The chronically relapsing disorder of drug addiction is the product of behavior and brain state transitions as impulsive drug use escalates to compulsive drug abuse. These transition states are well informed by animal models though their human representations are not known. In this revised proposal, we propose to define the human neurobiological mechanisms of transition to drug addiction by characterizing the impact and interaction effects for three putative addiction risk factors: the developmental period of adolescence, exposure to early life trauma, and the presence of potentially problematic drug abuse.
Four specific aims are proposed to test project hypotheses. A conceptual model would be tested in which the impact of early trauma on two intermediate personality traits involving negative (reactivity to stress, Aim 1) and positive (impulsivity, Aim 2) behavioral reinforcement processes mediates the heightened risk for transition from impulsive to compulsive drug use. These two traits are central to behavioral reinforcement models of compulsive drug abuse in which relief of stress or dysphoria reinforces drug use and impulsivity or deficits in inhibitory behavioral control reinforces drug use. Both traits are also heightened by early life stress. Groups of adolescent girls differing in having potentially problematic drug use (-/+) or trauma exposure histories (-/+), but not fulfilling syndromal criteria for drug dependence, PTSD or depression, would be compared by task- related functional magnetic resonance imaging (fMRI) responses. Further cross-sectional comparisons would determine whether risk for development of addiction shares a neural correlate of addiction processes with drug-dependent adults (Aim 3). Multivariate, individual-level analyses using fMRI pattern classification and prediction approaches would seek neurobiological explanations of addiction transition risk in the form of altered functional organization of neural information processing networks for the candidate reinforcement processes (Aim 4). The proposed cross-sectional study design would test an overall hypothesis that trauma exposure predisposes affected individuals towards drug use disorders by altering the brain maturation of two behavioral reinforcement processes linked to drug addiction risk: stress reactivity and impulsivity.

Public Health Relevance

The proposed project seeks to define the human brain functional correlates and imaging biomarkers of the antecedents of drug use disorders. The long-term goal of the project is to use project inferences to guide the develop of effective intervention strategies that curb the brain state transitions related to the development of human drug addiction and thus minimize the need for treatments of limited efficacy and adherence, and that are little sought.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Gordon, Harold
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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Cisler, Josh M; Bush, Keith; Scott Steele, J et al. (2015) Brain and behavioral evidence for altered social learning mechanisms among women with assault-related posttraumatic stress disorder. J Psychiatr Res 63:75-83
Bush, Keith; Cisler, Josh; Bian, Jiang et al. (2015) Improving the precision of fMRI BOLD signal deconvolution with implications for connectivity analysis. Magn Reson Imaging 33:1314-23
Bush, Keith; Zhou, Suijian; Cisler, Josh et al. (2015) A deconvolution-based approach to identifying large-scale effective connectivity. Magn Reson Imaging 33:1290-8
Cisler, Josh M; Bush, Keith; James, G Andrew et al. (2015) Decoding the Traumatic Memory among Women with PTSD: Implications for Neurocircuitry Models of PTSD and Real-Time fMRI Neurofeedback. PLoS One 10:e0134717
Cisler, Josh M; Sigel, Benjamin A; Kramer, Teresa L et al. (2015) Amygdala response predicts trajectory of symptom reduction during Trauma-Focused Cognitive-Behavioral Therapy among adolescent girls with PTSD. J Psychiatr Res 71:33-40