An important pathogenetic process of cocaine addiction is impairment in cognitive control. Cocaine dependent (CD) individuals often report inability to control their drug use despite knowledge of the untoward consequences. Behavioral and imaging studies have similarly provided evidence for deficits in cognitive control in CD individuals. Understanding the systems and molecular bases of this cognitive deficit may have significant contributions to research and treatment of cocaine dependence. Cognitive control is an executive function that involves complex biology. The research of this R01 study focuses on delineating the component processes of cognitive control and how these processes may predict relapse in a prospective cohort of cocaine addicted individuals. Combining functional magnetic resonance imaging (fMRI) and a stop signal task, a behavioral task widely used to investigate cognitive control, we described the neural processes underlying response inhibition, error processing, and post-error behavioral adjustment. CD individuals showed diminished regional brain activations and altered performance in these processes, as compared to healthy control participants. Importantly, logistic and Cox regressions identified gender shared and specific error-related neural processes that predict relapse and time to relapse. Decreased error-related activities of the dorsal anterior cingulate cortex and thalamus predict relapse in both men and women. Thalamic cortical connectivities for cognitive control also distinguish CD relapsors and non-relapsors. [In an R21 study of positron emission tomography (PET) imaging of a small number of CD individuals, we observed an increase in thalamic norepinephrine transporter (NET) binding potential in the CD as compared to HC participants. Importantly, greater NET availability is associated with diminished error processing in the thalamus. These results suggest that altered thalamic noradrenergic processes may underlie aberrant error- related cognitive control and dispose individuals to relapse to drug use. The renewal of this R01 seeks to pursue these findings and specify the role of altered thalamic noradrenergic signaling in cognitive dysfunction in CD individuals. By combining multimodal MRI, PET imaging, and longitudinal follow-up, we will examine whether and how NET availability associates with altered regional activations as well as functional and structural connectivity during thalamus-related cognitive processes and predict relapse in cocaine dependence. We hope that these new findings will provide a useful molecular biomarker and expedite development of novel pharmacotherapy for cocaine dependence.

Public Health Relevance

Deficits in cognitive control are associated with habitual, uncontrollable drug use in cocaine dependent individuals. Here we propose to combine brain imaging and longitudinal clinical follow-up to understand the molecular bases of these deficits. These new findings will further our understanding of the etiologies of cocaine addiction and facilitate development of new pharmacotherapy for people addicted to cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA023248-06A1
Application #
8696705
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Gordon, Harold
Project Start
2007-04-01
Project End
2019-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
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Zhang, Sheng; Hu, Sien; Sinha, Rajita et al. (2016) Cocaine dependence and thalamic functional connectivity: a multivariate pattern analysis. Neuroimage Clin 12:348-58
Zhang, Sheng; Tsai, Shang-Jui; Hu, Sien et al. (2015) Independent component analysis of functional networks for response inhibition: Inter-subject variation in stop signal reaction time. Hum Brain Mapp 36:3289-302
Zhang, Sheng; Hu, Sien; Hu, Jianping et al. (2015) Barratt Impulsivity and Neural Regulation of Physiological Arousal. PLoS One 10:e0129139

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