Biomarker Validation in Motor System Physiology in Attention Deficit Hyperactivity Disorder

NCT04421248 | Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: CHMC IRB 2020-0297
• Study Type: interventional
• Target: 214
• Locations: 1 country
• Sites: 2

Brief Summary

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in childhood. Children with ADHD struggle in school due to problems with attention and high levels of impulsivity and hyperactivity. They are at substantially increased risk for long-term difficulties into adulthood, including academic underachievement, substance abuse, and criminal behavior. The diagnosis of ADHD, which is based on subjective ratings by parents and teachers, likely results from multiple different, overlapping differences in circuits of the brain responsible for attention and impulse control. However, we do not have any scientific or clinical tests that allow us to understand these circuits. In an effort to improve ADHD outcomes, we have used a technology called Transcranial Magnetic Stimulation (TMS) to identify highly reliable measurements of brain function. We have identified two very promising measures that are abnormal in children with ADHD and, importantly, also predict the severity of ADHD behaviors. The goal of this project is to determine if these two TMS measurements could be used to help better guide ADHD treatment. To do this, we will perform three investigations in 8 to 12 year old children to determine: 1) test-retest reliability; 2) pharmacologic responsiveness; and 3) correlations with two domains of function relevant to ADHD: "Cognitive Control" and "Emotional Valence." Through these investigations, we aim to determine whether these two TMS brain measures are reliable and meaningful enough to be used to help improve precision of individually-targeted and effective ADHD treatments.

Conditions

Attention Deficit Hyperactivity Disorder Combined

Outcome Measures

Primary Outcomes (2)

• Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (SICI) Test-Retest Reliability

  A ratio of amplitudes of motor evoked potentials from paired (inhibitory) and single TMS pulses, obtained from dominant motor cortex with hand at rest

  less than one month

• Transcranial Magnetic Stimulation (TMS)-evoked Task Related Up Modulation (TRUM) Test-Retest Reliability

  A ratio of amplitudes of motor evoked potentials during engagement in a response inhibition task versus rest, obtained from dominant motor cortex

  less than one month

Study Arms (2)

Attention Deficit Hyperactivity Disorder (ADHD)

EXPERIMENTAL

8 to 12 year old children diagnosed with ADHD. Randomized, blinded, single dose, placebo controlled, crossover trial.

Drug: Methylphenidate; Drug: Placebo

Typically developing controls (TDC)

NO INTERVENTION

Typically developing controls - 8 to 12 year old children

Interventions

Methylphenidate DRUG

In ADHD participants only: blinded, randomized, placebo-controlled single dose, crossover on separate days separated by at least one week.

Also known as: Ritalin

Attention Deficit Hyperactivity Disorder (ADHD)

Placebo DRUG

In ADHD participants only: blinded, randomized, placebo-controlled, single dose, crossover on separate days separated by at least one week.

Attention Deficit Hyperactivity Disorder (ADHD)

Eligibility Criteria

• Age: 8 Years - 12 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Either gender, any race, ethnicity or socioeconomic status
• Currently between 8 years 0 months and 12 years, 11 months, 30 days
• Willing to answer questions about ADHD and related diagnoses
• For children with ADHD prescribed stimulant medications, willing to suspend taking medications as specified in the study procedures
• For children with ADHD, willing to participate in the single dose, randomized crossover study to probe acute effects of methylphenidate on biomarkers
• Right hand dominant (predominately right-handed)
• Able to participate in and sign an informed consent

You may not qualify if:

• Known diagnosis of mental retardation, cerebral palsy, Autism Spectrum Disorder, traumatic brain injury, brain tumor, epilepsy, or other serious neurological disorder.
• Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other Anxiety Disorders, or other developmental psychiatric diagnoses.
• For females, onset of menses, pregnancy.
• Current use of antidepressants, non-stimulant ADHD medications, dopamine blocking agents, mood stabilizers.
• Implanted brain stimulator, vagal nerve stimulator, ventriculo-peritoneal shunt, cardiac pacemaker, or implanted medication port.
• Diagnosis of a speech/language disorder or a Reading Disability (RD).

