Spatiotemporal alterations of thalamocortical circuitry functioning underlie pain

总结 疼痛是一种高度衰弱的疾病，复杂且难以管理。疼痛的神经基础包括 丘脑皮质（TC）电路功能的改变，可表现为TC连接障碍， 心律失常（尤其是α振荡受损）。虽然可能反映了固有的耦合（空间和 TC电路功能障碍的时间）方面，迄今为止，TC连接障碍和节律障碍仅被 独立审查，排除了对这一重要问题的基本理解和有效干预， 疼痛的病理学 利用我们充分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），当前R 01的目标是 弥补这一关键差距。目标1（实验1)将直接连接空间（通过fMRI TC连接）和时间 (via EEG/MEG α振荡）方面，以证明TC回路中的耦合时空变化 在实验性（强直性）和临床（慢性腰痛）疼痛中发挥作用。目标2和3将因果统一， 在实验和临床疼痛中上调时空耦合TC电路功能，作为因果关系， 通过α振荡的tACS（α-tACS）操纵一个方面（TC节律障碍）诱导TC回路范围 功能恢复。采用双盲双对照的方法进行严格对照实验， （主动和被动控制），交叉tACS设计（实验。2），目标2将建立一个实验模型， 这是迄今为止尚未探索的疼痛机制。在慢性低血糖患者中进行为期四周的α-tACS 背部疼痛（Expt.目的3将确定疼痛的这种统一的TC回路病理学（并揭示潜在的 α振荡的神经调节的治疗效果）。 利用我们两个实验室特殊但互补的专业知识和设施，三个目标追求广泛的 和深入的调查，将基本的实验见解转化为对急性和 慢性疼痛该项目还强调通过平行招募大型和大型的 不同样本（200名健康参与者和140名患者）和多点交叉/研究中心内验证， 一体化该项目的研究结果将为TC带来“新面貌”-统一的时空帐户 疼痛的病理学，从而激发新的疼痛治疗。

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.