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，上个月有超过1670万使用者。虽然吸食MJ的人数每年都在持续上升，但第一次经常使用MJ的平均年龄在持续下降，认为使用MJ有风险或危险的个人比例也在下降。鉴于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。一些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、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者的白质微结构测量方面的变化。然而，很少有人直接研究MJ使用年龄与这些措施的神经生物学影响，或者在长时间戒断后功能恢复的可能性。我们最近的工作强调了MJ使用的年龄对MJ使用频率和大小的影响，并发现1)每周吸烟的总数和MJ的数量（克数）显著增加，2)执行功能显著下降，3)早期和晚期吸烟者的大脑激活模式发生改变。我们还报道了前额白质扩散张量成像（DTI）测量的变化，这与冲动性测量相关。我们提出了一个新的实验设计，研究慢性重度MJ吸烟者首次定期使用MJ的年龄与执行功能下降、神经功能改变和微结构白质测量的关系，这些慢性重度MJ吸烟者被定义为早发（16岁之前第一次定期使用）或晚发（16岁之后第一次定期使用）。我们还将通过检查一组戒烟至少2年的重度MJ吸烟者和一组非MJ吸烟者来检查功能恢复的可能性。我们将应用BOLD功能磁共振成像和DTI来测量慢性重度MJ使用的年轻成人受试者（18-30岁）的脑激活和白质纤维束完整性的差异，这些受试者开始吸烟较早、较晚或曾经是重度MJ吸烟者或对照者，并进行一系列执行功能的神经认知测量，以及临床状态、冲动和个性的测量。提出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，这些信息可能最终确定MJ滥用或依赖易感性的生物标志物。此外，关于长期禁欲后功能恢复的数据可用于修改当前的公共服务信息并提高公众意识；“这是你的大脑，这是你吸毒后的大脑”的信息可以修改为包含希望的信息——“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的治疗策略。

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. .