Transcranial Magnetic Stimulation and Tobacco Use Disorder: A Network-Level Approach with Attention to Sex as a Biological Variable

摘要 吸烟仍然是美国和世界范围内可预防的主要死亡原因，导致近 全球十分之一的死亡病例。大多数吸烟者(70%)想戒烟，但大多数都不成功。 因此，迫切需要新的方法来帮助人们戒烟，而且男性之间的效果可能会有所不同 以及女性，她们的大脑差异已经被记录在案。在受体水平上，吸烟 诱导多巴胺在男性的腹侧纹状体释放，但在女性的背侧纹状体，也与 降低男性纹状体多巴胺D2型受体的可获得性，并增加中脑多巴胺D2型 受体在女性中的可用性。在网络层面，我们实验室的初步数据表明， 吸烟的渴望程度在女性之间的大规模网络之间耦合，而不是男性，在其中 相反，吸烟与脑岛连通性的变化有关。此应用程序以这些最新发现为基础 测试一种新的潜在戒烟辅助手段--重复经颅磁刺激(RTMS)的有效性， 一种非侵入性的脑刺激技术，特别关注性别作为一个生物变量。这包括 两个相辅相成的目标：分别测试rTMS对男性和男性吸烟临床特征的影响 妇女，并在这样做的过程中，提供额外的培训，以促进向独立的过渡 专门研究男性和女性吸烟者大脑差异的研究人员。这将通过以下两个途径实现 实验。在第一个实验中(K99阶段)，男性和女性吸烟者将接受rTMS刺激 靶向背外侧前额叶皮质(DlPFC)、辅助运动区(SMA)、后顶叶皮质 (PPC)，或假的，将评估rTMS对每个区域在渴求、戒断和影响方面的效果。这个 这些目标中最好的(即，在刺激产生最大程度的渴望、戒断和 消极影响)将被选为实验2(R00阶段)，其中将进行13次rTMS。 渴望，戒断，影响，每天吸烟，依赖程度将在七天前进行评估， 每天一次，并在rTMS后六周内每天一次。将评估静止状态的功能连通性 以提供有关男性和女性rTMS疗效基础的机制信息 女性吸烟者。K99阶段将在加州大学洛杉矶分校进行，主任将提供支持和培训 神经调节部门，这个项目的合作者，和另外两个在吸烟方面有专长的合作者 研究。这个合作者团队将提供有关rTMS和吸烟研究的培训。一个 除教师导师外，单独的团队还将提供专业发展反馈和指导 每季度召开一次会议。总而言之，这种方法将实现项目的具体目标：1.开发 RTMS作为治疗干预的专业知识；2.评估rTMS针对SMA、PPC和 DLPFC对渴求、戒断和情感的影响；3.用fMRI测量rTMS对RSFC的影响；4.测量 RTMS对随后吸烟和依赖的影响。

ABSTRACT Smoking remains the leading preventable cause of death in the United States and worldwide, causing nearly one in ten deaths worldwide. The majority (70%) of smokers want to quit, yet most are unsuccessful. Therefore, new approaches to help people quit are urgently needed, and may differ in efficacy between men and women, in whom a number of brain differences have been documented. At the receptor level, smoking induces dopamine release in the ventral striatum in men, but the dorsal striatum in women, and is also linked to decreased striatal dopamine D2-type receptor availability in men, and increased midbrain dopamine D2-type receptor availability in women. At the network level, preliminary data from our laboratory has linked the relief of cigarette craving to the extent of coupling between large-scale networks in women, but not men, in whom smoking instead is linked to changes in insula connectivity. This application builds on these recent findings to test the efficacy of a novel potential smoking cessation aid, repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique, with special attention to sex as a biological variable. This includes two complementary objectives: To test the effect of rTMS on clinical features of smoking separately in men and women, and in so doing, provide additional training that will facilitate the transition to independence as a researcher specializing in brain differences in male and female smokers. This will be achieved through two experiments. In the first experiment (K99 phase) male and female smokers will receive rTMS stimulation targeting the dorsolateral prefrontal cortex (dlPFC), supplementary motor area (SMA), posterior parietal cortex (PPC), or sham, and the effect of rTMS to each region on craving, withdrawal, and affect will be evaluated. The best of these targets (i.e., where stimulation produced the greatest decrease in craving, withdrawal, and negative affect) will be selected for Experiment 2 (R00 phase), in which 13 sessions of rTMS will be performed. Craving, withdrawal, affect, cigarettes per day, and level of dependence will be evaluated seven days before, daily throughout, and daily for six weeks following rTMS. Resting state functional connectivity will be evaluated before and after rTMS to provide mechanistic information regarding the basis of rTMS efficacy in male and female smokers. The K99 phase will take place at UCLA with support and training from the director of the Neuromodulation Division, a collaborator on this project, and two other collaborators with expertise in smoking research. This team of collaborators will provide training with respect to rTMS and smoking research. A separate team will provide professional development feedback and guidance in addition to the faculty mentor through quarterly meetings. Together, this approach will achieve the project's specific aims to: 1. Develop expertise in rTMS as a therapeutic intervention; 2. Measure the effect of rTMS targeting the SMA, PPC, and dlPFC on craving, withdrawal, and affect; 3. Measure the effect of rTMS on RSFC with fMRI; and 4. Measure effects of rTMS on subsequent smoking and dependence.