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.

项目摘要 精神分裂症患者（SCZ）的吸烟率高于一般人群，并做出反应 传统治疗差。这是非常关心的，因为吸烟有助于早期死亡率 在SCZ中，它可能会加剧持续的精神病症状。 2020年，深度重复的经颅磁 使用H4线圈以高频刺激（DTMS），以高频的刺激 - 也称为HADD 线圈 - 根据烟草使用障碍（TUD）的FDA清除，根据A的结果 大型，多站点临床试验。我们的初步数据表明这种新兴的神经刺激方法也可能 保持SCZ患者吸烟中断的希望。但是，迫切需要更好 了解治疗的潜在神经生物学机制。还有一个更基本的 科学问题与TMS实际上是否会重新布线，其声称的基本大脑机制 刺激的目标； TMS在体内改变脑电路的能力已被广泛假定，但是 行动机制仍然是一个悬而未决的问题。该R61/R33应用程序的总体目的是测试是否是否 DTMS能够诱导可塑性（即变化突触密度）并修改其功能电路 患者的推定（岛）靶标，并测试这些细胞和神经变化是否驱动潜力 SCZ中吸烟中断的治疗信号。 R61阶段将是16例患者的概念证明 如果在3周内进行15次DTM（相对于假手术）到岛和前额叶皮层：（1）修改insula 突触密度，用正电子发射断层扫描（PET）和[11C] UCB-J测量，这是一个充分验证的 与突触囊泡蛋白SV2A结合的放射性示例； （2）破坏吸烟行为，以 选择在烟草选择实验室模型中自我管理烟草。如果在R61阶段，我们观察到 变化对绝缘突触密度和烟草自我给药的变化，临床上的效果大小 （基准定义了先验的基准），我们将进入研究的R33阶段。在R33阶段，我们将 研究22个带有SCZ的吸烟者（在整个R61/R33研究中总计38例患者）。我们在 研究的R33阶段将是确认DTMS对突触密度和 自我管理。我们在R33阶段的其他目标将测试DTM对Insula网络的影响 连接性，使用静止状态fMRI；并测试DTM诱导的对各自PET的变化以及 FMRI测量与DTMS诱导的治疗后烟草自我管理的变化相关。 这项研究的结果有可能告知DTM的未来临床试验，以戒烟，以及 将基本知识提高到热神经刺激的神经力学中。