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: 10494515
• 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/10494515
• 关键词: Address; Aftercare; Behavior assessment; Behavioral; Benchmarking; Binding; Biological; Brain; Brain imaging; 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; Sum; Symptoms; Synapses; Synaptic Vesicles; Synaptic plasticity; Syndrome; Testing; Therapeutic; Therapeutic Effect; Time; Tobacco; Tobacco Use Disorder; Transcranial magnetic stimulation; Translating; Work; base; 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 circuit; neurobiological mechanism; neuromechanism; novel; psychotic symptoms; radiotracer; relating to nervous system; repetitive transcranial magnetic stimulation; smoking cessation; smoking prevalence; success; therapeutic target; treatment group

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.

项目概要 精神分裂症 (SCZ) 患者的吸烟率高于一般人群，并且对吸烟有反应 对传统治疗效果不佳。这是一个非常令人担忧的问题，因为吸烟会导致早期死亡 在 SCZ 中，它会加剧持续的精神病症状。 2020年，深度重复经颅磁 使用 H4 线圈对岛叶和前额皮质进行高频刺激 (dTMS) – 也称为 HADD 线圈 – 根据一项研究结果，获得 FDA 批准用于烟草使用障碍 (TUD) 戒烟 大型、多中心临床试验。我们的初步数据表明，这种新兴的神经刺激方法也可能 有望阻止 SCZ 患者吸烟。然而，迫切需要一个更好的 了解治疗的潜在神经生物学机制。还有一个更根本的 有关 TMS 是否确实重新连接其声称的潜在大脑机制的科学问题 刺激目标；人们普遍认为 TMS 能够改变体内大脑回路，但 作用机制仍然是一个悬而未决的问题。该 R61/R33 应用程序的总体目标是测试是否 dTMS 能够诱导可塑性（即改变突触密度）并修改其功能电路 患者的假定（岛叶）目标，并测试这些细胞和神经变化是否驱动潜在的 SCZ 中吸烟中断的治疗信号。 R61 阶段将在 16 名患者中进行概念验证，测试 如果在 3 周内对岛叶和前额皮质进行 15 次 dTMS（与假手术相比）：(1) 改变岛叶 突触密度，通过正电子发射断层扫描 (PET) 和 [11C]UCB-J 测量，这是一种经过充分验证的方法 与突触小泡蛋白 SV2A 结合的放射性示踪剂； (2) 扰乱吸烟行为，以 在烟草选择实验室模型中选择自我管理烟草。如果在 R61 阶段我们观察到 岛叶突触密度和烟草自我给药的变化具有临床意义的效应大小 （先验定义的基准），我们将进入 R33 阶段的研究。在R33阶段，我们将 对另外 22 名使用 SCZ 的吸烟者进行了研究（整个 R61/R33 研究中共有 38 名患者）。我们的第一个目标是 该研究的 R33 阶段将确认 dTMS 对突触密度和 自我管理。我们在 R33 阶段的额外目标将是测试 dTMS 对脑岛网络的影响 连接性，使用静息态功能磁共振成像；并测试 dTMS 是否会引起相应 PET 和 fMRI 测量结果与治疗后 dTMS 引起的烟草自我管理变化相关。 这项研究的结果有可能为 SCZ 未来 dTMS 戒烟临床试验提供信息，并且 增加治疗性神经刺激的神经机制的基础知识。