Inhibitory Mechanisms of Negative Urgency in Adolescent Suicidal Behavior

项目总结/摘要 这个K23职业发展项目将研究青少年自杀冲动的神经基础。 行为（SB）。候选人将获得关键的技能和经验，在青少年自杀和冲动 研究，先进的神经生理学和纵向方法，以及神经生理学研究的翻译 干预性研究需要一个职业生涯的重点是阐明青少年的大脑行为机制， 某人自杀是青少年死亡的第二大原因，青少年SB的发病率正在上升。 然而，其神经生物学仍然知之甚少，缺乏专门针对SB的治疗方法。SB 是一个关键的公共卫生问题，需要迫切关注，特别是研究， 将知识迅速转化为临床应用。消极紧迫感是冲动的一个组成部分， 在负面情绪的背景下，倾向于鲁莽行事。据发现，随着年龄的增长， SB和尝试，并且与背外侧前额叶对边缘回路的抑制受损有关 皮质（DLPFC），但确切的机制尚不清楚。经颅磁刺激（TMS）允许 DLPFC功能的非侵入性定量，如皮质抑制（CI），皮质抑制的过程， 中间神经元调节其他回路的活动。以前的研究表明，青少年与终身SB 在运动皮层中的CI降低，这将他们与非自杀青年区分开来。但是，DLPFC CI具有 没有在青少年SB中进行测量，也不清楚CI与认知和情感系统的关系 例如，在SB中涉及消极紧迫感。为了研究CI中负紧迫感的相关机制， 需要DLPFC、同时TMS和脑电图（TMS-EEG）。候选人提议 40例有自杀倾向的青少年抑郁症患者的抑制生理和负性紧迫感的纵向研究 本研究采用TMS-EEG和自我报告的方法， 负紧迫感的测量以检验失调的CI与负紧迫感相关的假设， 青少年SB患者DLPFC CI缺乏，且CI缺陷与 消极紧迫感和新出现的SB。候选人有更基本的TMS方法的经验; 然而，为了实现长期的职业目标，需要在脑电图分析方面进行额外的培训， 自杀青少年，纵向/神经发育研究方法是必要的。强大的职业生涯 发展计划，与多学科的指导和合作，将涉及校内和校外 课程、方法学专题研讨会和培训，以及明确的赠款和出版计划 基准。这将确保候选人成功过渡到独立的临床研究生涯。 长期目标是利用本项目收集的数据设计一个大规模的纵向研究， 发展SB的神经和行为风险因素，以及神经调节治疗的试验， 通过针对CI和消极紧迫感的改变来减少从自杀想法到行为的转变。

PROJECT SUMMARY / ABSTRACT This K23 career development project will study the neural underpinnings of impulsivity in adolescent suicidal behavior (SB). The candidate will obtain critical skills and experience in adolescent suicidology and impulsivity research, advanced neurophysiologic and longitudinal methods, and translation of neurophysiologic research to interventional studies needed for a career focused on elucidating brain-behavior mechanisms of adolescent SB. Suicide is the second leading cause of death in adolescence, and rates of adolescent SB are increasing. However, its neurobiology remains poorly understood, and treatments specifically targeting SB are lacking. SB in adolescents is a critical public health problem that demands urgent attention, particularly with research that will rapidly translate knowledge to clinical applications. Negative urgency, a component of impulsivity, is the tendency to act rashly in the context of negative emotion. It has been found to be increased among youth with SB and attempts, and has been linked to impaired inhibition of limbic circuitry by the dorsolateral prefrontal cortex (DLPFC), yet precise mechanisms are unclear. Transcranial magnetic stimulation (TMS) permits noninvasive quantification of DLPFC functions such as cortical inhibition (CI), the process by which cortical interneurons regulate the activity of other circuits. Previous research indicates that adolescents with lifetime SB have reduced CI in the motor cortex that distinguishes them from non-suicidal youth. However, DLPFC CI has not been measured in adolescents with SB, nor is it clear how CI relates to cognitive and emotional systems implicated in SB, such as negative urgency. In order to study CI-related mechanisms of negative urgency in the DLPFC, simultaneous TMS and electroencephalography (TMS-EEG) is required. The candidate proposes a longitudinal study of inhibitory physiology and negative urgency in 40 depressed adolescents with suicidal ideation (but no SB) and 40 depressed adolescents with SB. The study will utilize TMS-EEG and self-report measures of negative urgency to test hypotheses that dysregulated CI is associated with negative urgency, that DLPFC CI is deficient in adolescents with SB, and that CI deficits correlate longitudinally with changes in negative urgency and newly emergent SB. The candidate has prior experience with more basic TMS methods; however, to attain long-term career goals, additional training in EEG analysis, assessment of impulsivity in suicidal adolescents, and longitudinal/neurodevelopmental research methods is necessary. A robust career development plan, with multidisciplinary mentorship and collaboration, will involve intramural and extramural coursework, methodology-specific seminars and training, and a well-defined plan for grant and publication benchmarks. This will ensure the candidate’s successful transition to an independent clinical research career. The long-term goal is to utilize data gathered in this project to design a large-scale longitudinal study assessing neural and behavioral risk factors for developing SB, as well as trials of neuromodulatory treatments that will reduce the transition from suicidal thoughts to behaviors by targeting alterations in CI and negative urgency.