This revised proposal for a Mentored Clinical Scientist Development Award (MCSDA) provides the applicant with an optimal scientific environment for training in the functional neuroimaging of cocaine dependence. The career development and research plans are designed to enhance the applicant's scientific skills in both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), with the long term goals of linking changes in behavior with changes in neuronal function. In conjunction with the proposed research, the career development plan will foster the applicant's growth as an independent investigator in the cognitive neuroscience of addiction. A large body of evidence has implicated mesoaccumbal and mesolimbic circuits in cocaine dependence, yet elucidating the relationship between the function of these regions and the addiction syndrome has been hampered by the lack of knowledge about the role of these structures in human cognition. One impediment has been the absence of a functional, nonpharmacologic probe specific to the mesoaccumbal/limbic system. Targeted functional imaging paradigms, such as using working memory tasks to probe the frontal lobes, have made important advancements in the understanding of other psychiatric disorders. Based on computational models of cellular reward and information transmission, we have developed an innovative behavioral task anatomically targeted to the mesoaccumbal/limbic system. Preliminary PET data demonstrates that striatal activity normally increases in response to novel contextual information, but cocaine addicts display a decreased striatal response. The central hypothesis of this proposal is that monitoring for novelty is a normal function of the mesoaccumbal/limbic circuit, and this function becomes altered through chronic cocaine use. The preliminary findings further suggest that cocaine addicts have a different response to reinforcement, generating the secondary hypothesis that the neural substrates that code for reward will show a different response to monetary incentive. To test these hypotheses, three specific aims are identified: 1) Using PET, compare the striatal/accumbal response to novel information in a cohort of cocaine addicts and matched controls. 2) Simultaneously compare the striatal response to monetary reward in these cohorts. 3) Test the hypothesis that the striatum responds to novel information on a single-event basis by using fMRI to examine the time course of these responses. Taken together with a series of courses, seminars, and mentoring activities, this will yield important new insights into the cognitive neuroscience of human addiction and the specific roles that the mesoaccumbal and mesolimbic circuits play in cocaine dependence.
| Zink, Caroline F; Pagnoni, Giuseppe; Chappelow, Jonathan et al. (2006) Human striatal activation reflects degree of stimulus saliency. Neuroimage 29:977-83 |
| Berns, Gregory S; Chappelow, Jonathan; Cekic, Milos et al. (2006) Neurobiological substrates of dread. Science 312:754-8 |
| Zink, Caroline F; Pagnoni, Giuseppe; Martin-Skurski, Megan E et al. (2004) Human striatal responses to monetary reward depend on saliency. Neuron 42:509-17 |
| Dhamala, Mukeshwar; Pagnoni, Giuseppe; Wiesenfeld, Kurt et al. (2003) Neural correlates of the complexity of rhythmic finger tapping. Neuroimage 20:918-26 |
| Zink, Caroline F; Pagnoni, Giuseppe; Martin, Megan E et al. (2003) Human striatal response to salient nonrewarding stimuli. J Neurosci 23:8092-7 |
| McClure, Samuel M; Berns, Gregory S; Montague, P Read (2003) Temporal prediction errors in a passive learning task activate human striatum. Neuron 38:339-46 |
| Montague, P Read; Berns, Gregory S (2002) Neural economics and the biological substrates of valuation. Neuron 36:265-84 |
| Dhamala, Mukeshwar; Pagnoni, Giuseppe; Wiesenfeld, Kurt et al. (2002) Measurements of brain activity complexity for varying mental loads. Phys Rev E Stat Nonlin Soft Matter Phys 65:041917 |
| Berns, G S; McClure, S M; Pagnoni, G et al. (2001) Predictability modulates human brain response to reward. J Neurosci 21:2793-8 |
| Bischoff-Grethe, A; Martin, M; Mao, H et al. (2001) The context of uncertainty modulates the subcortical response to predictability. J Cogn Neurosci 13:986-93 |
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