Trial Outcomes & Findings for Large-scale Brain Organization During Cognitive Control in ADHD (NCT NCT04349917)
NCT ID: NCT04349917
Last Updated: 2021-01-12
Results Overview
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.
COMPLETED
PHASE4
37 participants
1 to 3 hours after administration of intervention
2021-01-12
Participant Flow
Participants were recruited between December 2016 and March 2020.
A total of 47 participants were screened during a behavioral visit. Of those not randomized, 8 did not meet inclusion criteria and 2 withdrew from study.
Participant milestones
| Measure |
Methylphenidate, Then Placebo
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before the first MRI scan. Approximately one week later, participants received a matching placebo pill before the second MRI scan.
|
Placebo, Then Methylphenidate
Participants received a matching placebo pill before the first MRI scan. Approximately one week later, participants received a single, low dose of methylphenidate (0.3 mg/kg) before the second MRI scan.
|
|---|---|---|
|
First Intervention (2-4 Hours)
STARTED
|
19
|
18
|
|
First Intervention (2-4 Hours)
Received Intervention
|
19
|
17
|
|
First Intervention (2-4 Hours)
COMPLETED
|
19
|
16
|
|
First Intervention (2-4 Hours)
NOT COMPLETED
|
0
|
2
|
|
Washout Period (4-20 Days)
STARTED
|
19
|
16
|
|
Washout Period (4-20 Days)
COMPLETED
|
19
|
16
|
|
Washout Period (4-20 Days)
NOT COMPLETED
|
0
|
0
|
|
Second Intervention (2-4 Hours)
STARTED
|
19
|
16
|
|
Second Intervention (2-4 Hours)
Received Intervention
|
19
|
16
|
|
Second Intervention (2-4 Hours)
COMPLETED
|
19
|
16
|
|
Second Intervention (2-4 Hours)
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
| Measure |
Methylphenidate, Then Placebo
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before the first MRI scan. Approximately one week later, participants received a matching placebo pill before the second MRI scan.
|
Placebo, Then Methylphenidate
Participants received a matching placebo pill before the first MRI scan. Approximately one week later, participants received a single, low dose of methylphenidate (0.3 mg/kg) before the second MRI scan.
|
|---|---|---|
|
First Intervention (2-4 Hours)
Withdrawal by Subject
|
0
|
1
|
|
First Intervention (2-4 Hours)
Unable to Swallow Pill
|
0
|
1
|
Baseline Characteristics
Large-scale Brain Organization During Cognitive Control in ADHD
Baseline characteristics by cohort
| Measure |
Methylphenidate, Then Placebo
n=19 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before the first MRI scan. Approximately one week later, participants received a matching placebo pill before the second MRI scan.
|
Placebo, Then Methylphenidate
n=18 Participants
Participants received a matching placebo pill before the first MRI scan. Approximately one week later, participants received a single, low dose of methylphenidate (0.3 mg/kg) before the second MRI scan.
|
Total
n=37 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
9.71 years
STANDARD_DEVIATION 0.92 • n=5 Participants
|
9.75 years
STANDARD_DEVIATION 1.41 • n=7 Participants
|
9.73 years
STANDARD_DEVIATION 1.17 • n=5 Participants
|
|
Sex: Female, Male
Female
|
9 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
18 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
10 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
19 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
17 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
33 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
17 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
31 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
19 Participants
n=5 Participants
|
18 Participants
n=7 Participants
|
37 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants excluded due to excessive head motion (mean framewise displacement (FD) \> 0.5mm or fewer than 150 timepoints remaining after scrubbing all timepoints with FD \> 0.2mm), incomplete brain coverage, or poor-quality fMRI data. Participants must have good data from both methylphenidate and placebo scan days to be included in this analysis.
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.
Outcome measures
| Measure |
Methylphenidate
n=22 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=22 Participants
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Resting State Brain Network Organization
|
0.223 units on a scale
Standard Deviation 0.026
|
0.228 units on a scale
Standard Deviation 0.034
|
PRIMARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants excluded due to excessive head motion (mean framewise displacement \[FD\] \> 0.5mm or fewer than 150 timepoints remaining after scrubbing all timepoints with FD \> 0.2mm), incomplete brain coverage, or poor-quality fMRI data. Participants must have good data from both methylphenidate and placebo scan days to be included in this analysis.
