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| ID | Type | Description | Link |
|---|---|---|---|
| R00MH102349 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Mental Health (NIMH) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
|
| 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylphenidate | Drug | A single, low dose of methylphenidate (0.3 mg/kg) will be administered on the drug day. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Go/No-go (GNG) Commission Rate | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jessica R Cohen, PhD | University of North Carolina, Chapel Hill | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | 27599 | United States |
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.
Participants were recruited between December 2016 and March 2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (2-4 Hours) |
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| ||||||||||||||||||||||||
| Washout Period (4-20 Days) |
| |||||||||||||||||||||||||
| Second Intervention (2-4 Hours) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo, Then Methylphenidate |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 to 3 hours after administration of intervention |
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Methylphenidate | Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Heart Racing | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jessica R. Cohen, PhD | University of North Carolina at Chapel Hill | (919) 843-3753 | jrcohen@unc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 15, 2020 | Jul 14, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D008774 | Methylphenidate |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D010648 | Phenylacetates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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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.
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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.
|
| Placebo | Other | A matching placebo pill will be administered on the placebo day. |
|
|
| 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 |
| 1 to 3 hours after administration of intervention |
| Go/No-go (GNG) Omission Rate | 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. | 1 to 3 hours after administration of intervention |
| Go/No-go (GNG) Response Time Variability | 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. | 1 to 3 hours after administration of intervention |
| NOT COMPLETED |
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| COMPLETED |
|
| NOT COMPLETED |
|
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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Methylphenidate | Participants received a single, low dose of methylphenidate (0.3 mg/kg) before MRI scan |
| OG001 | Placebo | Participants received a matching placebo pill before MRI scan. |
|
|
|
| Primary | 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 to 3 hours after administration of intervention |
|
|
|
|
| Primary | 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 to 3 hours after administration of intervention |
|
|
|
|
| Primary | 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. | 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. | Posted | Number | 95% Confidence Interval | correlation coefficient | 1 to 3 hours after administration of intervention |
|
|
|
|
| Secondary | Go/No-go (GNG) Commission Rate | 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 to 3 hours after administration of intervention |
|
|
|
|
| Secondary | Go/No-go (GNG) Omission Rate | 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 to 3 hours after administration of intervention |
|
|
|
|
| Secondary | Go/No-go (GNG) Response Time Variability | 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. | 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. | Posted | Mean | Standard Deviation | coefficient of variation | 1 to 3 hours after administration of intervention |
|
|
|
|
| 0 |
| 35 |
| 0 |
| 35 |
| 11 |
| 35 |
| EG001 | Placebo | Participants received a matching placebo pill before MRI scan. | 0 | 36 | 0 | 36 | 9 | 36 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Stomachache | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Increased Energy | General disorders | Systematic Assessment |
|
| Change in Appetite | Metabolism and nutrition disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Changes in Mood | Psychiatric disorders | Systematic Assessment |
|
| Difficulty Falling Asleep | Psychiatric disorders | Systematic Assessment |
|
Not provided
Not provided
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| D010880 |
| Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D002241 | Carbohydrates |
| 0.034 |
| Superiority |
| 0.169 |
| Superiority |
|
| Delta rest mod vs delta GNG rew commission rate |
|
| Delta rest mod vs delta GNG rew omission rate |
|
| Delta rest mod vs delta GNG rew RT variability |
|
| Delta GNG reg mod vs delta GNG reg commission rate |
|
| Delta GNG reg mod vs delta GNG reg omission rate |
|
| Delta GNG reg mod vs delta GNG reg RT variability |
|
| Delta GNG rew mod vs delta GNG rew commission rate |
|
| Delta GNG rew mod vs delta GNG rew omission rate |
|
| Delta GNG rew mod vs delta GNG rew RT variability |
|
| 0.022 |
| Superiority |
| Change in rest modularity vs Change in GNG regular RT Variability | Pearson correlation | 0.220 | Superiority |
| Change in rest modularity vs change in GNG reward commission rate | Pearson correlation | 0.496 | Superiority |
| Change in rest modularity vs change in GNG reward omission rate | Pearson correlation | 0.343 | Superiority |
| Change in rest modularity vs change in GNG reward RT variability | Pearson correlation | 0.988 | Superiority |
| Change in GNG regular modularity vs change in GNG regular commission rate | Pearson correlation | 0.892 | Superiority |
| Change in GNG regular modularity vs change in GNG regular omission rate | Pearson correlation | 0.473 | Superiority |
| Change in GNG regular modularity vs Change in GNG regular RT Variability | Pearson correlation | 0.409 | Superiority |
| Change in GNG reward modularity vs change in GNG reward commission rate | Pearson correlation | 0.351 | Superiority |
| Change in GNG reward modularity vs change in GNG reward omission rate | Pearson correlation | 0.238 | Superiority |
| Change in GNG reward modularity vs Change in GNG reward RT Variability | Pearson correlation | 0.909 | Superiority |
| 0.003 |
| Superiority |
| 0.0001 |
| Superiority |
| 0.0001 |
| Superiority |