Defining the forebrain neurophysiological representation of pain

定义疼痛的前脑神经生理学表征

• 批准号: 10592206
• 负责人: Sharona Ben-Haim
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592206
• 关键词: Adult; Affective; Amygdaloid structure; Anatomy; Animals; Anterior; Attenuated; Award; Biological Markers; Biometry; Brain; Brain region; Cerebrum; Chronic; Clinical; Clinical Research; Clinical Trials Design; Cognitive; Complex; Conventional Surgery; Coupling; Data; Deep Brain Stimulation; Development; Development Plans; Diagnosis; Dimensions; Double-Blind Method; Electrodes; Electroencephalography; Electrophysiology (science); Emotional; Epidemiologic Methods; Epilepsy; FDA approved; Foundations; Frequencies; Functional Imaging; Future; Goals; Human; Hybrids; Implant; Implanted Electrodes; Insula of Reil; Intervention; Intractable Pain; Link; Literature; Measures; Medical; Mentors; Methods; Modality; Modeling; Monitor; Neurobiology; Nociception; Operative Surgical Procedures; Opioid; Pain; Pain Measurement; Pain management; Pathway interactions; Patient Self-Report; Patients; Persons; Phase; Physiology; Postoperative Pain; Prefrontal Cortex; Prosencephalon; Psychophysics; Questionnaire Designs; Research; Resolution; Sampling; Sensory; Signal Transduction; Site; Societies; Specific qualifier value; Specificity; Surgical Management; Techniques; Technology; Testing; Therapeutic; Training; Translating; United States; Variant; Work; animal pain; archived data; career; career development; chronic pain; chronic pain management; chronic pain patient; chronic painful condition; cingulate gyrus; clinical pain; cohort; design; effective therapy; experience; implantation; improved; innovation; neural; neural circuit; neuromechanism; neurophysiology; neuroregulation; neurosurgery; novel; opioid epidemic; pain perception; pain processing; pain reduction; pain relief; patient subsets; predictive marker; pressure; prospective

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.

摘要 在美国，很大一部分患者会在一生中的某个时候遭受慢性疼痛的折磨， 对于这些患者中的一部分，我们目前的医疗和手术选择是不够的。新疗法 旨在刺激参与伤害性感觉的大脑回路用于临床缓解疼痛是有希望的，但需要 进一步发展目标和刺激战略。然而，人类如何通过神经机制 伤害性感觉表现为对大脑回路中疼痛的感知仍然知之甚少。这项建议 利用神经生理学途径获得皮质和皮质下靶点的患者接受置入 用颅内脑电电极表征人类大脑中具有特定通路的疼痛网络 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，包括前额叶皮质、杏仁核、岛叶和前扣带回区域。这个独一无二的 Access将允许在基于患者自我的自然环境中详细探索疼痛体验 报告的术后疼痛措施，然后将与阿片类药物诱导的止痛进行对比。这个 先前有慢性疼痛症状的患者的子组将被分析生物标志物的变化 信号。我们的初步发现产生了两个重要的假设：1)自我报告的后 手术疼痛将与前额叶皮质β能量降低有关，这种联系将是 通过给予与止痛相关的阿片类药物而逆转，以及2)Pre-Pre-Pre患者亚组 现有的慢性疼痛状况将具有可预测的差异，基线高β/低伽马水平会增加 与没有慢性疼痛的患者相比，这是一种信号。通过使用新型临床研究混合电极 允许进行定向、高分辨率电生理记录，那么候选靶区将 刺激是为了重新创造相关的疼痛减轻状态，从电生理和临床上。这 进入人类痛觉回路的独特途径将引导人们进一步了解这些神经的生理学 签名并推进开发治疗调节大脑的新范例的长期目标 治疗慢性顽固性疼痛的电路。 这个指导奖将提供神经生理学高级方面的关键和量身定做的培训 2)人体实验和临床试验设计，3)严谨的流行病学方法，4)先进 生物统计学，以及5)在指导下评估疼痛的经过验证的心理物理方法 埃里克·哈尔格伦博士，领先的人类神经生理学家。一个由共同导师、顾问、 已经召集了顾问，包括人力和社会领域的领导者玛丽·海因里赫 动物痛觉调制，理论神经生物学领域的先驱特里·塞诺斯基，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法德尔·扎伊丹 人类的生命之路。拟议的研究以及详细的职业发展计划将有助于 提高了对人类疼痛的解剖学和电生理基础的理解，并奠定了 为成功过渡到专注于数据驱动的独立研究事业奠定基础 慢性疼痛的神经外科治疗方法的进展。