A novel therapeutic application of closed-loop neuromodulation of the brain reward system in nicotine use disorder

项目总结/摘要 几十年的动物模型告诉我们，成瘾确实是一种神经回路失调的疾病。 然而，目前还没有针对人类患者的基于回路的生物标志物或治疗方法。经颅 磁刺激（TMS）有可能从根本上改变物质使用障碍（SUD） 治疗。目前，在左背外侧被动应用10 Hz重复TMS（rTMS）的多个会话 前额叶皮层（DLPFC）20至30分钟（2000-3000脉冲）最近已被用于治疗 尼古丁使用障碍（NUD），特别是减少烟瘾和香烟消费。有人建议 所观察到的10-Hz前额叶rTMS对中皮质边缘奖赏回路的调制可能介导了 TMS在NUD和其他物质相关疾病中的治疗效果。然而，在临床实践中，一半- 一周5天一小时的TMS治疗可能需要数周才能完全有效，并且其治疗效果仍然存在 有限，个体差异很大。因此，该提案的主要目标是开发一个更快， 更集中的TMS方案，可以减少治疗时间长度并提高其临床效率 通过更精确地识别和主动瞄准奖励电路和近端功能。根据最近 TMS与EEG相结合的进展，允许TMS协议直接由EEG信号控制 （闭环调制），我们的目标是测试一种新的闭环TMS干预能够实时跟踪， 尼古丁依赖性大鼠中不同的奖赏相关的中扣带皮层（MCC）活动的调节 个体这种方法潜在地提供了空间上、时间上和认知上的双向治疗。 准确我们的实验室和其他实验室已经在额叶部位（额叶）的θ波段中识别出振荡EEG信号。 中线θ，FMT），伴随多巴胺能奖励预测错误，并在NUD和 其他物质使用障碍。由于EEG中的振荡的相位可以反映局部处理，因此， TMS脉冲的精确周期在这些节奏应该有直接的神经，行为和计算 从而改善临床效果。因此，我们开发了一种新型的闭环系统， 实时跟踪这些θ振荡，并利用这些信息来控制TMS的输送。这项建议 试图测试这些调节MCC奖励的协议的神经，计算，行为功效 功能（目标1），然后测试精确触发TMS是否与FMT的峰或谷同步 振荡会暂时减少暴露于尼古丁中的吸烟线索所引发的主观渴望， 成人吸烟者（目标2）。这个项目是创新的，因为它使可能性， 探测MCC神经反应模式，并在奖励导向期间进行TMS操作 行为拟议的研究是重要的，因为科学知识将提供最佳做法， 选择刺激参数，这将促进对所涉及的特定神经认知过程的治疗 在NUD和其他物质相关疾病中。

PROJECT SUMMARY/ABSTRACT Decades of animal models have taught us that addiction is, indeed, a disorder of dysregulated neural circuits. However, there are currently no circuit-based biomarkers or treatments for human patients. Transcranial magnetic stimulation (TMS) has the potential to radically transform how substance use disorders (SUDs) are treated. Presently, multiple sessions of 10-Hz repetitive TMS (rTMS) passively applied over the left dorsal lateral prefrontal cortex (DLPFC) for 20 to 30 min (2000–3000 pulses) has recently been adopted for the treatment of nicotine use disorder (NUD), particularly reducing craving and cigarette consumption. It has been suggested that the observed modulation of the mesocorticolimbic reward circuitry by 10-Hz prefrontal rTMS might mediate the therapeutic effects of TMS in NUD and other substance-related disorders. However, in clinical practices, a half- hour TMS therapy 5 days a week could take weeks to be fully effective, and its therapeutic efficacy remains limited and varies greatly across individuals. Thus, the primary goal of this proposal is to develop a faster and more concentrated TMS protocol that may reduce the treatment time length and increase its clinical efficiency by more precisely identifying and actively targeting the reward circuitry and proximal functions. Building on recent advances in combining TMS with EEG, which allow TMS protocols to be directly controlled by the EEG signal (closed-loop modulation), we aim to test a novel close-loop TMS intervention capable of real-time tracking and modulation of distinct episodes of reward-related midcingulate cortex (MCC) activity in nicotine-dependent individuals. This approach potentially offers bidirectional treatments that are spatially, temporally, and cognitively precise. Our lab and others have identified oscillatory EEG signals in the theta band over frontal sites (frontal midline theta, FMT) that accompany dopaminergic reward prediction errors, and that are altered in NUD and other substance use disorders. Since the phase of oscillations in the EEG can reflect local processing, the timing of TMS pulses to precise periods during these rhythms should have direct neural, behavioral, and computational effects, and thereby improved clinical outcomes. Thus, we have developed a novel closed-loop system capable of tracking these theta oscillations in real-time and using that information to control delivery of TMS. This proposal seeks to test the neural, computational, behavioral efficacy of these protocols for modulating MCC reward function (Aim 1), and then test whether precisely triggering TMS synchronized with the peak or trough of FMT oscillations would temporarily reduce the subjective craving triggered by exposure to smoking cues in nicotine- dependent adult smokers (Aim 2). This project is innovative because it enables the possibility to instantaneously probe the MCC neural response pattern and to deliver TMS manipulations as they occur during reward-directed behavior. The proposed research is significant, because the scientific knowledge will provide best practices to choose stimulation parameters that will advance the treatment for particular neurocognitive processes involved in both NUD and other substance-related disorders.