Cognitive flexibility and reward motivation in adolescent cannabis use: An investigation of neurobehavioral mechanisms and intrinsic resting state connectivity.

7.项目概要： 青少年开始使用大麻（CU）与认知方面的重大后果有关。 减少上瘾。虽然CU可能会破坏青少年大脑发育的正常过程， 关于青少年CU如何破坏介导认知灵活性（适应变化）的电路， 奖励和惩罚）和内在静息状态功能连接（RSFC），并影响奖励 动机（目标导向行为的数量，以获得强化）。这些领域都是未充分研究的 与成人CU相关的区域，但对这些过程的深入了解可能解释了为什么 与功能障碍和较高的问题物质使用率有关。托马斯医生的长期 职业目标是成为一名独立的研究人员，确定风险和影响的生物行为机制 为改进有针对性的预防和治疗的识别方法，的 在这个为期4年的以病人为导向的指导职业奖励中要检验的中心假设是，CU在这种情况下 青少年大脑发育与额纹状体改变和认知灵活性受损有关， 动机和内在RSFC，将作为CU暴露的函数而变化。核心方法是使用 症状，电路和行为数据在14-17岁的青少年谁是从事CU，也通常- 发育中的对照青少年（每组n=40）。NIDA K23的职业发展目标 申请是为了获得实践指导（a）青少年CU的现象学和评估，（B） 使用功能磁共振成像来测量青少年CU的大脑/行为改变，以及（c）高级统计学 通过学习计算精神病学模型，从这些数据中获得更高水平的推理方法。的 本K23的研究目标是：（1）识别认知灵活性的大脑/行为机制， 使用fMRI与CU相关的RSFC;（2）定义奖励动机的行为改变;（3）使用 先进的统计方法，包括特定的计算模型，以整合神经和行为 在认知灵活性任务期间对决策的贡献，并确定决策如何 CU青少年和对照青少年的成分不同。布朗大学是一个丰富的科学环境 进行这项研究，由于导师在青少年物质使用，神经科学， 先进的统计方法，有充足的资源来执行托马斯博士的培训计划，包括手- 关于指导、讲习班、课程（例如，神经解剖学）和专业发展（会议 出版物）。这个项目意义重大，因为解决了缺乏知识的问题， 认知灵活性、奖励动机和RSFC是促进基于机制的第一步（a） 从常规CU进展到成瘾的预测因子，和（B）青少年中CU的治疗。这 该项目在使用功能磁共振成像来探索认知灵活性的相对欠研究领域方面具有创新性， 使用计算精神病学分析的青少年与非CU之间的奖励动机。

7. PROJECT SUMMARY: Cannabis use (CU) initiated in adolescence is associated with substantial consequences, from cognitive decline to addiction. While CU may disrupt normal processes of adolescent brain development, relatively little is known about how adolescent CU disrupts circuits mediating cognitive flexibility (adaptation to changing rewards and punishments) and intrinsic resting state functional connectivity (RSFC), and impacts reward motivation (the amount of goal-directed behavior to earn reinforcement). These domains are all understudied areas relative to adult CU yet advancing knowledge of these processes may explain why adolescent-onset CU is linked to functional impairments and higher rates of problematic substance use. Dr. Thomas’s long-term career goal is to become an independent researcher identifying bio-behavioral mechanisms of risks and effects of adolescent drug use in order to improve identification methods for targeted prevention and treatment. The central hypothesis to be tested in this 4-year patient-oriented mentored career award is that CU in the context of adolescent brain development is linked to frontostriatal alterations and impaired cognitive flexibility, reward motivation, and intrinsic RSFC that will vary as a function of CU exposure. The central methodology is to use symptom, circuit, and behavioral data in 14-17 year old adolescents who are engaged in CU and also typically- developing control adolescents (n=40 of each). The career development objectives of this NIDA K23 application are to gain hands-on mentorship in (a) phenomenology and assessment of adolescent CU, (b) the use of fMRI to measure brain/behavior alterations underlying adolescent CU, and (c) advanced statistical methods for greater level of inference from these data, by learning a computational psychiatry model. The research objectives of this K23 are to: (1) to identify the brain/behavior mechanisms of cognitive flexibility and RSFC associated with CU using fMRI; (2) to define behavioral alterations in reward motivation; (3) to use advanced statistical methods, including a specific computational model, to integrate the neural and behavioral contributions to decision-making during a cognitive flexibility task and determine how decision-making components vary for CU adolescents and control adolescents. Brown University is a rich scientific environment to conduct this research due to the expertise of mentors in adolescent substance use, neuroscience, and advanced statistical methods with ample resources to carry out Dr. Thomas’s training plan consisting of hands- on mentorship, workshops, coursework (e.g., neuroanatomy), and professional development (conference presentations, publications). This project is significant because addressing the dearth of knowledge about cognitive flexibility, reward motivation, and RSFC is the first step towards facilitating mechanism-based (a) predictors of progression from regular CU to addiction, and (b) treatments for CU among adolescents. This project is innovative in its use of fMRI to probe the relatively understudied domains of cognitive flexibility and reward motivation among adolescents with and without CU using computational psychiatry analyses.