Sponsors & Collaborators

• Donald Gilbert, MD, MS, FAAN, FAAP: lead
• Hugo W. Moser Research Institute at Kennedy Krieger, Inc.: collaborator

Study Sites (2)

Kennedy Krieger Institute

Baltimore, Maryland, 21205, United States

RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Related Publications (6)

• Doherty AC, Huddleston DA, Horn PS, Ratner N, Simpson BN, Schorry EK, Aschbacher-Smith L, Prada CE, Gilbert DL. Motor Function and Physiology in Youth With Neurofibromatosis Type 1. Pediatr Neurol. 2023 Jun;143:34-43. doi: 10.1016/j.pediatrneurol.2023.02.014. Epub 2023 Mar 3.

  PMID: 36996759 BACKGROUND

• Luo Y, Adamek JH, Crocetti D, Mostofsky SH, Ewen JB. Dissociation in Neural Correlates of Hyperactive/Impulsive vs. Inattentive Symptoms in Attention-Deficit/Hyperactivity Disorder. Front Neurosci. 2022 Jun 22;16:893239. doi: 10.3389/fnins.2022.893239. eCollection 2022.

  PMID: 35812240 BACKGROUND

• Luo Y, Chen C, Adamek JH, Crocetti D, Mostofsky SH, Ewen JB. Altered cortical activation associated with mirror overflow driven by non-dominant hand movement in attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jan 10;112:110433. doi: 10.1016/j.pnpbp.2021.110433. Epub 2021 Aug 27.

  PMID: 34454990 BACKGROUND

• Chen C, Rosch KS, Seymour KE, Crocetti D, Mahone EM, Mostofsky SH. Sex Effects on Mirror Overflow during Finger Tapping in Children with ADHD. J Int Neuropsychol Soc. 2022 Apr;28(4):371-381. doi: 10.1017/S1355617721000576. Epub 2021 May 17.

  PMID: 33998435 BACKGROUND

• Nikolaidis A, He X, Pekar J, Rosch K, Mostofsky SH. Frontal corticostriatal functional connectivity reveals task positive and negative network dysregulation in relation to ADHD, sex, and inhibitory control. Dev Cogn Neurosci. 2022 Apr;54:101101. doi: 10.1016/j.dcn.2022.101101. Epub 2022 Mar 23.

  PMID: 35338900 BACKGROUND

• Thapaliya G, Carnell S, Mostofsky SH, Rosch KS. Neurobehavioral phenotypes of delay discounting and cognitive control in child attention-deficit/hyperactivity disorder and obesity: Shared or distinct? Pediatr Obes. 2023 Apr;18(4):e13001. doi: 10.1111/ijpo.13001. Epub 2023 Jan 18.

  PMID: 36655309 BACKGROUND

MeSH Terms

Interventions

Methylphenidate

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Donald L Gilbert, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

• Stewart H Mostofsky, MD

  Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Donald L Gilbert, MD

CONTACT

800-344-2462; donald.gilbert@cchmc.org

Steve W Wu, MD

CONTACT

800-344-2462; steve.wu@cchmc.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Preparation of identical single dose capsules of methylphenidate and placebo prepared by study pharmacy.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: This is a randomized, blinded, placebo-controlled, single-dose crossover study. The objective is to estimate, in a rigorous, unbiased manner, the effect of 10 mg methylphenidate (MPH) on two putative biomarkers of ADHD, measured using Transcranial Magnetic Stimulation (TMS). Outcomes will be evaluated via repeated measures, mixed model analysis with MEP amplitude as the dependent variable and Treatment and Treatment-Sequence as class variables. Participants will include 144 children with ADHD. Study measures will also be compared in 70 matched, typically developing children who do not have ADHD and who will not receive methylphenidate or placebo.

Study Record Dates

• First Submitted: June 4, 2020
• First Posted: June 9, 2020
• Study Start: September 1, 2020
• Primary Completion: February 1, 2026
• Study Completion: April 1, 2026
• Last Updated: June 19, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data uploads to the NIMH Data Archive from the study will occur every 6 months, consistent with the NIMH Data Sharing Policy.
• Access Criteria: Determined by NIMH.

Locations

US (2)