Frontostriatal glutamate in ADHD: Neuropsychological and Behavioral Correlates

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DESCRIPTION (provided by applicant): The overall goal of the proposed investigation, "Frontostriatal Glutamate in ADHD: Neuropsychological and Behavioral Correlates" is to investigate the role of frontostriatal glutamatergic metabolism in medication-naive children with ADHD using proton magnetic resonance spectroscopy at 7.0 Tesla, and to determine the specific mechanisms of cognitive and behavioral dysfunction associated with these glutamatergic as well as other neurochemical anomalies. This study will be the first investigation of the neurobiology of ADHD in children using MR spectroscopy at 7.0 Tesla. Glutamate is an excitatory neurotransmitter and the most abundant amino acid in the brain. It is the primary excitatory neurotransmitter for the cortico-striato-thalamo-cortical loop (previously shown to abnormal in ADHD via volumetric MRI, fMRI, resting state fMRI, and DTI studies). Glutamate is also the primary excitatory neurotransmitter for the cortico-striatal afferents to the basal ganglia-playing a crucial neuromodulatory role in the striatum, and contributing to efficiency of both cognitive and motor function. Abnormal glutamate concentrations in the brain have been linked to a variety of neurological and psychiatric disorders. In ADHD, glutamate also serves to modulate the release of other neurotransmitters implicated in the disorder, including dopamine and serotonin. Converging findings from animal models, pharmacologic interventions, genetic and neuroimaging studies have identified increased glutamate neurotransmission in the development of core symptoms of ADHD. Using a cross sectional design of single voxel 1H MR spectroscopy obtained with short-echo time at 7.0 Tesla, along with neuropsychological assessment, the current study proposes to: 1) measure frontostriatal and (as a control region) parietal glutamate levels in medication-naove children with ADHD, ages 5-9 years (compared to age- sex- and socioeconomic status [SES]-matched typically developing children), emphasizing glutamate in frontal (prefrontal, anterior cingulate), and striatal regions of interest, as well as other metabolites observed in the spectrum (NAA, Cr, Cho, mI, Gln) in all brain regions; and; 2) search for relationships among glutamate levels in regions identified as abnormal in ADHD via Aim 1, and behavioral measures of executive function (EF), non-EF skills, and severity of ADHD symptoms. PUBLIC HEALTH RELEVANCE: Glutamate is an excitatory amino acid and the most abundant neurotransmitter in the brain. Glutamate levels are linked to a variety of neurological and psychiatric disorders, and have been implicated in the development of core symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Prior neuroimaging studies examining glutamate levels in ADHD had limited success, because at field strengths less than 2.0 Tesla, it is difficult to measure the absolute levels of glutamate in the human brain. The overall goal of the proposed investigation is to investigate the role of frontostriatal glutamatergic metabolism in medication-naive children with ADHD using proton magnetic resonance spectroscopy at 7.0 Tesla, and to determine the specific mechanisms of cognitive and behavioral dysfunction associated with these glutamatergic as well as other neurochemical anomalies. This study will be the first investigation of the neurobiology of ADHD in children using MR spectroscopy at 7.0 Tesla.