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Developmental trajectories of glutamate and the variable clinical course of ADHD in youth
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  • Published: 13 February 2026

Developmental trajectories of glutamate and the variable clinical course of ADHD in youth

  • Marine Bouyssi-Kobar  ORCID: orcid.org/0000-0001-9526-21821,
  • Yan Zhang2,
  • Luke Norman1,
  • Saadia Choudhury1,
  • Wendy Sharp1,
  • Gustavo Sudre3,
  • Tonya White  ORCID: orcid.org/0000-0003-0271-18961 na1 &
  • …
  • Philip Shaw  ORCID: orcid.org/0000-0002-1313-25263 na1 

Translational Psychiatry , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • ADHD
  • Diagnostic markers
  • Molecular neuroscience

Abstract

Recent evidence suggests the brain’s major excitatory neurotransmitter, glutamate, plays a key role in attention-deficit/hyperactivity disorder (ADHD). Here we ask if glutamate also plays a role in the variable clinical courses of ADHD. While some children ‘grow out’ of ADHD by adolescence, others experience persistent symptoms into adulthood. Prior work implicates structural and functional differences in medial prefrontal cortex as pivotal in these different ADHD symptom courses, and we now ask if glutamate developmental change also contributes. Given the role of glutamate in neurotransmission, we also investigate potential impacts on the brain’s intrinsic connectivity. Using a glutamate-specific magnetic resonance spectroscopy sequence at 3 T, we analyzed 241 spectra on 161 participants, including 69 with persistent ADHD, 20 with remitting ADHD, and 72 never affected controls. Intrinsic functional connectivity was also assessed in a subset of 104 participants with 141 functional MRI scans. Using linear mixed models, we found an age-related increase in medial prefrontal glutamate in the persistent ADHD group which differed significantly from an age-related decrease among those who remitted and the never affected controls. Furthermore, altered prefrontal glutamate concentrations were associated with changes in intrinsic connectivity between the default mode network (which includes medial frontal cortex) and subcortical regions. These findings may indicate altered maturation of glutamate in the medial prefrontal cortex in youth with persistent ADHD.

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Data availability

We will share de-identified data where the participant or participant’s parent has given consent for sharing. These data will be available by the end of 2026 on the database of Genotypes and Phenotypes (#55949; dbGaP; https://www.ncbi.nlm.nih.gov/gap/).

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Acknowledgements

We are grateful to the children, young people, and families that participated in this clinical research. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) including programs from the National Human Genome Research Institute (Dr. Shaw: ZIAHG200378) and from the National Institute of Mental Health (Dr. White: ZIAMH002986). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. This work utilized the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov).

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Open access funding provided by the National Institutes of Health.

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Author notes

  1. These authors contributed equally: Tonya White, Philip Shaw.

Authors and Affiliations

  1. Section on Social and Cognitive Developmental Neuroscience, National Institute of Mental Health, 10 Center Drive, Bethesda, MD, 20892, USA

    Marine Bouyssi-Kobar, Luke Norman, Saadia Choudhury, Wendy Sharp & Tonya White

  2. Magnetic Resonance Spectroscopy Section, National Institute of Mental Health, 10 Center Drive, Bethesda, MD, 20892, USA

    Yan Zhang

  3. King’s Maudsley Partnership for Children and Young People, Institute of Psychiatry, Psychology & Neuroscience at King’s College, London, WC2R 2LS, United Kingdom

    Gustavo Sudre & Philip Shaw

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  1. Marine Bouyssi-Kobar
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Contributions

Conceptualization and design: MBK, PS. Data collection and curation: MBK, SC, WS, GS. Investigation: MBK, LN, GS, TW, PS. Methodology: MBK, YZ, LN. Statistical analysis: MBK. Creation of figures: MBK, YZ. Interpretation: MBK, LN, TW, PS. Resources: PS, TW. Supervision: PS. Writing original draft: MBK, PS. Writing, reviewing and editing: all authors.

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Correspondence to Marine Bouyssi-Kobar.

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Bouyssi-Kobar, M., Zhang, Y., Norman, L. et al. Developmental trajectories of glutamate and the variable clinical course of ADHD in youth. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03898-7

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  • Received: 12 May 2025

  • Revised: 17 December 2025

  • Accepted: 01 February 2026

  • Published: 13 February 2026

  • DOI: https://doi.org/10.1038/s41398-026-03898-7

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