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Anomalous Motor Physiology in ADHD: Inhibitory and Reward Mechanisms

Principal Investigator:
Stewart
Mostofsky

Attention Deficit Hyperactivity Disorder (ADHD), the most common behavioral diagnosis in children, incurs high medical costs and results in poor academic achievement, adult mental illness, substance abuse, and criminal behavior. An 8-year follow up of the comprehensive Multimodal Treatment of ADHD (MTA) study showed that children who received 14 months of intensive, expert pharmacologic and behavioral treatments had the same high rates of adverse social outcomes as those who received community-based treatment; all MTA groups fared worse than typically developing (TD) peers.

This failure to improve long term outcomes, despite intensive interventions, suggests that we still have a poor understanding of the biological substrates of ADHD. Substantial progress in identifying structural differences as well as DNA sequence variations in ADHD have failed to influence understanding of prognosis or treatment. Alternative approaches to unravel the neurobiology of ADHD are critical to improving outcomes and will likely depend on the development of reliable methods to quantify outputs of biologically relevant neurobehavioral systems which reflect dimensions of function impaired in ADHD children. One such system may be motor control, given that neural systems critical for development of motor control parallel those for behavioral control. For this reason, our group’s approach has been to focus on developing quantitative biomarkers of ADHD-associated behaviors based in development and physiology of motor control circuitry.

In the first period of this grant, we developed systems to precisely measure motor function and motor physiology in children with ADHD. Using Transcranial Magnetic Stimulation (TMS), we found that TMS-evoked Short Interval Cortical Inhibition (SICI) is reduced in 8-12 year old children with ADHD and, importantly, that this reduction correlates with ADHD behavioral symptom severity (both hyperactivity/impulsivity and inattention) as well as measures of motor impairment. Thus, SICI, which is mediated by gamma-aminobutyric acid (GABA)ergic interneurons and modulated by dopaminergic/reward input, may reflect a fundamental mechanism related to impaired motor/behavioral control in ADHD. However, interpretation of these preliminary, correlative data requires caution.

Therefore, the overarching goal of this renewal proposal is to build on the successes in the first period of this grant as well as novel preliminary findings revealing decreased motor cortex GABA in ADHD. We propose to use TMS and Magnetic Resonance Spectroscopy (MRS) to quantify neural correlates of ADHD, linking these data to clinical ratings, motor and behavioral response control, and altered reward responses. These data may help identify clusters of measures in children that could lay a foundation for more accurate predict high risk of poor outcomes and identify directions for novel, effective treatments. To this end, we propose the following aims:

AIM 1: To quantify functional Short Interval Cortical Inhibition (fSICI) during response inhibition as a biomarker of ADHD. Hypothesis: In a matched, 8-12 year old cohort of ADHD vs. TD children, fSICI during response inhibition will be significantly diminished in ADHD. Rationale: Children with ADHD demonstrate impairments in response inhibition. In healthy adults, TMS studies show that fSICI increases during “Stop trials.” This suggests that fSICI during response inhibition will provide a quantitative biomarker relevant to behavioral disinhibition in ADHD.

AIM 2: To quantify fSICI during immediate and delayed reward presentation as a biomarker of ADHD. Hypothesis: In the same ADHD/TD children as Aim 1, fSICI during a reward delay discounting paradigm will be significantly diminished in ADHD. Rationale: Prioritizing choices based on rewards underlies adaptive learning and goal setting. In healthy adults, fSICI increases during reward expectation. This suggests that fSICI during reward will provide a quantitative biomarker relevant to motivational problems in ADHD.

AIM 3: To quantify effects of dopamine (DA) on resting Short Interval Cortical Inhibition (rSICI) and fSICI. Hypothesis: In the same children as Aim 1/2, levodopa will increase both rSICI and fSICI, normalizing these measures in children with ADHD. Rationale: DA increases rSICI and may influence fSICI measured during response inhibition and reward experiences. Evaluating DA effects will clarify mechanisms of impaired behavioral control by providing an understanding of the neural basis for rSICI and fSICI as biomarkers of ADHD.

AIM 4: To determine whether motor cortex GABA levels 1) differ in ADHD vs. TD and 2) correlate with rSICI and fSICI in Aims 1 and 2. Hypotheses: 1) In the same ADHD/TD cohort as Aims 1-3, GABA concentrations in motor cortex will be significantly diminished in ADHD; and 2) variation in these levels will correlate with rSICI and fSICI. We will use Magnetic Resonance Spectroscopy (MRS) to measure GABA. Rationale: GABA mediates inhibitory neural transmission, and GABA-A agonists increase rSICI. We now have novel, preliminary data showing M1 GABA is reduced in ADHD and correlates with rSICI. Evaluating M1 GABA will clarify mechanisms of impaired behavioral control in ADHD by providing an understanding of the neural basis for rSICI and fSICI as biomarkers of ADHD.

AIM 5: To identify the contributions of genetic variation to the SICI endophenotype data in aims 1-4. Hypothesis: ADHD susceptibility genotypes will significantly influence SICI. Rationale: Motor-cortex based markers of behavioral control may function as an efficient basis for investigating genetic contributions to ADHD, suggesting novel pathways for pharmacological intervention.

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