Request for Information (RFI): National Longitudinal Study of Neurodevelopmental Consequences of Substance Use

Notice Number: NOT-DA-14-014

Key Dates
Release Date: July 2, 2014
Response Date: August 31, 2014

Related Announcements

Issued by
National Institute on Drug Abuse (NIDA)
National Cancer Institute (NCI)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


This Request for Information (RFI) is for information and planning purposes only, and should not be construed as a solicitation or an obligation on the part of the Federal Government, the National Institutes of Health (NIH), the Collaborative Research on Addiction at NIH (CRAN), and/or the participating NIH Institutes or Centers. The NIH does not intend to make any awards based on responses to this RFI or to otherwise pay for the preparation of any information submitted or for the Government's use of such information.

Terminology: For the purposes of this RFI, the term "substance" refers to the full spectrum of addictive substances including but not limited to nicotine, tobacco products, alcohol, cannabis, synthetic cannabinoids or cathinones, cocaine, and opiates. The term "substance use" refers broadly to experimentation, use, regular use, hazardous use, risky use, abuse, and compulsive use. While it is recognized that these concepts are not interchangeable, the term "substance use" is used throughout this RFI in order to capture the broad range of use that is relevant to this project. Substance-use disorders (SUDs) refer to clinical diagnoses defined in the Diagnostic and Statistical Manual of Mental Disorders V (DSM-5).

Problem Statement: Preclinical research suggests that substance use affects the developing brain in profound and lasting ways, and cross-sectional comparisons of magnetic resonance imaging (MRI) data in humans indicate that substance use correlates with structural and functional brain abnormalities. However, no large prospective cohort study has been conducted to comprehensively assess the effects of substance use on human brain development and the resulting consequences.
As substance-use policy in the United States continues to evolve, there is growing concern about increased access to and permissiveness around substance use, particularly marijuana and emerging tobacco products among youth. Therefore, the need to understand the effects of substance use on the human brain becomes more urgent than ever before.  Fortunately, advances in neuroimaging provide an enormous capacity to better understand normal and atypical human brain development.

The NIH is exploring optimal ways to configure a large longitudinal cohort study to prospectively examine the effects of substance use on the human brain during early adolescence into young adulthood.


Input for this project from the extramural community was initially provided in an open on-site workshop at the NIH held on May 27-28, 2014. A full summary of recommendations and commentary from this workshop is available at The attendees expressed that the most useful study would address all of the following research questions:

What is the impact of diverse patterns of substance use on the structure and function of the developing brain, as revealed by brain imaging?

What are the consequences of substance use on physical health, psychosocial development, information processing, learning, memory, academic achievement, motivation, emotional regulation, and other behaviors?

How does substance use affect the expression of psychopathology, including substance use disorders, and how does the emergence of psychopathology influence substance use.

What factors (prenatal exposure, genetic, epigenetic, neurobiological, psychosocial, family history) influence substance use and its consequences during development?

In what way does use of each substance contribute to the use of other substances (gateway interactions)?

Key workshop recommendations for study design elements include:

*The study should have a pharmacological/toxicological emphasis, with patterns of substance use carefully collected to serve as the key independent variables.

*A large sample size (~10,000) is needed to permit the differentiation of brain and behavioral effects between and among different combinations, exposure levels, and patterns of substance use. In addition, the sample size should enable the investigation of sex differences, other individual differences, and environmental factors (including geography, such as states that have legalized marijuana for medical or recreational purposes). Consideration should be given to the inclusion of siblings in the sample.

*It is important that data collection begins before the earliest onset of substance use, around ages 10-12, and continuing into young adulthood (ages 19-21). Recruitment is expected to be completed over a two-year period.

* The study should be able to follow an individual's developmental trajectory, including substance use, brain development, and other neurobehavioral and functional measures.

*High-risk youth should be oversampled at baseline to promote a higher proportion of subjects who will engage in substance use during adolescence.

*In depth characterization of the sample at baseline is required to identify predisposing risk factors, such as family history, fetal exposure to substances, early exposure to stress or abuse, or socioeconomic status.

