental Health Research Network (, particularly Dr. James McKirdy, who assisted with subject recruitment.

Funding Information:
This work was funded by a research grant to MRD, ASC and SML from the RS MacDonald Charitable Trust, Edinburgh [2011]. The Patrick Wild center contributed to PhD costs for JES. These funding sources have no involvement in the article preparation

Publisher Copyright:
© 2021 The Author(s)


  • Anterior cingulate cortex
  • Glutamate
  • Glutamate+Glutamine
  • Magnetic Resonance Imaging
  • Proton Magnetic Resonance Spectroscopy
  • Resting-state functional connectivity

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Radiology Nuclear Medicine and imaging
  • Psychiatry and Mental health


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