Recovery of reward function in nicotine use disorder using a combination of robotics, electrophysiology, and TMS

项目总结/摘要 物质使用障碍（SUD）与奖励相关的前中扣带回异常有关 大脑皮层（MCC）是一个与目标导向决策密切相关的大脑区域。我们最近的发现表明， 奖励积极性，一种电生理信号，被认为是MCC对奖励的敏感性的指标， SUD异常：滥用物质的人对金钱奖励产生了迟钝的奖励积极性，但 经过一夜的药物戒断，奖励积极性的大小是由药物相关的增强， 奖励这种适应不良的过程被认为是偏置的MCC行动选择机制，有利于行为 最终汇聚在吸毒上重要的是，我们提供了令人信服的证据，表明FDA批准了 治疗抑郁症，10赫兹经颅磁刺激（TMS）的前额叶皮层，可以恢复 MCC在问题物质使用者中的奖励功能，并进一步逆转奖励的大小 戒烟者的金钱和药物相关奖励之间的偏差。这些重要发现表明， (i)奖励阳性是SUD严重程度和治疗功效高度敏感的生物标志物，以及（ii）调节 MCC与TMS可以纠正维持SUD的异常奖励过程。然而，考虑到 和用于针对MCC的常规TMS方法的可变性，MCC的最佳TMS方案 调制目前是未知的。因此我们建议使用一种叫做机器人辅助的尖端技术 图像引导TMS（Ri-TMS），以确定旨在恢复 以最高精度测量SUD中的MCC。在UG 3阶段，我们将建立最佳的Ri-TMS 在依赖性条件下， 吸烟者和健康对照组。在研究1中，我们将利用强大的定量神经成像方法来构建 刺激目标的基础上，前额叶的结构，功能，并与MCC的连接，并测试的目标 有效性，以调节奖励积极性，决策的表现，并渴望分数在弃权 吸烟者（目标1）。在目标2中，我们将评估各种脉冲方案增强和抑制 在戒烟者中，对金钱和香烟奖励的积极性。目标协议 达到我们的Go标准并在这些目标中具有最大效应量的药物将进入UH 3阶段。在 目标3，我们将应用我们的候选Ri-TMS协议来增强对金钱奖励的奖励积极性， 抑制戒烟者对药物相关奖励的奖励积极性。我们还将评估 对决策和渴望分数的影响。在目标4中，我们将评估Ri-TMS的长期效果 在多个关于奖励积极性、决策和吸烟行为（渴望， 戒烟和香烟估价）。我们的长期目标是提供治疗方案， 神经认知治疗选择，这可能会增加物质使用者在治疗中的成功， 禁欲，以及实现更广泛的生活目标。

PROJECT SUMMARY/ABSTRACT Substance use disorders (SUDs) are associated with reward-related abnormalities of the anterior midcingulate cortex (MCC), a brain region strongly implicated in goal-directed decision-making. Our recent findings show the reward positivity, an electrophysiological signal believed to index sensitivity of the MCC to rewards, to be abnormal in SUDs: People who abuse substances produce a blunted reward positivity to monetary rewards, but following an overnight period of drug abstinence, the size of the reward positivity is enhanced by drug-related rewards. This maladaptive process is thought to bias the MCC action-selection mechanism to favor behaviors that ultimately converge on drug use. Importantly, we provided compelling evidence that an FDA approved treatment for depression, 10-Hz transcranial magnetic stimulation (TMS) to the prefrontal cortex, can recover the reward function of the MCC in problematic substance users, and further, reverse the magnitude of the reward bias between monetary and drug-related rewards in abstained smokers. These important findings suggest that (i) the reward positivity is a highly sensitive biomarker of SUD severity and treatment efficacy and (ii) modulating MCC with TMS may correct the aberrant reward processes that sustain SUDs. However, given the limitations and variability of conventional TMS methods used to target the MCC, the optimal TMS protocol for MCC modulation is currently unknown. We therefore propose to use a cutting-edge technology called robot-assisted image-guided TMS (Ri-TMS) to identify the optimal TMS protocol aimed to restore the reward function of the MCC in SUDs with the highest level of precision. In the UG3 phase, we will establish the optimal Ri-TMS parameters needed to maximize excitatory effects on reward-related MCC electrophysiology in dependent smokers and healthy controls. In Study 1, we will utilize powerful quantitative neuroimaging methods to construct stimulation targets based on prefrontal structure, function, and connectivity with MCC, and test the targets efficacy to modulate the reward positivity, decision-making performance, and craving scores in abstained smokers (Aim 1). In Aim 2, we will evaluate the efficacy of various pulse protocols to enhance and suppress the reward positivity to monetary and cigarette rewards, respectively, in abstained smokers. The targeting protocol achieving our Go criteria and with the largest effect size across these aims will advance to the UH3 phase. In Aim 3, we will apply our candidate Ri-TMS protocol to enhance the reward positivity to monetary rewards and suppress the reward positivity to drug-related rewards in abstinent smokers. We will also assess the protocols impact on decision-making and craving scores. In Aim 4, we will assess the long-term effects of the Ri-TMS across multiple Ri-TMS sessions on reward positivity, decision-making, and smoking behavior (craving, abstinence, and cigarette valuation). Our long-term goal is to provide treatment programs with a more relevant neurocognitive treatment option, which may increase substance users' success in treatment, maintaining abstinence, as well as achieving broader life goals.