*The study would be best performed by a consortium of imaging sites comprising multi-disciplinary teams of developmental experts, cognition experts, and MRI technical experts to enable cross-site standardization and harmonization of substance use image-collection and other baseline, modifying and outcome measures. Sites should also have a history of success in recruitment of subjects within this age range and retention over lengthy timeframes.

*Harmonized multimodal neuroimaging, neuropsychological testing, psychiatric evaluation, and granular measures of substance use should be applied at logistically-feasible intervals to document changes in adolescent brain structure and function over the span of the study. Due to limitations in scanner access and expense, neuroimaging assessments might be conducted bi-annually (over 10 years), with more frequent collection of other measures during the interim between scans.

*Neuroimaging sessions should include: basic structural and resting functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and task activated fMRI.

*Neurocognitive/neuropsychological and other measures should be age-appropriate, engaging to subjects, with standardized and automated (i.e. computerized) data-collection procedures to enable robust harmonization of methods across sites.

*Measures should include those that evoke brain circuits involved in substance use, substance use disorders, and other mental disorders, e.g., reward, attention, motivation, salience, working memory, interoception, and self-control.

*Other crucial indicators and outcomes are academic achievement, intelligence, physical health, affect/emotional health, traumatic brain injury (TBI), and others of public-health importance.  

*Biological specimens should be collected (blood, saliva) to enable analysis of genetic factors, gene-by- environment interactions associated with substance use, and to allow for the potential of more exploratory analyses (e.g., epigenetic modifications).

*Biological specimens should also be collected to detect presence of substances, although limitations related to timing and accuracy of measurement for specific substances need to be considered.

*Data standardization, harmonization, and data sharing are key requirements for this study. Data from each data-collection wave should be shared in an open-access arrangement (after a reasonable interval to enable quality control measures) akin to data from the Human Connectome Project,

*Ethical issues must be considered due to the wide age range and vulnerability of participants. Confidentiality and strategies for addressing incidental findings through neuroimaging studies should be addressed.

Information Requested

This RFI solicits further guidance and input to this project from the extramural research community and other public stakeholders. The NIH especially seeks input on study elements that include (but are not limited to):

*The optimal sampling strategies to establish a rich, informative, and representative community-based cohort.

*The sample size required for higher-order interaction effects of substance use exposures on measures of brain structure and function. This includes subjects needed to be recruited at baseline to accommodate subject attrition, and whether the study should replenish the sample at follow-up waves.

*A reasonable data-sharing arrangement that balances the incentives for the data-collecting Principle Investigators with the need for open access.

*A strategy to replicate or otherwise validate findings and avoid false positives due to the large number of experiment-wide comparisons. For example, the dataset could be split into an exploratory and confirmatory dataset, with access to the confirmatory dataset contingent on conducting an initial exploratory analysis to establish effect size and appropriate statistical power.

*The most essential domains to assess via neuroimaging techniques, and tasks with high validity, generalizability, and the potential to be translated for study in animal models.

*The most essential domains to assess outside of the scanner using neurocognitive and other behavioral measures that reflect the function of brain circuits most likely to be affected by substance use across development.

*The most essential domains to assess psychosocial, environmental, and other risk and protective factors.

*The obstacles or challenges that are likely to arise in a project of this magnitude and duration.

*The title (and acronym) for the study, which can be determined by the awarded grantees. However, consideration should be given to whether or not to include the term "substance use" in the title.  Concern was expressed regarding parents' perceptions and/or reluctance to enroll their child in a substance use study, particularly since recruitment will begin prior to initiation of substance use, and the term could be stigmatizing.

In addition, the NIH intends to host an open satellite event/meeting about this project at the 2014 Society for Neuroscience Annual Meeting in Washington DC, in November 2014.

How to Submit a Response

Responses will be accepted until August 31, 2014, via email to: Please mark your responses with this RFI identifier NOT-DA-14-014. Reponses are expected to be no longer than approximately 2000 words.

Respondents will receive an automated email confirmation acknowledging receipt of their response, but will not receive individualized feedback.

Any identifiers (e.g., names, institutions, e-mail addresses, etc) will be removed when responses are compiled. Only the processed, anonymized results will be shared internally with NIH program staff and participating IC leadership, as appropriate. Nonetheless, no proprietary information should be submitted.


Please direct all inquiries to:

Susan R.B. Weiss, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-6487