Developing Brain, Impulsivity and Compulsivity

Study Overview
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Brief Summary
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Background: Impulsivity is acting 'without thinking.' Compulsivity is being overly inflexible. People vary in how impulsive or compulsive they are. Extreme versions of these behaviors play a role in mental disorders. Researchers want to study changes in the brain to learn more about these behaviors. Differences in genes may also play a role. Objective: To learn about genetic and brain features that explain why levels of impulsivity and compulsivity vary across people. Eligibility: People ages 6-80 Design: Participants will be screened with a medical history and medical record review. Participants will talk about their mental and behavioral development. They may discuss topics like drug use and sexual activity. They will complete surveys about their compulsivity and impulsivity. Parents of child participants may also complete these surveys. Participants may take memory, attention, and thinking tests. They may give blood or saliva samples for gene studies. Participants may have a magnetic resonance imaging scan. It will take pictures of their brain. The scanner is shaped like a cylinder. Participants will lie on a table that slides in and out of the scanner. A coil will be placed over their head. They will lie still, watch a movie, and play a game. Participants may have a magnetoencephalography scan. It records brain activity. Participants will sit in a room. A 'cone' of magnetic field detectors will be lowered around their head. They will rest and play a game. Participants may ask family members to join the study. Participants under age 25 may repeat these tests every 1-2 years until they turn 25 or until the study ends. For those over age 25, participation will last less than 1 month.

Detailed Description
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Study Description: Many neuropsychiatric disorders have extreme impairing impulsivity and compulsivity behaviors at their core. We hypothesized that the development of symptoms of impulsivity and compulsivity during childhood/adolescence and early adulthood will be associated with atypical trajectories of brain features including cortical glutamate (the main excitatory neurotransmitter) and functional/structural brain connectivity. Additionally, we hypothesize that cortical glutamate will be under genetic control (i.e., heritable) and that common genetic variant risk for disorders characterized by extreme impulsivity (e.g., attention deficit hyperactivity disorder) and by extreme compulsivity (e.g., obsessive compulsive disorder) will also be associated with atypical cortical glutamate trajectories. To elucidate the relationships between the developing brain, compulsivity/impulsivity and genomics, we will collect clinical assessments including clinician-led interviews, neurobehavioral assessments, neuroimaging data, and genomic samples using 1) a prospective longitudinal design to answer developmental hypotheses; 2) an extended multigenerational family design to assess genomic hypotheses. Objectives: Primary Objectives: A) To assess the effects of impulsivity and compulsivity on the developmental trajectories of cortical glutamate. B) To determine the heritability of cortical glutamate. Secondary Objectives: A) To establish the reliability of glutamate measurements. B) To examine the impact of atypical glutamate levels on developing structural and functional connections within the fronto-striatal circuits. Endpoints: Primary Endpoint: A) Age-related change in cortical glutamate levels and its moderation by individual differences in levels of impulsivity and compulsivity. B) Heritability of cortical glutamate (proportion of variance explained by additive genetic factors). Secondary Endpoints: A) 1. Glutamate levels estimated at 3 Tesla at short intervals to establish test-retest reliability. 2. Glutamate levels estimated at both 3 Tesla and 7 Tesla (cross scanner validation). B) Measures of the brain s structural and functional connectivity. Study Population: We aim to recruit 1100 participants over the next 7 years. Individuals between 6 and 80 years of age with a wide range of impulsivity/compulsivity behaviors - ranging from normal to mildly/extremely impaired - will be recruited. No specific demographic groups will be targeted. Recruitment will be mainly done in the District of Columbia/Maryland/Virginia area, however some participants needed for primary aim B (heritability) might travel from elsewhere. Description of Sites/Facilities Enrolling Participants: The National Institute of Health is the sole site for enrollment of participant. Study Duration: The estimated study duration from the beginning of the study (study opens to enrollment) to the end (completion of data analyses) is 10 years. Participant Duration: Primary Objective A: Participants may complete follow-up visits for as long as the study is open; thus, they might complete visits over a 7 to 10-year period. Primary Objective B: Participants will complete the study after one visit and may complete forms at home; thus, the estimated time for participation is less than a month.

Official Title
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An Observational Study of the Developing Brain, Impulsivity and Compulsivity.

Conditions
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Typical Development, Attention Deficit Hyperactivity Disorder, Conduct Disorder, Obsessive Compulsive Disorder

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Stated willingness to comply with all study procedures and availability for the duration of the study. Male or female, 6 years of age and under 80 years of age. Ability of participant to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: Cognitively not capable of performing study procedures or lack of capacity to provide informed consent. Indications of a lack of cognitive capacity could include a known full-scale IQ under 70, or a history from the screening interview that implies global intellectual disabilities (e.g., placement in a school for children with intellectual disability etc.) Very premature birth (i.e., birth before 32 weeks of gestational age). Any known brain abnormalities (e.g., tumor, periventricular leukomalacia, microcephaly) or history of medical conditions known to affect cerebral anatomy (e.g., epilepsy, history of stroke, head injury with a loss of consciousness of one hour or more). Psychotic disorders (including schizophrenia, psychosis not otherwise specified). Dementia, or other conditions that, in the opinion of the investigators, would impede compliance or possibly hinder completion of the study. Pregnant women. Additional exclusion criteria for optional MRI procedure: Individuals who are not able to receive an MRI (e.g., metal bioimplants, claustrophobia, inability to lie flat on their backs, pregnant women, and any other contraindications for MRI scanning according to the NMR Center MRI safety guidelines). Medications that are known to affect glutamate levels (e.g., riluzole, memantine, C- cycloserine). Antipsychotic medication (as these have a major impact on dopamine levels).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| impulsive compulsive<br>Individuals between 6 and 80 years of age with a wide range of impulsivity/compulsivity behaviors - ranging from normal to mildly/extremely impaired. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glutamate concentration measured using Magnetic Resonance Spectroscopy | Age-related change in cortical glutamate levels and its moderation by individual differences in levels of impulsivity and compulsivity. | Yearly if possible | 
| Heritability of cortical glutamate (proportion of variance explained by additive genetic factors). | Degree to which glutamate levels are under genetic control. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glutamate levels | Glutamate measurement at 7 Tesla is now the gold standard for glutamate measurements, against which we will compare measurements at 3 Tesla. | weeks to months | 
| Structural and functional connectivity | Structural and functional connectivity measured throughout development using Magnetic Resonance Imaging and Magnetoencephalography. | Yearly if possible | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glutamate, Heritability, NEUROPSYCHIATRIC DISORDER, Brain Connectivity, developmental trajectory, Natural History