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

项目摘要/摘要 物质使用障碍(Suds)与奖赏相关的前中扣带核异常有关。 大脑皮质(MCC)，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， 奖励正性，一种被认为指示MCC对奖励的敏感性的电生理信号， 肥皂水异常：滥用药物的人会对金钱奖励产生迟钝的积极奖励，但 在戒毒一夜之后，与毒品有关的奖励正性程度会增强。 奖励。这种不适应的过程被认为使MCC的行动选择机制偏向于支持行为 最终集中在吸毒问题上。重要的是，我们提供了令人信服的证据，表明FDA批准了 对抑郁症的治疗，对前额叶皮质进行10赫兹经颅磁刺激(TMS)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幅度 戒烟者的金钱奖励和与药物有关的奖励之间的偏差。这些重要的发现表明 (I)奖赏阳性是反映SUD严重程度和治疗效果的高度敏感的生物标记物，以及(Ii)调节 MCC联合TMS可纠正维持SUDS的异常奖赏过程。然而，考虑到这些限制 以及用于针对MCC的传统TMS方法的可变性，MCC的最佳TMS协议 目前尚不清楚调制方式。因此，我们建议使用一种名为机器人辅助的尖端技术 图像引导TMS(Ri-TMS)确定最佳TMS方案，旨在恢复TMS患者的奖赏功能 肥皂中的MCC具有最高的精确度。在UG3阶段，我们将建立最优的Ri-TM 最大限度地兴奋依赖大鼠奖赏相关MCC电生理所需的参数 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 基于前额叶结构、功能和与MCC的连通性的刺激靶点，并对靶点进行测试 戒酒对奖励积极性、决策绩效和渴求得分的调节作用 吸烟者(目标1)。在目标2中，我们将评估各种脉冲方案的疗效，以增强和抑制 在戒烟者中，积极的奖励分别是金钱奖励和香烟奖励。目标协议 达到我们的GO标准，并在这些目标上实现最大的影响规模，将进入UH3阶段。在……里面 目标3，我们将应用我们的候选Ri-TMS协议来增强金钱奖励和 抑制戒烟者对药物相关奖励的奖励正性。我们还将评估协议 对决策和渴望得分的影响。在目标4中，我们将评估Ri-TMS的长期影响 在多个Ri-TMS会议上讨论奖励积极性、决策和吸烟行为(渴望， 禁欲和香烟估值)。我们的长期目标是为治疗方案提供更相关的 神经认知治疗选项，这可能会增加药物使用者的治疗成功率，维持 禁欲，以及实现更广泛的人生目标。

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.