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Relationship between GABA levels and task-dependent cortical excitability in children with attention-deficit/hyperactivity disorder

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Ashley D. Harris, Donald L. Gilbert, Paul S. Horn, Deana Crocetti, Kim M. Cecil, Richard A.E. Edden, David A. Huddleston, Stewart H. Mostofsky, Nicolaas A.J. Puts

Original languageEnglish
Pages (from-to)1163-1172
Number of pages10
JournalClinical Neurophysiology
Issue number5
PublishedMay 2021

Bibliographical note

Funding Information: This project was supported by funding from the National Institutes of Health; R01 MH078160, R01 MH085328 and R00MH107719. This study applies tools developed under NIH R01 EB016089 and P41 EB015909; RAEE also receives salary support from these grants. Funding Information: Dr. Gilbert has received honoraria and/or travel support from the Tourette Association of America/ Centers for Disease Control and Prevention, the American Academy of Pediatrics, the Child Neurology Society, the Texas Neurological Society, and the American Academy of Neurology. He has received compensation for expert testimony for the U.S. National Vaccine Injury Compensation Program, through the Department of Health and Human Services, and for the US Armed Services/US Attorney’s Office of VA. Dr. Gilbert has received research support from the NIH (NIMH, NINDS). He has received funding for work as a clinical trial site investigator from Ecopipam Pharmaceuticals (clinical trial, Tourette Syndrome) and EryDel (clinical trial, Ataxia Telangiectasia). He has received book royalties from Elsevier and Wolters Kluwer. Dr. Edden has received grants from Siemens. Publisher Copyright: © 2021 International Federation of Clinical Neurophysiology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Objective: Compared to typically developing (TD) peers, children with attention deficit hyperactivity disorder (ADHD) manifest reduced short interval cortical inhibition (SICI) in the dominant motor cortex measured with transcranial magnetic stimulation (TMS). This multimodal study investigates the inhibitory neurophysiology and neurochemistry by evaluating the relationship between SICI and γ-amino butyric acid (GABA+) levels, measured with magnetic resonance spectroscopy (MRS). Methods: Across two sites, 37 children with ADHD and 45 TD children, ages 8–12 years, participated. Single and paired pulse TMS to left motor cortex quantified SICI during REST and at times of action selection (GO) and inhibition (STOP) during a modified Slater-Hammel stop signal reaction task. MRS quantified GABA+ levels in the left sensorimotor cortex. Relationships between SICI and GABA+, as well as stopping efficiency and clinical symptoms, were analyzed with correlations and repeated-measure, mixed-models. Results: In both groups, higher GABA+ levels correlated with less SICI. In TD children only, higher GABA+ levels correlated with larger TMS motor evoked potentials (MEPs) at REST. In GO and STOP trials, higher GABA+ was associated with smaller MEP amplitudes, for both groups. Overall, GABA+ levels did not differ between groups or correlate with ADHD clinical symptoms. Conclusions: In children with higher motor cortex GABA+, motor cortex is less responsive to inhibitory TMS (SICI). Comparing the relationships between MRS-GABA+ levels and responses to TMS at REST vs. GO/STOP trials suggests differences in inhibitory neurophysiology and neurotransmitters in children with ADHD. These differences are more prominent at rest than during response inhibition task engagement. Significance: Evaluating relationships between GABA+ and SICI may provide a biomarker useful for understanding behavioral diagnoses.

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