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

基本信息

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
项目类别：
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

项目摘要

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，并且对吸烟有反应传统治疗效果不佳，这一点值得高度关注，因为吸烟会导致早期死亡。在 SCZ 中，它可能会使持续的精神病症状在 2020 年恶化，深度重复性经颅磁。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) 戒烟我们的初步数据表明，这种新兴的神经刺激方法也可能有效。有望阻止 SCZ 患者吸烟。然而，迫切需要更好的方法。了解治疗的潜在神经生物学机制还有一个更根本的问题。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人们普遍认为 TMS 具有改变体内大脑回路的能力，但作用机制仍然是一个悬而未决的问题，该 R61/R33 应用的总体目标是测试是否有效。 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 R61 阶段将在 16 名患者中进行概念验证，并进行测试。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) 破坏吸烟行为，测量为如果在 R61 阶段，我们观察到在烟草选择实验室模型中自我管理烟草的选择。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。研究了另外 22 名 SCZ 吸烟者（整个 R61/R33 研究中总共 38 名患者）。该研究的 R33 阶段将确认 dTMS 对突触密度和影响的统计可靠性我们在 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 fMRI；并测试 dTMS 是否引起相应 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。