Early Onset Cigarette smoking effects on brain structure, function and chemistry

描述（由申请人提供）：这是一个通过K 01“指导研究科学家发展奖”机制提供5年支持的请求。候选人是一位行为神经科学家，有使用可卡因成瘾临床前啮齿动物模型的经验，他在姆克林医院提出了一项临床研究培训计划，该计划结合了尼古丁依赖人群在几种神经成像方法以及神经心理学和自我报告评估方面的丰富学习经验。该计划包括1对1专家指导，MR技术课程，数据处理和分析策略，药物依赖和脑成像科学会议的出席和演示，参加精神病学和神经科学研讨会，以及正在进行的负责任的研究培训。通过这些培训机会获得的技能将通过应用程序的研究部分实施和磨练。由于成年吸烟者表现出一些结构，功能/认知和神经化学变化，可能直接导致早期吸烟，这将是研究计划的重点。具体来说，拟议的研究将实现一个短期的职业目标，即整合多模态神经成像和神经心理学和自我报告评估，以开发早发性（<16岁）与晚发性（？16岁）尼古丁依赖的成年人。为此，将通过3个独立的研究目标研究早发性与迟发性吸烟对成年吸烟者神经生物学和认知能力的影响。首先，申请人将应用EEG/ERP技术、生理活动和自我报告的渴望评级来测量戒断条件期间增加的吸烟提示反应性和渴望。其次，申请人将学习磷磁共振波谱[31 P MRS]方法，并对多个认知领域（即注意力、工作记忆、冲动）进行神经心理学评估，以评估在急性尼古丁给药和戒断条件下测量的生物能量和磷脂神经代谢物水平以及认知处理的变化。第三，申请人将学习如何应用扩散张量成像（DTI）方法来测量组间改变的白色物质结构。总的来说，早发性吸烟导致的成人神经改变和认知缺陷的经验证据可用于预测某些治疗方法是否应与早发性吸烟者不同地应用于改善戒烟结果。总体而言，拟议的培训和研究项目将提供多种神经成像技术的理论和实施以及最佳研究设计，研究管理，数据分析和解释方面的详细知识和培训。因此，候选人将获得必要的研究技能和工具，以过渡到一个长期的职业目标，通过整合多模态脑成像和神经心理学技术，作为一个创新和多才多艺的独立研究者，对理解成瘾的神经生物学病因和认知后果做出有意义的贡献。 公共卫生相关性：青少年烟草使用仍然是对公共健康的最大威胁，因为相对于那些较晚开始吸烟的人（> 16岁），早期暴露于尼古丁（<16岁）可能会独特地破坏神经成熟发育。使用多模态成像方法来检查尼古丁使用开始年龄的影响，将澄清相对于那些开始吸烟较晚的人，早期暴露于尼古丁是否会导致更大的结构，认知和神经化学变化。早发性吸烟导致的神经改变和认知缺陷的证据将提供关键信息，说明应将哪些特定治疗方法应用于早发性吸烟者和迟发性吸烟者，这可能会改善戒烟结果。

DESCRIPTION (provided by applicant): This is a request for 5 years of support through the K01 "Mentored Research Scientist Development Award" mechanism. The Candidate, a behavioral neuroscientist with experience using a preclinical rodent model of cocaine addiction, proposes a clinical research training program at McLean Hospital that combines extensive learning experience in several neuroimaging methods and in neuropsychological and self-report assessments, in a nicotine-dependent population. The program includes 1-on-1 expert mentorship, coursework in MR technology, data processing and analysis strategies, attendance and presentations at drug dependence and brain imaging scientific conferences, participation in psychiatric and neuroscience seminars, and ongoing Responsible Conduct of Research training. Skills acquired through these training opportunities will be implemented and honed through the application's research component. As adult smokers exhibit a number of structural, functional/cognitive and neurochemical changes that may result directly from early smoking, this will be the focus of the research plan. Specifically, the proposed studies will fulfill a short-ter career goal of integrating multimodal neuroimaging and neuropsychological and self-report assessments to develop a biological and cognitive profile of early- (<16 yrs. old) vs. late-onset (? 16 yrs. old) nicotine-dependent adults. To this end, the effects of early- vs. late-onset smoking on the neurobiology and cognitive performance of adult smokers will be investigated by 3 independent research aims. First, the applicant will apply EEG/ERP technology, physiological activity, and self-reported ratings of craving to measure increased smoking cue reactivity and craving during withdrawal conditions. Second, the applicant will learn phosphorus magnetic resonance spectroscopy [31P MRS] methods and to conduct neuropsychological assessments of multiple cognitive domains (i.e. attention, working memory, impulsivity) to assess alterations in bioenergetic and phospholipid neurometabolite levels and cognitive processing measured during acute nicotine administration and withdrawal conditions. Third, the applicant will learn how to apply diffusion tensor imaging (DTI) methods to measure altered white matter structure between groups. Collectively, the empirical evidence of adult neural alterations and cognitive deficits resulting from early-onset smoking may be used to predict if certain treatment approaches should be applied differentially too late- vs. early-onset smokers to improve smoking cessation outcomes. Overall, the proposed training and research projects will confer detailed knowledge and training in the theory and implementation of multiple neuroimaging techniques as well as in optimal study design, study management, and data analysis and interpretation. The Candidate will therefore acquire the research skills and tools necessary to transition into a long-term career goal of making meaningful contributions towards understanding the neurobiological etiology and cognitive sequel of addiction by integrating multimodal brain imaging and neuropsychological techniques as an innovative and versatile independent investigator. PUBLIC HEALTH RELEVANCE: Adolescent tobacco use remains the largest threat to public health, as early exposure (< 16 years old) to nicotine may uniquely disrupt neuromaturational development relative to those with a later onset of smoking (> 16 years old). Using multimodal imaging approaches to examine the impact of age of onset of nicotine use will clarify whether early exposure to nicotine results in greater structural, cognitive and neurochemical alterations relative to those who begin smoking later. Evidence of neural alterations and cognitive deficits resulting from early onset smoking will provide critical information regarding which specific treatment approaches should be applied to early vs. late onset smokers, which is likely to improve smoking cessation outcomes.