Defining the forebrain neurophysiological representation of pain

摘要 在美国，很大一部分患者在他们生命中的某个时候会遭受慢性疼痛， 对于这些病人中的一部分，我们目前的医疗和手术选择是不够的。新疗法 旨在刺激涉及伤害感受的脑回路用于临床疼痛缓解是有希望的，但需要 进一步制定目标和刺激战略。然而，人类的神经机制 伤害感受表现为大脑回路中的疼痛感知，但对这种感觉的理解仍然很少。这项建议 利用神经生理学途径进入接受植入的患者的皮质和皮质下目标， 颅内EEG电极，以表征人类大脑中的疼痛网络， 经常被研究的“疼痛网络”中的节点被认为与情绪和认知领域有关， 疼痛处理，包括前额叶皮层，杏仁核，杏仁核和前扣带区域。这种独特 访问将允许在基于患者自我的自然环境中详细探索疼痛体验， 报告了术后疼痛的测量结果，然后将其与阿片类药物引起的疼痛减轻进行对比。的 将分析既存慢性疼痛疾病患者亚组的生物标志物变化 信号了我们的初步研究结果产生了两个总体假设：1）自我报告的后 手术疼痛将与前额叶皮层的β功率降低有关，这种联系将被 通过给予与疼痛缓解相关的阿片类药物逆转，2）具有前 现有的慢性疼痛状况将具有可预测的方差，基线高β/低γ 与没有慢性疼痛的患者相比。通过使用新型临床研究混合电极 允许有针对性的、高分辨率的电生理记录，然后将 在电生理学和临床上努力重新产生相关的疼痛减轻状态。这 进入人类疼痛回路的独特途径将指导进一步了解这些神经系统的生理学。 签名并推进开发新范式来治疗性调节大脑的长期目标 治疗慢性顽固性疼痛的电路。 这个指导奖将提供关键的和定制的培训1）神经生理学的先进方面 2)人类实验和临床试验设计，3）严格的流行病学方法，4）先进的 生物统计学，和5）有效的心理物理学方法的指导下评估疼痛 埃里克·哈尔格伦博士，一位顶尖的人类神经生理学家一个由共同导师，顾问， 和顾问已经聚集，包括玛丽海因里希，在人类和 动物疼痛调制，特里Sejnowski，在理论神经生物学领域的先驱，马克华莱士， 成人疼痛管理领域的专家，以及疼痛功能成像专家Fadel Zeidan 人类的道路。拟议的研究以及详细的职业发展计划将有助于 提高对人类疼痛的解剖学和电生理学基础的理解， 为成功过渡到专注于数据驱动的独立研究生涯奠定了基础 慢性疼痛神经外科治疗模式的进展。

ABSTRACT A significant portion of patients in the United States will suffer from chronic pain at some point in their lives, and for a portion of these patients, our current medical and surgical options are inadequate. Novel treatments aimed at stimulating cerebral circuits involved in nociception for clinical pain relief are promising, but require further development of both targeting and stimulation strategies. Yet, the neural mechanisms of how human nociception manifests as the perception of pain in cerebral circuits remains poorly understood. This proposal leverages neurophysiological access to cortical and subcortical targets in patients undergoing the placement of intracranial EEG electrodes to characterize pain networks in the human brain with specific access to the less often studied nodes in the “pain network” thought to be associated with the emotional and cognitive spheres of pain processing, including the prefrontal cortex, amygdala, insula, and anterior cingulate regions. This unique access will allow detailed exploration of the pain experience in a naturalistic setting based on patients’ self- reported measures of post surgical pain, which will then be contrasted with opiate induced pain reduction. The subset of patients with pre-existing chronic pain conditions will be analyzed for variation in the biomarker signal. Our preliminary findings have yielded two overarching hypotheses: 1) periods of self-reported post- surgical pain will be associated with reduced beta power in prefrontal cortex, an association that will be reversed by the administration of opioids associated with pain relief and 2) the subset of patients with pre- existing chronic pain conditions will have predictable variance, with increases in baseline high beta/low gamma signal compared to patients without chronic pain. Through the use of novel clinical-research hybrid electrodes that allow for targeted, high-resolution electrophysiological recordings, candidate target regions will then be stimulated in an effort to re-create the associated pain reduced state electrophysiologically and clinically. This unique access into human pain circuits will guide further understanding of the physiology of these neural signatures and advance the long-term goal of developing novel paradigms to therapeutically modulate cerebral circuits for the treatment of chronic, intractable pain. This mentored award will provide critical and tailored training in 1) advanced aspects of neurophysiology 2) human experimental and clinical trial design, 3) rigorous epidemiological methods, 4) advanced biostatistics, and 5) validated psychophysical methods for the assessment of pain under the direction of Dr. Eric Halgren, a leading human neurophysiologist. A complementary team of co-mentors, advisors, and consultants has been assembled, including Mary Heinricher, a leader in the field of human and animal pain modulation, Terry Sejnowski, a pioneer in the field of theoretical neurobiology, Mark Wallace, an expert in the field of adult pain management, and Fadel Zeidan, an expert in the functional imaging of pain pathways in humans. The proposed research alongside a detailed career-development plan will facilitate an improved understanding of the anatomical and electrophysiological substrates of human pain, and lay the foundation for a successful transition towards an independent research career focused on the data-driven advancement of neurosurgical therapeutic modalities for chronic pain.