The program of research and training described in this Mentored Research Scientist Development Award (MRSDA) K01 application will provide the candidate with the requisite skills to become an independent investigator in the field of addictions neuroscience, studying the neural mechanisms of emerging pharmacotherapies in order to improve treatments for cocaine-dependence. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas: (1) clinical intervention research science; (2) addictions pharmacology (in particular the pharmacology of emerging medications); and (3) advanced functional magnetic resonance (fMRI) analysis methods (e.g., spatial independent component analysis; sICA). The opportunities afforded by the K01 mechanism would enable the candidate to embark on a rigorous, structured 5-year program of training and research, designed to provide her with the necessary skills in the three areas highlighted above. This program of study will combine formal didactic training (e.g., courses on Ethical and Practical Issues in Clinical Investigation and on Pharmacology at the School of Medicine), one-on-one tutorials, attendance at scientific research conferences and mentored research experience. The research component of this 5-year plan involves the application of advanced fMRI analysis methods to identify the functional brain mechanisms associated with: 1) Galantamine treatment for cocaine dependence: Pre- and post-treatment fMRI data from 60 individuals who participated in a newly completed randomized clinical trial (RCT) of galantamine alone and in combination with computerized cognitive behavioral therapy (2x2 factorial design) will be analyzed using sICA. This work will focus on fMRI Stroop-task data to understand the relationship between cognitive control processes and cocaine-use outcomes following treatment with galantamine. 2) N-acetylcysteine (NAC) administration in cocaine dependence: FMRI data will be collected before and after 7-day NAC administration using a randomized, placebo-controlled, cross-over design (n=40) and will be analyzed using sICA. This work will focus on the neural networks engaged during response-inhibition and during emotion-regulation, in order to provide mechanistic insight into findings from recently completed and ongoing clinical trials of NAC treatment for cocaine-dependence. This combination of secondary data analyses and novel data collection is designed to maximize the candidate's training via provision of hands-on experience in both: (1) the analysis and interpretation of neuroimaging data from a large-scale pharmacotherapy trial (CBT4CBT & Galantamine; P50DA009241) and; (2) the theory and conduct of her own combined fMRI-medication study under guided supervision of recognized experts.

Public Health Relevance

Cocaine use is a major public health problem, however the effectiveness of current treatments remains limited with treatment responses highly variable across individuals. The proposed research will identify the neural mechanisms of a two possible medications for cocaine dependence - galantamine and N-acetyl cysteine - using network-based analyses of functional magnetic resonance imaging data. Isolating the neurobiological mechanisms associated with emerging medications can aid in the development of more effective treatments and may help in the individual assignment of patients to effective therapies, reducing the overall burden of care.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Volman, Susan
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Yale University
Schools of Medicine
New Haven
United States
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Jensen, Kevin P; DeVito, Elise E; Yip, Sarah et al. (2018) The Cholinergic System as a Treatment Target for Opioid Use Disorder. CNS Drugs 32:981-996
Zhai, Zu Wei; Yip, Sarah W; Morie, Kristen P et al. (2018) Substance-use initiation moderates the effect of stress on white-matter microstructure in adolescents. Am J Addict 27:217-224
Yip, Sarah W; Gross, James J; Chawla, Megha et al. (2018) Is Neural Processing of Negative Stimuli Altered in Addiction Independent of Drug Effects? Findings From Drug-Naïve Youth with Internet Gaming Disorder. Neuropsychopharmacology 43:1364-1372
Yip, Sarah W; Worhunsky, Patrick D; Xu, Jiansong et al. (2018) Gray-matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions. Addict Biol 23:394-402
Yip, Sarah W; Potenza, Marc N (2018) Application of Research Domain Criteria to childhood and adolescent impulsive and addictive disorders: Implications for treatment. Clin Psychol Rev 64:41-56
Pezzoli, Stefania; Emsell, Louise; Yip, Sarah W et al. (2018) Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data. Neurosci Biobehav Rev 84:162-170
Carroll, Kathleen M; Nich, Charla; Frankforter, Tami L et al. (2018) Accounting for the uncounted: Physical and affective distress in individuals dropping out of oral naltrexone treatment for opioid use disorder. Drug Alcohol Depend 192:264-270
Morie, Kristen P; Yip, Sarah W; Zhai, Zu Wei et al. (2017) White-matter crossing-fiber microstructure in adolescents prenatally exposed to cocaine. Drug Alcohol Depend 174:23-29
Liu, Lu; Yip, Sarah W; Zhang, Jin-Tao et al. (2017) Activation of the ventral and dorsal striatum during cue reactivity in Internet gaming disorder. Addict Biol 22:791-801
Yip, Sarah W; Morie, Kristen P; Xu, Jiansong et al. (2017) Shared microstructural features of behavioral and substance addictions revealed in areas of crossing fibers. Biol Psychiatry Cogn Neurosci Neuroimaging 2:188-195

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