Igor Elman - US grants

DESCRIPTION: (Provided by Applicant) This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) entitled "Neuroimaging of Drug-Primed Craving in Cocaine Dependence." The candidate's previous training was in clinical psychiatry, clinical psychiatric research and addiction psychiatry and includes familiarity with neuroimaging technology. Through this proposal, the candidate seeks to gain advanced training in: (1) functional magnetic resonance imaging (fMRI) physics and analytic techniques, (2) cognitive neuroscience methodology relevant to addiction research, (3) the interface of neuroendocrinology and addiction psychiatry, and (4) clinical research design and analysis, including advanced statistical analysis relevant to fMRI data, power analyses, ethics and responsible conduct of clinical research. The research project that is designed to complement this training program will investigate the functional networks subserving craving through the use of cocaine infusions, fMRI, neuroendocrinology and experimental psychology. Studies involving the candidate and an extended group of investigators suggest dissociation between those brain regions that are active during drug craving vs. drug-induced euphoria. Specifically, they find that the nucleus accumbens and amygdala show distinct changes in fMRI signal that correlate with craving in response to cocaine. The proposed project will expand and elaborate upon the previous findings. Specific Aim 1 will replicate and refine the findings from the initial study in a larger cohort of cocaine dependent subjects. It will characterize the fMRI craving response across various doses and compare between two pre-selected groups of high vs. low cravers matched for euphorogenesis. Embedded in this Specific Aim is also an assessment of the association between neural correlates of craving and mood, stress and the main neuroendocrine modulators of stress response, ACTH and cortisol. Understanding how cocaine produces its behavioral effect further necessitates study of the cognitive context of craving. Specific Aim 2 accordingly will explore expectancy condition effects i.e., whether circuitry associated with craving respond differently in a situation in which the subject knows that more cocaine is available vs. a situation where additional consumption of the drug is impossible. Finally, Specific Aim 3 will determine the specificity of the findings concerning cocaine craving through low dose morphine infusions in healthy comparison subjects vs. cocaine dependent subjects. This program will provide the applicant with needed training on the integration of neuroimaging technologies and behavioral pharmacology paradigms for the study of the pathophysiology of addictions. The multidisciplinary mentorship plan will foster the candidate's development toward becoming an independent investigator in substance abuse neuropsychiatry. The research plan will allow him to determine the roles of specific subcortical structures that mediate cocaine-primed craving, thus improving the understanding of the mechanisms underlying cocaine dependence. Furthermore, it may point the way for the development of novel therapeutic strategies for this disease

DESCRIPTION (provided by applicant): This proposal, entitled "PTSD and drug dependence: neuroimaging of reward circuitry" is a response to NIDA Request for R01 Applications (#DA-04-001; Stress and Drug Abuse: Epidemiology, Etiology, Prevention and Treatment). The primary goal of this proposal is to investigate brain reward function as a potential neuropathological basis for substance use disorders (SUDs) comorbidity in posttraumatic stress disorder (PTSD). Basic neuroscience and clinical findings suggest that brain reward circuitry is altered by chronic stress exposure in ways that may be important for facilitating SUDs. We hypothesize that: 1) functionally impaired brain reward mechanisms may comprise a neural substrate underlying core PTSD symptoms of reduced reactivity to natural rewarding stimuli or emotional numbing and that 2) this neural substrate is further altered by the presence of comorbid SUDs. The proposed project is designed to test these hypotheses integrating functional magnetic resonance imaging, psychopharmacology and cognitive psychology to empirically measure reward responses in PTSD, cocaine dependence, PTSD with comorbid cocaine dependence and in health. The proposed experiments have already been successfully performed in separate cohorts of healthy volunteers and piloted in PTSD subjects with and without cocaine dependence. The published data and preliminary results suggest unique patterns of hemodynamic responses in the nucleus accumbens (NAc) and related structures during reward processing along with PTSD-related abnormalities in performance on a behavioral probe of reward function. Three distinct experimental paradigms to be used in this project include a) low doses of an FDA-approved euphorigenic drug, morphine, which can be safely administered to drug-naive subjects, b) social reward in the form of visual processing of attractive faces and c) monetary incentive stimuli incorporated into a gambling task. We expect to find that in PTSD patients the magnitude of the NAc's activation in response to the three rewarding stimuli will be smaller relative to healthy controls, but larger than in individuals with comorbid PTSD and cocaine dependence. This research plan will provide important leads for understanding and preventing the development of SUDs in the context of chronic stress exposure or PTSD. Furthermore our project may offer insights on the pathogenesis of emotional numbing symptoms, which cause severe disability not only in PTSD patients, but also in those suffering from other neuropsychiatric conditions such as SUDs, schizophrenia and major depression.

DESCRIPTION (provided by applicant): This proposal, entitled "PTSD and drug dependence: neuroimaging of reward circuitry" is a response to NIDA Request for R01 Applications (#DA-04-001; Stress and Drug Abuse: Epidemiology, Etiology, Prevention and Treatment). The primary goal of this proposal is to investigate brain reward function as a potential neuropathological basis for substance use disorders (SUDs) comorbidity in posttraumatic stress disorder (PTSD). Basic neuroscience and clinical findings suggest that brain reward circuitry is altered by chronic stress exposure in ways that may be important for facilitating SUDs. We hypothesize that: 1) functionally impaired brain reward mechanisms may comprise a neural substrate underlying core PTSD symptoms of reduced reactivity to natural rewarding stimuli or emotional numbing and that 2) this neural substrate is further altered by the presence of comorbid SUDs. The proposed project is designed to test these hypotheses integrating functional magnetic resonance imaging, psychopharmacology and cognitive psychology to empirically measure reward responses in PTSD, cocaine dependence, PTSD with comorbid cocaine dependence and in health. The proposed experiments have already been successfully performed in separate cohorts of healthy volunteers and piloted in PTSD subjects with and without cocaine dependence. The published data and preliminary results suggest unique patterns of hemodynamic responses in the nucleus accumbens (NAc) and related structures during reward processing along with PTSD-related abnormalities in performance on a behavioral probe of reward function. Three distinct experimental paradigms to be used in this project include a) low doses of an FDA-approved euphorigenic drug, morphine, which can be safely administered to drug-naive subjects, b) social reward in the form of visual processing of attractive faces and c) monetary incentive stimuli incorporated into a gambling task. We expect to find that in PTSD patients the magnitude of the NAc's activation in response to the three rewarding stimuli will be smaller relative to healthy controls, but larger than in individuals with comorbid PTSD and cocaine dependence. This research plan will provide important leads for understanding and preventing the development of SUDs in the context of chronic stress exposure or PTSD. Furthermore our project may offer insights on the pathogenesis of emotional numbing symptoms, which cause severe disability not only in PTSD patients, but also in those suffering from other neuropsychiatric conditions such as SUDs, schizophrenia and major depression.