Enhancing Relapse Prevention with rTMS: Dose-Response Parameters for Smoking Cessation

项目摘要/摘要。烟草使用仍然是导致死亡和疾病的一个重要原因。大多数吸烟者 想不干了。超过一半的人每年都会尝试戒烟，但超过90%的人在12个月内复发，选择 立即加强吸烟对戒烟的长期益处。创新的预防方法 需要故态复萌。竞争神经行为决策系统(CNDS)模型假设决策 是由位于前额叶皮质(PFC)的执行功能网络之间的相互作用驱动的； 位于边缘和边缘旁脑区的冲动网络。行为经济学，神经成像， 神经生物学和神经行为研究支持这一概念。更大的PFC活动与 更多的自制力，更谨慎的选择，降低延迟打折率，提高禁酒率。 背外侧前额叶皮质(DLPFC)是PFC中的一个功能节点，在执行中起着重要的作用 功能网络。我们建议，增加DLPFC的活动将减少再次吸烟。 高频重复经颅磁刺激(RTMS)选择性地调节神经元的活动。在一个 随机、双盲、假对照试验，我们发现8次治疗(1次/天)，活动的或假的20赫兹rTMS(900 脉冲)的左侧DLPFC结合认知行为干预(CBI)以增加潜伏期至 复发率、短期戒断率和延迟折扣复发的平均/中值潜伏期为活跃 RTMS分别为45.2天和33.5天，而假手术组分别为20.5天和8天。活动的rtms减少了 复发的相对风险是对照组的3倍(RR为0.29，CI为0.10-0.76，p=0.01)。积极的rTMS也增加了12周的禁欲 (50%比15.4%，p=0.05)，降低了延迟贴现率，并增加了CBI的摄入量。而当 这一证据令人信服，在进行长期疗效试验之前，必须确定最佳给药策略 是可以进行的。该项目的目标是确定20赫兹rTMS的剂量策略， 以最少的不良影响产生最好的长期禁欲结果。 我们将使用完全交叉、双盲、随机析因设计，包括三个因素：持续时间(刺激 天：8天、12天和16天)，强度(每天900或1800次脉冲)，以及针对每种情况的假对照。伪装 对照将允许对照组计算效果大小并考虑与非特定治疗相关的因素 效果。结果将包括复发的潜伏期、12周和24周的戒断率、延迟 贴现率、认知行为技能获得和潜在的不良影响(例如， 由于参与者负担而导致的合规性)。目标一将检验刺激持续时间和强度的影响 关于有动机的吸烟者的所有结果(n=258)。目标二将确定最有希望的给药策略 通过系统地平衡效果大小和不良影响。建立剂量-反应关系是 对于开发rTMS作为烟草依赖的潜在治疗方法至关重要。这一创新项目将 显著推进了rTMS在烟草依赖治疗中的临床应用研究。

Project Summary / Abstract. Tobacco use remains a significant cause of death and disease. Most smokers want to quit. Over half make a quit attempt every year, but over 90% relapse within 12 months, choosing the immediate reinforcement of smoking over the long-term benefits of quitting. Innovative methods for preventing relapse are needed. The Competing Neurobehavioral Decision Systems (CNDS) model posits that decisions are driven by interactions between the executive function network, located in the prefrontal cortex (PFC); and the impulsive network, located in limbic and paralimbic brain regions. Behavioral economic, neuroimaging, neurobiological, and neurobehavioral studies support this conceptualization. Greater PFC activity is linked with more self-control, more prudent choices, decreased delay discounting rates, and increased abstinence rates. The dorsolateral prefrontal cortex (DLPFC), a functional node in the PFC, has a significant role in executive function network. We propose that increasing activity in the DLPFC will reduce relapse to smoking. High frequency repetitive transcranial magnetic stimulation (rTMS) selectively modulates neuronal activity. In a randomized, double-blind, sham-controlled trial, we found 8 sessions (1/day), active or sham 20Hz rTMS (900 pulses) of the left DLPFC combined with a cognitive-behavioral intervention (CBI) to increase latency to relapse, short-term abstinence rates, and delay discounting The mean/median latency to relapse for active rTMS was n=45.2 and n=33.5 days compared with n=20.5 and n=8 days for sham. Active rTMS reduced the relative risk of relapse 3-fold (RR 0.29, CI 0.10-0.76, p =.01). Active rTMS also increased 12-week abstinence rates (50% vs. 15.4%, p=.05), decreased delay discounting rates, and increased the uptake of the CBI. While this evidence is compelling, an optimal dosing strategy must be determined before a long-term efficacy trial can be conducted. The goal of this project is to determine a dosing strategy for 20Hz rTMS that will produce the best long-term abstinence outcomes with the fewest undesirable effects. We will use a fully crossed, double-blinded, randomized factorial design with three factors: duration (stimulation days: 8, 12, and 16), intensity (900 or 1800 pulses per day), and a sham control for each condition. The sham control will allow for a comparison group to calculate effect sizes and account for non-specific treatment-related effects. Outcomes will include latency to relapse, 12 and 24-week point prevalence abstinence rates, delay discounting rates, cognitive-behavioral skills acquisition, and potential undesirable effects (e.g., non- compliance due to participant burden). Aim One will examine the effects of stimulation duration and intensity on all outcomes among motivated smokers (n=258). Aim Two will identify the most promising dosing strategy by systematically balancing effect sizes and undesirable effects. Establishing a dose-response relationship is critical to developing rTMS as a potential treatment for tobacco dependence. This innovative project will significantly advance research in the clinical application of rTMS in the treatment for tobacco dependence.