NEUROCOGNITIVE CONSEQUENCES OF ADOLESCENT MARIJUANA USE

项目摘要（摘要） 这项研究的总体目标是描述青少年的后果和决定因素， 大麻（MJ）消费使用双胞胎控制方法。MJ是最常用的非法 一种典型的在青春期开始使用的药物，这是一个大脑持续发育的时期， 易受滥用药物的有害影响。先前的研究已经建立了 慢性和/或早期MJ暴露以及脑功能、行为和认知的改变，包括 行为的自我调节和冲动的增加，可能会增加过渡到使用的风险 “更难”的药物，以及类似于精神分裂症的神经认知功能障碍。然而，在这方面， 大多数现有的研究依赖于病例对照、相关性设计，排除了强有力的因果推论。它 目前尚不清楚MJ使用者中发现的缺陷是否代表了MJ使用的后果，或者相反， MJ使用的现有风险因素。这一悬而未决的问题是知识上的一个关键差距，阻碍了 预防、干预和治疗方法的发展，以及基于证据的MJ相关公众 政策拟议的研究旨在通过实施强有力的 共孪生控制设计。在MJ使用史不一致的单卵双胞胎对中，双胞胎具有相同程度的 遗传责任和共享环境的许多关键方面，但在MJ暴露方面有所不同。因此，在本发明中， 未暴露的双胞胎代表了其暴露于MJ的共同双胞胎的理想对照。共孪生控制方法， 因此，这是一种节省成本和时间的方法，可以被视为对纵向研究的补充， 需要非常大的样本，以确保充分代表高暴露情况和长时间（约10 年），以取得最终成果。本研究将采用一套理论驱动的实验方法， 范式收集神经生理学，行为和认知措施，利用特定的 神经认知成分过程与（i）冲动和成瘾风险（反应 抑制、错误监控和选择性注意）和/或（ii）精神分裂症（感觉和 感觉运动门控、听觉偏差检测）。这些措施将在280名青少年和 年龄在19-36岁之间有和没有MJ使用史的年轻成年双胞胎。双胞胎将从现有的 PI和合作研究者的流行病学研究，并根据现有数据进行选择，以确保充分 发病年龄、暴露程度、禁欲时间和双胞胎一致性与 MJ使用不一致。具体目标将是：1）检查MJ使用与 神经认知功能在青少年和年轻人，并确定在多大程度上，这些 相关性取决于暴露的严重程度，MJ使用的开始年龄和禁欲时间，2） 使用双胞胎对照方法，将MJ使用的后果与脑功能的预先存在的改变分离 和认知。

Project Summary (Abstract) The overall goal of the proposed study is to delineate consequences and determinants of adolescent marijuana (MJ) consumption using the co-twin control approach. MJ is the most commonly used illicit drug with a typical onset of use in adolescence, a period of continued brain development and increased vulnerability to detrimental effects of drugs of abuse. Previous studies have established associations between chronic and/or early MJ exposure and alterations in brain function, behavior, and cognition, including deficits in self-regulation of behavior and increased impulsivity that may increase the risk for transition to the use of “harder” drugs, as well as neurocognitive dysfunctions that resemble those seen in schizophrenia. However, most existing studies relied on case-control, correlational designs precluding strong causal inferences. It remains unclear whether deficits found in MJ users represent the consequences of MJ use or, conversely, pre- existing factors of risk for MJ use. This unresolved issue represents a critical gap in knowledge that hinders the development of prevention, intervention, and treatment methods, as well as evidence-based MJ related public policy. The proposed study seeks to address this gap in knowledge through the implementation of the powerful co-twin control design. In monozygotic twin pairs discordant for MJ use history, twins have the same degree of genetic liability and share many critical aspects of environment but differ with respect to MJ exposure. Thus, the non-exposed twins represent ideal controls for their MJ-exposed co-twins. The co-twin control method is thus a cost- and time-efficient approach that can be viewed as complimentary to longitudinal studies that require very large samples to ensure sufficient representation of high-exposure cases and long time (about 10 years) to achieve conclusive results. The proposed study will use a set of theory-driven experimental paradigms to collect neurophysiological, behavioral, and cognitive measures that tap into specific neurocognitive component processes that have been linked to (i) impulsivity and addiction risk (response inhibition, error monitoring, and selective attention) and/or (ii) increased risk for schizophrenia (sensory and sensorimotor gating, auditory deviance detection). These measures will be assessed in 280 adolescent and young adult twins with and without MJ use history aged 19-36. The twins will be drawn from existing epidemiological studies of the PI and co-investigators and selected, based on existing data, to ensure sufficient variability in the age of onset, extent of exposure, length of abstinence, and twin pair concordance versus discordance for MJ use. Specific aims will be: 1) To examine associations between MJ use and neurocognitive functioning in adolescents and young adults and to determine the extent to which these associations depend on severity of exposure, age of onset of MJ use, and length of abstinence and 2) To isolate, using co-twin control approach, consequences of MJ use from pre-existing alterations in brain function and cognition.