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.
Outcome measures
| Measure |
Methylphenidate
n=23 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=23 Participants
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Task-Based Brain Network Organization
GNG regular
|
0.213 units on a scale
Standard Deviation 0.041
|
0.218 units on a scale
Standard Deviation 0.040
|
|
Task-Based Brain Network Organization
GNG reward
|
0.235 units on a scale
Standard Deviation 0.051
|
0.213 units on a scale
Standard Deviation 0.055
|
PRIMARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants excluded due to excessive head motion (mean framewise displacement \[FD\] \> 0.5mm or fewer than 150 timepoints remaining after scrubbing all timepoints with FD \> 0.2mm), incomplete brain coverage, or poor-quality fMRI data. Participants must have good data from both scan days and all tasks being compared to be included in this analysis.
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.
Outcome measures
| Measure |
Methylphenidate
n=22 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=22 Participants
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Rest-Task Reconfiguration
GNG regular
|
0.104 units on a scale
Standard Deviation 0.055
|
0.119 units on a scale
Standard Deviation 0.058
|
|
Rest-Task Reconfiguration
GNG reward
|
0.122 units on a scale
Standard Deviation 0.074
|
0.150 units on a scale
Standard Deviation 0.074
|
PRIMARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants excluded due to excessive head motion (mean framewise displacement \[FD\] \> 0.5 mm or fewer than 150 timepoints remaining after scrubbing all timepoints with FD \> 0.2 mm), incomplete brain coverage, or poor-quality fMRI data. Participants excluded if incomplete behavioral GNG data. Must have good data from both scan days to be included.
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.
Outcome measures
| Measure |
Methylphenidate
n=18 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Drug-induced Normalization
Delta rest mod vs delta GNG reg commission rate
|
-0.361 correlation coefficient
Interval -0.693 to 0.097
|
—
|
|
Drug-induced Normalization
Delta rest mod vs delta GNG reg omission rate
|
0.508 correlation coefficient
Interval 0.084 to 0.776
|
—
|
|
Drug-induced Normalization
Delta rest mod vs delta GNG reg RT variability
|
0.287 correlation coefficient
Interval -0.178 to 0.647
|
—
|
|
Drug-induced Normalization
Delta rest mod vs delta GNG rew commission rate
|
0.162 correlation coefficient
Interval -0.303 to 0.564
|
—
|
|
Drug-induced Normalization
Delta rest mod vs delta GNG rew omission rate
|
-0.224 correlation coefficient
Interval -0.606 to 0.243
|
—
|
|
Drug-induced Normalization
Delta rest mod vs delta GNG rew RT variability
|
0.003 correlation coefficient
Interval -0.44 to 0.445
|
—
|
|
Drug-induced Normalization
Delta GNG reg mod vs delta GNG reg commission rate
|
-0.033 correlation coefficient
Interval -0.468 to 0.416
|
—
|
|
Drug-induced Normalization
Delta GNG reg mod vs delta GNG reg omission rate
|
-0.170 correlation coefficient
Interval -0.57 to 0.271
|
—
|
|
Drug-induced Normalization
Delta GNG reg mod vs delta GNG reg RT variability
|
-0.195 correlation coefficient
Interval -0.587 to 0.271
|
—
|
|
Drug-induced Normalization
Delta GNG rew mod vs delta GNG rew commission rate
|
0.220 correlation coefficient
Interval -0.246 to 0.604
|
—
|
|
Drug-induced Normalization
Delta GNG rew mod vs delta GNG rew omission rate
|
-0.276 correlation coefficient
Interval -0.64 to 0.189
|
—
|
|
Drug-induced Normalization
Delta GNG rew mod vs delta GNG rew RT variability
|
-0.027 correlation coefficient
Interval -0.464 to 0.42
|
—
|
SECONDARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants must have good data from both methylphenidate and placebo scan days to be included in this analysis. Participants included if they completed at least one task.
