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

描述（由申请人提供）：这是一份通过K01“指导研究科学家发展奖”机制获得5年支持的申请。候选人是一名行为神经科学家，具有使用临床前啮齿动物可卡因成瘾模型的经验，他在麦克莱恩医院提出了一项临床研究培训计划，该计划结合了在尼古丁依赖人群中多种神经成像方法和神经心理学和自我报告评估方面的广泛学习经验。该计划包括一对一的专家指导，核磁共振技术课程，数据处理和分析策略，出席药物依赖和脑成像科学会议并发表演讲，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行为培训。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得到实施和磨练。由于成年吸烟者表现出许多结构、功能/认知和神经化学变化，这些变化可能是早期吸烟直接导致的，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，即整合多模态神经影像学、神经心理学和自我报告评估，以开发早期（<16岁）儿童的生物学和认知特征。老)和晚发(？16岁。老年)依赖尼古丁的成年人。为此，早期和晚期吸烟对成年吸烟者神经生物学和认知能力的影响将通过3个独立的研究目标进行调查。首先，申请人将应用脑电图/ERP技术、生理活动和自我报告的渴望等级来测量戒断条件下吸烟提示反应和渴望的增加。其次，申请人将学习磷磁共振波谱[31P 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和认知加工的变化。第三，申请人将学习如何应用扩散张量成像（DTI）方法来测量组间白质结构的变化。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以用来预测某些治疗方法是否应该区别于晚发性吸烟者和早发性吸烟者，以改善戒烟结果。总的来说，拟议的培训和研究项目将提供详细的知识和培训，包括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。因此，候选人将获得必要的研究技能和工具，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。

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.