Marijuana: Neurobiologic Correlates of Age of Onset

描述（由申请人提供）：大麻（MJ）仍然是使用最广泛的非法物质，过去一个月有超过1670万人使用。虽然吸食MJ的人数每年持续上升，但首次定期使用MJ的平均年龄继续下降，认为使用MJ有风险或危险的人的比例也在下降。考虑到正在进行的关于大麻合法化和医用大麻使用的辩论，这也许并不奇怪。几项研究报告了慢性重度MJ吸烟者在认知表现的额叶/执行测量、通过功能性磁共振成像（fMRI）测量的皮质活动模式以及相对于非吸烟对照受试者的白色微结构测量上的改变。然而，很少有人直接研究开始使用MJ的年龄与这些措施相结合的神经生物学影响，或者在长时间禁欲后功能恢复的可能性。我们最近的工作强调了MJ使用开始的年龄对MJ使用频率和幅度的影响，并发现1）每周吸烟的总人数和MJ吸烟量（克）显着增加，2）执行功能显着下降，3）早发与晚发吸烟者的大脑激活模式发生改变。我们还报道了额叶白色物质的扩散张量成像（DTI）测量值的改变，这与冲动性测量值相关。我们提出了一种新的实验设计，探讨在何种程度上发病的年龄首次定期使用MJ与递减的执行功能，改变神经功能和微观结构的白色物质措施在慢性重度MJ吸烟者被定义为早发性（16岁之前的第一次定期使用）或晚发性（16岁之后的第一次定期使用）。我们还将通过检查一组戒烟至少2年的既往重度MJ吸烟者和一组非MJ吸烟对照受试者来检查功能恢复的潜力。我们将应用BOLD功能磁共振成像和弥散张量成像来测量年轻成年受试者（18-30岁）的大脑激活和白色纤维束完整性的差异，这些受试者长期大量使用MJ，开始吸烟的时间较早，较晚或以前是大量使用MJ的吸烟者或对照组，并实施一系列执行功能的神经认知测量，以及临床状态，冲动性和个性的测量。拟议的一系列实验利用成像技术和神经认知任务的创新组合来收集关键信息，这些信息最终可以确定MJ滥用或依赖的脆弱性生物标志物。此外，关于长期禁欲后功能恢复的数据可用于修改目前的公共服务信息，提高公众认识;“这是你的大脑，这是你吸毒后的大脑”的信息可加以修改，以包括一个希望的信息-“这是你停止吸毒后的大脑”，这可能有助于那些认为损害已经造成的人制定治疗战略。.

DESCRIPTION (provided by applicant): Marijuana (MJ) remains the most widely used illicit substance, with more than 16.7 million past month users. While the number of people who smoke MJ continues to rise each year, the average age of first regular use continues to fall, as does the percentage of individuals who perceive the use of MJ as risky or dangerous. This is perhaps not surprising in light of the ongoing debate regarding legalizing marijuana and the use of medical marijuana. Several investigations have reported alterations in chronic, heavy MJ smokers on frontal/ executive measures of cognitive performance, patterns of cortical activity as measured by functional magnetic resonance imaging (fMRI), and on measures of white matter microstructure relative to non-smoking control subjects. However, few have directly examined the neurobiologic impact of age of onset of MJ use in conjunction with these measures or the possibility of recovery of function following an extended period of abstinence. Our recent work highlighted the impact of age of onset of MJ use on both frequency and magnitude of MJ use, and found 1) significantly higher total number of smokes and amount (grams) of MJ smoked per week, 2) significant decreases in executive function and 3) alterations in brain activation patterns in early vs. late onset smokers. We have also reported alterations in diffusion tensor imaging (DTI) measures of frontal white matter which correlated with measures of impulsivity. We propose a novel experimental design that examines the extent to which age of onset of first regular MJ use is associated with decrements in executive function, alterations in neural function and microstructural white matter measures in chronic heavy MJ smokers who are defined as early onset (1st regular use prior to age 16) or late onset (1st regular use after age 16). We will also examine the potential for recovery of function by examining a group of former heavy MJ smokers who have abstained from use for a minimum of 2 years and a group of non-MJ smoking control subjects. We will apply BOLD fMRI and DTI to measure differences in brain activation and white matter fiber tract integrity in young adult subjects (18-30 years) with chronic, heavy MJ use who started smoking early, late or are former heavy MJ smokers or controls, and administer a battery of neurocognitive measures of executive function, as well as measures of clinical state, impulsivity, and personality. The proposed series of experiments utilizes an innovative combination of imaging techniques and neurocognitive tasks to collect key information that could ultimately identify biomarkers for vulnerability to MJ abuse or dependence. In addition, data regarding recovery of function following extended abstinence could be used to modify current public service messages and increase public awareness; the "this is your brain, this is your brain on drugs" message could be amended to include a message of hope - "and this is your brain after you stop using drugs" which may facilitate treatment strategies for those under the impression that the damage is already done. .