Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach

The growing number of medications used to treat attention-deficit/hyperactivity disorder (ADHD) raises important questions about whether different medications have similar or different therapeutic mechanisms of action. We have recently shown that the stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) produce clinical improvement via a common mechanism in motor cortex, and distinct actions in frontostriatal and midline cingulate-precuneus regions. These exciting findings offer a window into the common and unique neurophysiological mechanisms of response to stimulant and non-stimulant treatments. However, the interpretation and clinical utility of these results would be greatly enhanced by in-depth investigation of the impact of the two treatments on relevant neural networks, and analyses which evaluate whether improvement is achieved via normalization or other adaptive changes in brain function.

The specific aims of this project are to use functional magnetic resonance imaging (fMRI) to determine the significance of activation changes over treatment related to clinical improvement, and the impact of treatment on neural connectivity within and between the anti-correlated frontostriatal 'task-positive' circuit and cingulate-precuneus 'task-negative' network. Our central hypotheses are that clinical improvement is associated with: (i) normalization of reduced connectivity of regions within the 'task-positive' network, with resultant increased inhibition of motor cortex, and (ii) normalization of low task-related connectivity in regions within the task-negative network for MPH and the 'task-positive' network for ATX.

This research proposes to test a model which posits a neurophysiological basis of mechanisms of response to stimulant and non-stimulant medications, and fits with our long term objectives of being able to match treatments to individual patients. Testing this model requires large samples of youth scanned using fMRI before and after treatment, and matched healthy controls also scanned twice. We will use an innovative network-based approach to study the effects of treatment, building on results from our current fMRI treatment study, and incorporating new theoretical approaches to understanding ADHD and its treatment.

Eligibility Criteria:
Inclusion Criteria:

General inclusion criteria for subjects with ADHD and healthy controls are:

* aged 7-17 years;
* Wechsler Intelligence Scale for Children (WISC) scores ≥ 75;
* informed consent and assent to study participation.

Specific inclusion criteria for youth with ADHD are:

* diagnosis of ADHD, any subtype, determined by Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Versions (K-SADS-PL);
* ADHD Rating Scale-IV-Parent Version: Investigator Administered (ADHD-RSIV) total score ≥ 1.5 SD above age and gender means for subtype
* Clinical Global Impressions-ADHD-Severity (CGI-S) score \> 4;
* ADHD must be the primary diagnosis and focus of treatment, and the treatments offered in the study must not be contraindicated for the comorbid disorder.

Exclusion Criteria:

General exclusion criteria are:

* history of head injury with loss of consciousness or any CNS disease that is likely to affect brain function;
* diagnosis of autism or pervasive developmental, psychotic, major mood, and Tourette's disorder;
* alcohol or drug abuse in the past 3 months or a positive urinary toxic screen on initial evaluation;
* use of psychotropic medication within 2 weeks of the study (8 weeks for fluoxetine);
* pre-existing medical or psychological condition which precludes being in the scanner (e.g., claustrophobia, morbid obesity);
* metal in the body that precludes scanning (e.g., braces, metal plate);
* positive urine pregnancy test.

Specific exclusion criteria for the treatment trial include:

* previous unsuccessful trial of MPH or ATX that was adequately dosed (≥ 1 mg/kg for MPH or 1.0 mg/kg for ATX) and of adequate duration (≥ 4 weeks);
* abnormal findings on physical exam, or vital signs
* pulse and blood pressure \> 95% of age and gender mean;
* inability to swallow capsules;
* weight is \< 20 kg or \> 85 kg.

Specific exclusion criteria for control youth include:

* no past history or current diagnosis of any psychiatric disorder, determined by the K-SADS-PL interview;
* ADHD-RS-IV and CBCL scores for each symptom domain ≤ 1 SD of age and gender means.