Evaluation of commission errors assessed during the GNG regular and GNG reward tasks. 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. In both tasks, commission errors occur on trials on which participants respond to a stimulus ("go" response) when they are supposed to withhold a response ("no-go" trial). Commission errors are scored from 0 (no commission errors) to 1 (100% commission errors), with lower values indicating better performance.
Outcome measures
| Measure |
Methylphenidate
n=33 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=33 Participants
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Go/No-go (GNG) Commission Rate
GNG regular
|
0.396 units on a scale
Standard Deviation 0.213
|
0.403 units on a scale
Standard Deviation 0.206
|
|
Go/No-go (GNG) Commission Rate
GNG reward
|
0.292 units on a scale
Standard Deviation 0.176
|
0.348 units on a scale
Standard Deviation 0.181
|
SECONDARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants must have good data from both methylphenidate and placebo scan days to be included in this analysis. Participants included if they completed at least one task.
Evaluation of omission errors assessed during the GNG regular and GNG reward tasks. 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. In both tasks, omission errors occur on trials on which participants do not respond to a "go" stimulus to which they are supposed to respond. Omission errors are scored from 0 (no omission errors) to 1 (100% omission errors), with lower values indicating better performance.
Outcome measures
| Measure |
Methylphenidate
n=33 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=33 Participants
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Go/No-go (GNG) Omission Rate
GNG regular
|
0.071 units on a scale
Standard Deviation 0.116
|
0.104 units on a scale
Standard Deviation 0.119
|
|
Go/No-go (GNG) Omission Rate
GNG reward
|
0.040 units on a scale
Standard Deviation 0.055
|
0.101 units on a scale
Standard Deviation 0.111
|
SECONDARY outcome
Timeframe: 1 to 3 hours after administration of interventionPopulation: Participants must have good data from both methylphenidate and placebo scan days to be included in this analysis. Participants included if they completed at least one task.
Evaluation of response time variability assessed during the GNG regular and GNG reward tasks. 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. Coefficient of variation (standard deviation / mean) will be calculated for response time in GNG regular and GNG reward tasks separately to account for group differences in mean response time.
Outcome measures
| Measure |
Methylphenidate
n=33 Participants
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=33 Participants
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Go/No-go (GNG) Response Time Variability
GNG regular
|
0.298 coefficient of variation
Standard Deviation 0.104
|
0.344 coefficient of variation
Standard Deviation 0.155
|
|
Go/No-go (GNG) Response Time Variability
GNG reward
|
0.253 coefficient of variation
Standard Deviation 0.071
|
0.342 coefficient of variation
Standard Deviation 0.146
|
Adverse Events
Methylphenidate
Placebo
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Methylphenidate
n=35 participants at risk
Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan
|
Placebo
n=36 participants at risk
Participants received a matching placebo pill before MRI scan.
|
|---|---|---|
|
Cardiac disorders
Heart Racing
|
0.00%
0/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Gastrointestinal disorders
Nausea
|
2.9%
1/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Gastrointestinal disorders
Stomachache
|
0.00%
0/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
General disorders
Fatigue
|
20.0%
7/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
11.1%
4/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
General disorders
Increased Energy
|
0.00%
0/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Metabolism and nutrition disorders
Change in Appetite
|
2.9%
1/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Nervous system disorders
Dizziness
|
2.9%
1/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
0.00%
0/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Nervous system disorders
Headache
|
8.6%
3/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
5.6%
2/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Psychiatric disorders
Changes in Mood
|
11.4%
4/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
|
Psychiatric disorders
Difficulty Falling Asleep
|
2.9%
1/35 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
2.8%
1/36 • From the First Intervention through 24-48 hours following the Second Intervention, an overall total of between 5-22 days depending on the length of the Washout Period (Washout Period range: 4-20 days).
Safety Population includes all participants who received at least one dose of intervention
|
Additional Information
Jessica R. Cohen, PhD
University of North Carolina at Chapel Hill
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place