Altered Glutamate Development in Adolescents with Persistent ADHD

A neuroimaging investigation published in *Translational Psychiatry* examined glutamate concentrations in the medial prefrontal cortex (mPFC) of adolescents aged 14-15. Researchers selected 161 participants from the Neurobehavioral Clinical Research longitudinal cohort, including 69 with persistent ADHD, 20 whose symptoms remitted, and 72 who never met ADHD criteria. Proton magnetic resonance spectroscopy (¹H-MRS) and structural MRI were used, with follow-up scans conducted for roughly half of the sample about two years later. Follow-up imaging was obtained for 78 participants, allowing assessment of within-subject changes over time.

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Attention-deficit/hyperactivity disorder is a neurodevelopmental condition linked to dysregulation of dopamine and noradrenaline pathways. The present study extends this framework by focusing on glutamate, the brain’s primary excitatory neurotransmitter, and its role in the mPFC—a region implicated in attention allocation, decision-making, and emotional regulation. Interactions between glutamatergic and catecholaminergic systems are considered central to ADHD symptomatology. Prior imaging work has implicated dysregulation of dopamine and noradrenaline systems in ADHD, but glutamate has received less attention.

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The sample was predominantly male: 80 % of the persistent-ADHD group, 75 % of the remitting group, and 64 % of the never-ADHD group. The male predominance reflects the higher reported prevalence of ADHD among boys in clinical samples. All participants completed ¹H-MRS to quantify mPFC glutamate levels; nearly 50 % also underwent a second scan after an average interval of two years, enabling longitudinal assessment of developmental trajectories.

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Adolescents with persistent ADHD displayed an age-related increase in mPFC glutamate, whereas both remitting-ADHD participants and those without ADHD showed age-related decreases. The altered glutamate trajectory in the persistent group correlated with changes in intrinsic connectivity between the default mode network and subcortical regions, suggesting a link between neurochemical maturation and functional network organization. Specifically, reduced synchrony between the default mode network and basal ganglia structures was observed in the persistent group.

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The research team, comprising Marine Bouyssi-Kobar, Yan Zhang, Luke Norman, Saadia Choudhury, Wendy Sharp, Gustavo Sudre, Tonya White, and Philip Shaw, concluded that the observed glutamate pattern may reflect delayed or atypical neurodevelopment in youth with enduring ADHD symptoms. By contrast, the decreasing glutamate levels in remitting individuals align with typical adolescent brain maturation, supporting the notion that glutamatergic trajectories differentiate clinical courses.

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The authors acknowledge that the combined cross-sectional and longitudinal design precludes definitive causal inference. The study examined only a single, predefined brain region, limiting broader neurochemical insight. Additionally, hormonal fluctuations associated with puberty were not controlled for, a factor that could influence glutamate dynamics. Future studies should incorporate multi-region spectroscopy and hormonal assessments to clarify causal pathways.

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“These findings may indicate altered maturation of glutamate in the medial prefrontal cortex in youth with persistent ADHD.” — Marine Bouyssi-Kobar, lead author

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