Spatiotemporal alterations of thalamocortical circuitry functioning underlie pain

摘要 疼痛是一种非常令人虚弱的疾病，很复杂，很难管理。疼痛的神经基础包括 丘脑皮质(TC)回路功能改变，可表现为TC连接障碍和 节律不齐(尤其是阿尔法振荡受损)。虽然可能反映固有的耦合(空间和 时间)方面的TC回路功能障碍，到目前为止，TC连接障碍和心律失常 独立审查，排除对这一重要问题的基本理解和有效干预 疼痛的病理学。 充分利用我们全面开发的多模式神经成像方法(同步EEG-fMRI和 结合EEG-MEG-fMRI)和经颅交流电刺激(TACS)，电流R01旨在 解决这一关键差距。目标1(摘录1)将直接链接空间(通过fMRI TC连接)和时间 (通过脑电/脑磁α振荡)展示TC电路中耦合时空变化的方面 在实验性(强直性)和临床(慢性腰背)疼痛中起作用。目标2和目标3将因果统一和 在实验和临床疼痛中上调时空耦合TC回路的功能，作为原因 通过α振荡的Tacs(α-Tacs)操纵一个方面(TC节律失常)会导致整个电路的TC 功能恢复。用双盲、双对照方法实施严格对照实验 (主动和被动控制)，交叉TAC设计(试验2)，目标2将建立一个实验模型 这种迄今未被探索的疼痛机制。慢性低血压病患者四周α-TACS检查结果分析 背部疼痛(例3)，目标3将确定疼痛的这种统一的TC回路病理(并揭示潜在的 阿尔法振荡神经调节的治疗效果)。 利用我们两个实验室的特殊但互补的专业知识和设施，三个目标追求广泛的 和深入调查，将基本的实验见解转化为对急性和慢性疾病的机械性理解 慢性疼痛。该项目还强调通过同时招聘大型和可重复性的 不同的样本(200名健康参与者和140名患者)和多点交叉/现场验证 整合。这个项目的发现将给TC带来一个新的面貌--一个统一的时空描述 疼痛的病理学，因此启发了新的疼痛治疗方法。

SUMMARY Pain is a highly debilitating condition that is complex and difficult to manage. The neural basis of pain involves alterations in thalamocortical (TC) circuitry functioning, which can manifest as TC dysconnectivity and dysrhythmia (especially, impaired alpha oscillations). While likely reflecting inherently coupled (spatial and temporal) aspects of TC circuitry dysfunction, to date, TC dysconnectivity and dysrhythmia have only been examined independently, precluding fundamental understanding and effective intervention of this important pathology of pain. Capitalizing on our fully developed multimodal neuroimaging methodology (simultaneous EEG-fMRI and combined EEG-MEG-fMRI) and transcranial alternating current stimulation (tACS), the current R01 aims to address this critical gap. Aim 1 (Expt. 1) will directly link the spatial (via fMRI TC connectivity) and temporal (via EEG/MEG alpha oscillations) aspects to demonstrate coupled spatiotemporal alterations in TC circuitry functioning in experimental (tonic) and clinical (chronic low back) pain. Aims 2 & 3 will causally unify and upregulate the coupled spatiotemporal TC circuitry functioning in experimental and clinical pain, as causal manipulation of one aspect (TC dysrhythmia) via tACS of alpha oscillations (α-tACS) induces TC-circuit-wide functional restoration. Implementing a rigorously controlled experiment with a double-blind, double-controlled (active and passive control), crossover tACS design (Expt. 2), Aim 2 will establish an experimental model of this hitherto unexplored mechanism of pain. Through four weeks of α-tACS among patients with chronic low back pain (Expt. 3), Aim 3 will ascertain this unified TC circuitry pathology of pain (and reveal potential therapeutic effects of neuromodulation of alpha oscillations). Leveraging special but complementary expertise and facilities of our two labs, the three Aims pursue a broad and in-depth investigation, translating basic experimental insights into mechanistic understanding of acute and chronic pain. The project also emphasizes rigor and reproducibility through parallel recruitment of large and diverse samples (200 healthy participants and 140 patients) and multi-point cross/within-site validation and integration. Findings from this project will cast a “new look”—a unified spatiotemporal account—on TC pathology of pain and hence inspire novel pain treatments.