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.

项目摘要 精神分裂症（SCZ）患者的吸烟率高于一般人群， 与常规治疗相比，这是一个非常令人关注的问题，因为吸烟会导致过早死亡 会加重持续的精神病症状到2020年，深度重复经颅磁共振成像技术将在 使用H4线圈-也称为HADD-以高频率刺激岛叶和前额皮质（dTMS） coil -被FDA批准用于烟草使用障碍（TUD）的戒烟，基于一项研究的结果， 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 有望在SCZ患者中实现吸烟中断。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。还有一个更基本的 这是一个科学问题，关于TMS是否真的重新连接了它声称的潜在大脑机制， 目标与刺激; TMS的能力，改变脑回路在体内已被广泛认为，但 作用机制仍然是一个悬而未决的问题。本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）和修改其功能电路 在患者中的假定（靶点），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， 如果在3周内对小脑和前额叶皮层进行15次dTMS（与假手术相比）：（1）改变小脑和前额叶皮层的功能， 突触密度，用正电子发射断层扫描（PET）和[11 C]UCB-J测量，是一种经过充分验证的 结合突触囊泡蛋白SV 2A的放射性示踪剂;和（2）破坏吸烟行为，测量为 在烟草选择的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 突触密度和烟草自我给药的变化具有临床意义的效应量 （先验定义的基准），我们将进入研究的R33阶段。在R33阶段， 研究22名额外的吸烟者与SCZ（总共38名患者在整个R61/R33研究）。我们的第一个目标是 研究的R33阶段将确认dTMS对突触密度影响的统计可靠性， 自我管理。在R33阶段，我们的额外目标将是测试dTMS对网络的影响 连接性，使用静息状态fMRI;并测试dTMS是否引起相应PET的变化， fMRI测量结果与dTMS诱导的治疗后烟草自我给药的变化相关。 这项研究的结果有可能为未来的dTMS用于SCZ戒烟的临床试验提供信息， 增加治疗性神经刺激的神经机制的基本知识。