Deep rTMS modulating insula synaptic density and smoking behavior in schizophrenia

深度 rTMS 调节精神分裂症患者的岛叶突触密度和吸烟行为

• 批准号: 10710181
• 负责人: Anissa Abi-Dargham
• 金额: $ 35.86万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710181
• 关键词: Address; Aftercare; Behavior assessment; Behavioral; Benchmarking; Binding; Biological; Brain; Brain imaging; Cephalic; Cigarette; Clinical; Clinical Trials; Clinical assessments; Data; Decision Making; Disease; Frequencies; Functional Magnetic Resonance Imaging; Future; General Population; Goals; High Prevalence; Hour; Human; Insula of Reil; Joints; Knowledge; Laboratories; Link; Measurement; Measures; Mediating; Mental disorders; Modeling; Multi-Institutional Clinical Trial; Occipital lobe; Outcome Measure; Pathologic; Pathology; Patients; Phase; Positron-Emission Tomography; Prefrontal Cortex; Proteins; Protocols documentation; Psychoses; Research Design; Rest; Role; Schizophrenia; Self Administration; Signal Transduction; Smoker; Smoking; Smoking Behavior; Specific qualifier value; Symptoms; Synapses; Synaptic Vesicles; Synaptic plasticity; Syndrome; Testing; Therapeutic; Therapeutic Effect; Tobacco; Tobacco Use Disorder; Tobacco smoking behavior; Transcranial magnetic stimulation; Translating; Work; cigarette smoke; cigarette smoking; cohort; comorbidity; conventional therapy; craving; density; electric field; high reward; high risk; imaging study; in vivo; information processing; mortality; multimodality; neural; neural circuit; neurobiological mechanism; neuromechanism; novel; psychiatric comorbidity; psychotic symptoms; radiotracer; repetitive transcranial magnetic stimulation; smoking cessation; smoking initiation; smoking prevalence; success; therapeutic target

PROJECT SUMMARY Patients with schizophrenia (SCZ) have a higher prevalence of smoking than the general population and respond poorly to conventional treatments. This is of great concern, as cigarette smoking contributes to earlier mortality in SCZ and it can exacerbate ongoing psychotic symptoms. In 2020, deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the H4 coil – also termed the HADD coil – was given FDA clearance for smoking cessation in tobacco use disorder (TUD), based on results from a large, multisite clinical trial. Our preliminary data indicate that this emerging neurostimulation approach may also hold promise for smoking disruption among patients with SCZ. However, there is a critical need for a better understanding of the underlying neurobiological mechanisms of the treatment. There is also a more fundamental scientific question pertaining to whether TMS in fact rewires the underlying brain mechanisms that it purports to target with the stimulation; the ability of TMS to change brain circuity in vivo has been widely assumed, but the mechanism of action remains an open question. The overall aims of this R61/R33 application are to test whether dTMS is capable of inducing plasticity (i.e., changing synaptic density) and modifying functional circuits of its putative (insula) target in patients, and to test whether these cellular and neural changes drive a potential therapeutic signal for smoking disruption in SCZ. The R61 phase will be a proof-of-concept in 16 patients, testing if 15 sessions of dTMS over 3 weeks (versus sham) to the insula and prefrontal cortex: (1) modifies insula synaptic density, measured with positron emission tomography (PET) and [11C]UCB-J, a well-validated radiotracer that binds to a synaptic vesicle protein, SV2A; and (2) disrupts smoking behavior, measured as the choice to self-administer tobacco in a laboratory model of tobacco choice. If during the R61 phase we observe a change to insula synaptic density and tobacco self-administration with clinically-meaningful effect sizes (benchmarks defined a priori), we will proceed to the R33 phase of the study. During the R33 phase, we will study 22 additional smokers with SCZ (totaling 38 patients over the entire R61/R33 study). Our first goal during the R33 phase of the study will be to confirm statistical reliability of the dTMS effects on synaptic density and self-administration. Our additional goals during the R33 phase will be test the effects of dTMS on insula network connectivity, using resting-state fMRI; and to test whether dTMS-induced changes to the respective PET and fMRI measurements correlate with dTMS-induced changes to tobacco self-administration following treatment. Results of this study have the potential to inform future clinical trials of dTMS for smoking cessation in SCZ, and to increase basic knowledge into the neural mechanisms of therapeutic neurostimulation.

项目总结 精神分裂症(SCZ)患者的吸烟率高于普通人群，并对 对常规治疗效果不佳。这一点非常令人担忧，因为吸烟会导致更早的死亡。 在SCZ中，它会加剧持续的精神症状。2020年，深重复经颅磁化 使用H4线圈高频刺激(DTMS)岛叶和前额叶皮质--也称为HADD COIL-根据一项研究的结果，FDA批准了烟草使用障碍(TUD)的戒烟 大型、多点临床试验。我们的初步数据表明，这种新兴的神经刺激方法也可能 承诺在SCZ患者中停止吸烟。然而，迫切需要一种更好的 了解治疗的潜在神经生物学机制。还有一个更根本的 关于TMS是否真的改变了它声称的潜在大脑机制的科学问题 靶点与刺激；TMS在体内改变大脑回路的能力已被广泛假设，但 行动机制仍然是一个悬而未决的问题。此R61/R33应用程序的总体目标是测试 DTMS能够诱导可塑性(即改变突触密度)，并改变其功能回路 假设的(岛)靶，并测试这些细胞和神经的变化是否驱动潜在的 SCZ戒烟治疗信号。R61阶段将在16名患者中进行概念验证，测试 如果在3周内对脑岛和前额叶皮质进行15次DTMS(与假手术相比)：(1)修改脑岛 用正电子发射断层扫描(PET)和[11C]UCB-J测量的突触密度，得到了很好的验证 与突触囊泡蛋白SV2a结合的放射性示踪剂；以及(2)干扰吸烟行为，测量为 在烟草选择的实验室模型中自我给药烟草。如果在R61阶段期间我们观察到 脑岛突触密度的改变和烟草自我给药与临床有意义的效应大小 (事先定义了基准)，我们将进入研究的R33阶段。在R33阶段，我们将 研究另外22名患有SCZ的吸烟者(在整个R61/R33研究中总共有38名患者)。我们的第一个目标是 R33阶段的研究将确认DTMS对突触密度和 自治。我们在R33阶段的其他目标将是测试DTMS对半岛网络的影响 连接性，使用静息状态的功能磁共振成像；并测试DTMS是否导致相应的PET和 功能磁共振成像测量与DTMS诱导的烟草治疗后自我给药的变化相关。 这项研究的结果有可能为未来在SCZ进行DTMS戒烟的临床试验提供参考，以及 增加对治疗性神经刺激的神经机制的基础知识。