Large-scale Brain Organization During Cognitive Control in ADHD

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

Inclusion Criteria: 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 Exclusion Criteria: 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