Large-scale Brain Organization During Cognitive Control in ADHD

NCT04349917 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: 16-0112R00MH102349
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test whether children with attention-deficit/hyperactivity disorder (ADHD) are impaired in the ability to flexibly adapt brain network organization in response to shifting cognitive demands during the exertion of cognitive control, by assessing changes in network dynamics resulting from stimulant administration in children with ADHD, and how those changes relate to behavioral and symptom improvements. Subjects will be children with ADHD aged 8-12. Subjects will participate in multiple testing sessions that include: diagnosis and eligibility screening, neuropsychological and behavioral testing, and, if eligible, MRI scans and a medication challenge. Children with ADHD who are enrolled in the medication challenge will undergo one MRI scan on placebo and one MRI scan on stimulant medication, counterbalanced and double-blind. Functional connectivity will be measured using functional MRI and innovative graph theoretical analytic tools will be implemented. Network metrics will be related to symptomatology and behavioral testing measures. It is hypothesized that stimulant administration in children with ADHD will increase flexibility in network reconfiguration in response to changing cognitive control demands as compared to when they are on placebo. It is further hypothesized that the degree to which brain network organization is changed will be related to the degree of improvement in cognitive control performance.

Conditions

Attention Deficit Hyperactivity Disorder

Keywords

methylphenidate; functional connectivity; graph theory; cognitive control

Outcome Measures

Primary Outcomes (4)

• Resting State Brain Network Organization

  Assessment of network topology during a resting state using functional connectivity estimates. Modularity will be determined by applying graph theoretical methods to functional connectivity estimates acquired during functional magnetic resonance imaging (fMRI) scans. Modularity is measured on a -1 to 1 scale, with higher scores indicating stronger community structure, or a stronger tendency of clusters of brain regions to separate into distinct, highly interconnected networks with sparse connections across networks. The optimal modularity value depends on the context. For example, during complex tasks lower modularity is better, while during basic, automatic tasks higher modularity is better.

  1 to 3 hours after administration of intervention

• Task-Based Brain Network Organization

  Assessment of network topology during the Go/No-go (GNG) regular and GNG reward tasks. Subjects see a series of sports balls and are told to respond to most balls (go trials), but not to some specific balls (no-go trials). GNG tasks are identical, except in the rewarded task, correct fast go responses and correct withholding on no-go trials are rewarded with 1 cent and 5 cents respectively. Graph theoretical methods are applied to functional connectivity estimates from fMRI scans to determine modularity during each task. Modularity (-1 to 1 scale) measures the degree to which the whole-brain system separates into distinct communities, such that greater modularity reflects stronger community structure, or stronger tendency of brain regions to separate into distinct, highly interconnected networks with few connections across networks. Optimal modularity value depends on context. During complex tasks lower modularity is better, while higher modularity is better for basic tasks.

  1 to 3 hours after administration of intervention

• Rest-Task Reconfiguration

  Assessment of reconfiguration of network topology between the GNG regular task and the resting state and GNG reward task and resting state. In the GNG tasks, subjects see a series of sports balls and are told to respond to most of the balls (go trials), but not to some specific balls (no-go trials). GNG tasks are identical, except in the rewarded task, correct fast go responses and correct withholding on no-go trials are rewarded with 1 cent and 5 cents respectively. Normalized mutual information will be determined by applying the same graph theoretical methods to functional connectivity estimates acquired during fMRI scans for each rest-task pair. Normalized mutual information is measured on a 0 to 1 scale, with higher scores indicating more similarity in network structure across task and rest conditions.

  1 to 3 hours after administration of intervention

• Drug-induced Normalization

  Assessment of how changes in brain network topology relate to improvements in behavioral performance on the GNG regular and reward tasks, in which subjects respond to go stimuli and withhold responses to no-go stimuli. GNG tasks are identical, except subjects are rewarded for good performance on the reward task. Brain measures include change in modularity during rest, GNG regular, and GNG reward (Outcome Measures 1, 2); behavioral measures include change in commission rate, omission rate, and coefficient of variation of response time during GNG tasks (Outcome Measures 5-7). Pearson correlations are used to relate change in brain measures with change in behavioral measures from the placebo to the methylphenidate scans. Positive correlations indicate that subjects with greater change in the brain measure had greater change in the behavioral measure. Negative correlations indicate that subjects with less change in the brain measure had greater change in the behavioral measure.

  1 to 3 hours after administration of intervention

Secondary Outcomes (3)

• Go/No-go (GNG) Commission Rate

  1 to 3 hours after administration of intervention

• Go/No-go (GNG) Omission Rate

  1 to 3 hours after administration of intervention

• Go/No-go (GNG) Response Time Variability

  1 to 3 hours after administration of intervention

Study Arms (2)

Placebo, then Methylphenidate

PLACEBO COMPARATOR

All children with ADHD in this study will receive one dose of methylphenidate and one dose of placebo over the course of two sessions approximately one week apart (order randomized and double-blind).

Drug: Methylphenidate; Other: Placebo

Methylphenidate, then Placebo

EXPERIMENTAL

All children with ADHD in this study will receive one dose of methylphenidate and one dose of placebo over the course of two sessions approximately one week apart (order randomized and double-blind).

Drug: Methylphenidate; Other: Placebo

Interventions

Methylphenidate DRUG

A single, low dose of methylphenidate (0.3 mg/kg) will be administered on the drug day.

Also known as: Ritalin

Methylphenidate, then Placebo; Placebo, then Methylphenidate

Placebo OTHER

A matching placebo pill will be administered on the placebo day.

Also known as: Sugar pill

Methylphenidate, then Placebo; Placebo, then Methylphenidate

Eligibility Criteria

• Age: 8 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Between 8-12 years old
• Diagnosis of ADHD (for ADHD group); ADHD group only can have comorbid Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnoses of oppositional defiant disorder, conduct disorder, depressive disorders, or anxiety disorders
• ADHD subjects must never have been treated with medication for their ADHD

You may not qualify if:

• Wechsler Intelligence Scale for Children-Fifth Edition Full-Scale Intelligence Quotient (IQ) \< 80
• Wechsler Individual Achievement Test-Third Edition Word Reading \< 85
• Any neurologic or developmental disabilities
• Any reading or learning disabilities
• Visual impairment that cannot be corrected-to-normal
• Color blindness
• Documented hearing impairment greater than 25 decibels (dB) loss in either year
• Have already gone through puberty (Tanner Stage II or higher)
• Medical contraindication to MRI
• Any psychoactive medication

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity

Interventions

Methylphenidate; Sugars

Condition Hierarchy (Ancestors)

Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Jessica R. Cohen, PhD
• Organization: University of North Carolina at Chapel Hill

jrcohen@unc.edu

(919) 843-3753

Study Officials

• Jessica R Cohen, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The pharmacy that provides the drug/placebo works from a randomized subject order defining whether each subject received drug first or placebo first. Only the pharmacists know this order, and the drug and placebo look identical to the participants and the investigators.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled, crossover design. Each subject with ADHD participates in two sessions, one on drug and one on placebo (order randomized ). Both subjects and experimenters are blind to the order.

Study Record Dates

• First Submitted: April 13, 2020
• First Posted: April 16, 2020
• Study Start: December 16, 2016
• Primary Completion: March 14, 2020
• Study Completion: March 14, 2020
• Last Updated: January 12, 2021
• Results First Posted: January 12, 2021

Record last verified: 2020-04

Locations

US (1)