# 1/2 - Anomalous Motor System Physiology in ADHD: Biomarker Validation and Modeling Domains of Function

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $382,092

## Abstract

PROJECT SUMMARY
Attention Deficit Hyperactivity Disorder (ADHD), the most common childhood behavioral diagnosis, is a
heterogeneous disorder linked to poor adult outcomes including high rates of academic underachievement,
mental illness, substance abuse, and criminal activity. A critical obstacle to improving long-term ADHD
outcomes is the current lack of quantitative neurophysiologic markers that could be used to improve precision
treatment (behavioral and pharmacologic). In research funded during two grant periods, we addressed this
barrier: Leveraging observed associations of ADHD-associated impairments in motor control with core
impairments in cognitive and emotional control to pursue motor physiologic biomarkers linked to ADHD
diagnosis and symptom severity. Engaging expertise of two research teams in different cities, we developed,
refined, and effectively implemented innovative methods for evaluating motor physiology in school-age children
with ADHD. During the first grant period we initiated Transcranial Magnetic Stimulation (TMS) investigations of
motor cortex, discovering that Short Interval Cortical Inhibition (SICI) is reduced in children with ADHD and that
this reduced SICI correlates with parent-ratings of ADHD symptom severity, with consistent findings across the
two sites. During the second grant period, we developed (TMS-compatible) child-friendly games as paradigms
for evaluation of motor cortex physiology under conditions requiring cognitive and emotional control. We found
that SICI is reduced in children with ADHD during action selection and inhibition (as well as rest). Further, we
discovered that TMS-evoked increases in motor evoked potential (MEP) amplitude from rest to task
engagement (which we have denoted as “Task Related Up Modulation” - TRUM) are significantly diminished in
ADHD. Interestingly, while both TRUM and SICI robustly correlate with ADHD severity, they show limited
correlation with each other. These published findings, in conjunction promising preliminary analyses of TMS-
behavioral associations, suggest a model in which these two promising, distinct physiologic biomarkers reflect
differential domains of dysfunction in ADHD, with SICI reflecting mechanisms linked to maintaining attention
and filtering distractions, while TRUM reflects the capacity to modulate response control particularly under
cognitively and emotionally demanding conditions. To pursue validation of SICI and TRUM as physiologic
biomarkers, we now propose: AIM 1 To establish test-retest reliability of SICI and TRUM in children with ADHD
and typically developing (TD) controls. AIM 2 To quantify stimulant treatment-induced changes in SICI and
TRUM in children with ADHD as a validation of utility of these biomarkers for treatment focused studies. AIM 3
To explore the differential association of SICI and TRUM with ADHD-relevant RDoC constructs of Cognitive
Control and Emotional Positive/Negative Valence. Achieving these aims will lay groundwork f...

## Key facts

- **NIH application ID:** 10434826
- **Project number:** 5R01MH095014-08
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** DONALD L GILBERT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,092
- **Award type:** 5
- **Project period:** 2012-05-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434826

## Citation

> US National Institutes of Health, RePORTER application 10434826, 1/2 - Anomalous Motor System Physiology in ADHD: Biomarker Validation and Modeling Domains of Function (5R01MH095014-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434826. Licensed CC0.

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