Ashley D Harris1, Donald L Gilbert2, Paul S Horn2, Deana Crocetti3, Kim M Cecil4, Richard A E Edden5, David A Huddleston2, Stewart H Mostofsky6, Nicolaas A J Puts7. 1. Radiology, University of Calgary, Calgary, AB, Canada; Child and Adolescent Imaging Research Program, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. Electronic address: ashley.harris2@ucalgary.ca. 2. Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, United States. 3. Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States. 4. Department of Radiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati College of Medicine, OH, United States. 5. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, United States; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States. 6. Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States; Department of Behavioral Science and Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, United States. 7. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, United States; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States; Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Abstract
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.
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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