Imaging the Effects of Intermittent Thetaburst Stimulation on Cannabis Self-Administration in Heavy Cannabis Users

项目总结/摘要 美国大麻合法化的扩大与大麻使用的增加有关， 因此，大麻使用障碍（CUD）的人数增加。复发的一个预测因素 是对药物线索的注意力偏差升高，以及在药物线索存在下认知控制减弱。 对药物线索的注意偏向与显著性网络（前扣带回）的活动增加有关 皮层和双侧前额叶皮层），背外侧前额叶皮层（DLPFC）的活动减弱， 认知控制电路当用户暴露于大麻线索。我们实验室的数据表明， 通过减弱VMPFC和奖赏回路， （策略1）与抑制性重复经颅磁刺激（rTMS）。然而，有可能， 提高后外侧前额叶皮层和认知控制回路的活性也会降低对药物提示的神经反应 （策略2-本K01的主题）。通过本K01提案中概述的研究和培训计划，我力求 评估DLPFC rTMS减弱显着网络药物线索反应性和减少大麻自我- 局这将通过施加间歇性θ爆发刺激（iTBS）来实现，iTBS是一种兴奋性刺激形式。 rTMS，在重度大麻使用者中的DLPFC。目标：K01研究项目的主要目标 是（1）确定DLPFC iTBS是否减少了住院和门诊患者的大麻自我给药 在自然生态中，和（2）确定iTBS诱导的大麻自我给药的变化是否 与显着网络药物线索反应性的变化有关。设计：60例非寻求治疗患者， 重度（几乎每天）大麻吸烟者将随机接受10次每日活动或假活动 iTBS到DLPFC。参与者将住院17天。在住院期间，大麻自我- 将在10次iTBS治疗之前和之后收集给药和fMRI数据。大麻在自然环境中的使用 将在入院前2周（基线）和出院后2周对门诊患者进行生态学测量 生态瞬时评估（EMA）首次使用的时间和恢复使用大麻的数量将 使用EMA测量并通过3次随访访视证实，其中TLFB和尿液毒理学将采集 大麻和其他毒品的使用。我们将测试积极的iTBS治疗会降低神经反应性的假设 大麻线索（目标2），并将减少大麻自我管理，无论是住院（目标1），并在自然 生态学（探索性目标）。通过这份为期5年的提案，我将获得该领域所需的关键数据集 用于CUD的治疗开发。此外，它将为我提供关键数据， 随后R01申请，其中我计划扩展该治疗开发研究线。此外，委员会认为， 该项目将极大地促进人类行为药理学和临床研究设计方面的培训， 我寻求发展成为一个独立的，跨学科的临床成瘾神经科学家。

PROJECT SUMMARY/ABSTRACT The expanding legalization of cannabis across the U.S. is associated with increases in cannabis use, and accordingly, an increase in the number of individuals with cannabis use disorder (CUD). One predictor of relapse is an elevated attentional bias to drug cues and attenuated cognitive control in the presence of drug cues. Attentional bias to drug cues is associated with elevated activity in the Salience Network (anterior cingulate cortex and bilateral anterior insula), and attenuated activity in the dorsolateral prefrontal cortex (DLPFC) and cognitive control circuitry when users are exposed to cannabis cues. Data from our laboratory demonstrates that it is possible to decrease the neural response to drug cues by attenuating the VMPFC and reward circuitry (Strategy 1) with inhibitory repetitive transcranial magnetic stimulation (rTMS). It is possible, however, that elevating activity in the DLPFC and cognitive control circuitry will also decrease the neural response to drug cues (Strategy 2 - topic of this K01). Through the research and training plan outlined in this K01 proposal, I seek to evaluate the ability of DLPFC rTMS to attenuate Salience Network drug cue reactivity and reduce cannabis self- administration. This will be achieved by applying intermittent theta burst stimulation (iTBS), a form of excitatory rTMS, to the DLPFC in heavy cannabis users. GOAL: The primary objectives of this K01 research project are to (1) determine if DLPFC iTBS decreases cannabis self-administration, both inpatient and outpatient in the natural ecology, and (2) determine if iTBS-induced changes in cannabis self-administration are related to changes in Salience Network drug cue reactivity. DESIGN: Sixty (60) non-treatment-seeking, heavy (near daily) cannabis smokers will be randomized to receive 10 daily sessions of either active or sham iTBS to the DLPFC. Participants will remain inpatient for 17 days. During the inpatient stay, cannabis self- administration and fMRI data will be collected before and after the 10 iTBS sessions. Cannabis use in the natural ecology will be measured outpatient for 2 weeks prior to admission (baseline) and for 2 weeks following discharge using Ecological Momentary Assessment (EMA). Time to first use and amount of resumed cannabis use will be measured using EMA and corroborated by 3 follow-up visits where TLFB and urine toxicology will capture cannabis and other drug use. We will test the hypotheses that active iTBS treatment will reduce neural reactivity to cannabis cues (Aim 2) and will reduce cannabis self-administration, both inpatient (Aim 1), and in the natural ecology (Exploratory Aim). Through this 5-year proposal, I will acquire a critical dataset that is needed in the field of brain stimulation for treatment development in CUD. Additionally, it will provide me with critical data for a subsequent R01 application wherein I plan to extend this line of treatment development research. Furthermore, this project will greatly facilitate the training in human behavioral pharmacology and clinical research design and analysis that I seek for advancement into an independent, interdisciplinary clinical addiction neuroscientist.