Assessing the role of the interoceptive brain system in the pathophysiology and treatment of chemotherapy-induced peripheral neuropathy

评估内感受脑系统在化疗引起的周围神经病变的病理生理学和治疗中的作用

• 批准号: 10288334
• 负责人: Ian Robert Kleckner
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288334
• 关键词: Affect; Anterior; Awareness; Base of the Brain; Biological Markers; Brain; Brain region; Chemotherapy-induced peripheral neuropathy; Clinical Trials; Colorectal Cancer; Development; Dose-Limiting; Eating; Exercise; FDA approved; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Hand; Hematopoietic Neoplasms; Hyperactivity; Impairment; Insula of Reil; Intervention; Learning; MRI Scans; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mediating; Muscle Cramp; Numbness; Operative Surgical Procedures; Pain; Patients; Peripheral; Peripheral Nerves; Phase; Physiological; Platinum; Process; Randomized Clinical Trials; Reaction; Research; Rest; Role; Sampling; Seminal; Sensory; Severities; Signal Transduction; Spinal Cord; Sterile coverings; Symptoms; System; Testing; Thalamic structure; Time; Toxic effect; Vinca Alkaloids; Vision; Walking; Work; Writing; afferent nerve; base; chemotherapy; chronic depression; chronic pain; clinically significant; effective therapy; efficacy testing; experience; foot; improved; innovation; malignant breast neoplasm; mortality; nerve damage; neurotoxic; neurotoxicity; neurotransmission; novel; peripheral nerve damage; relating to nervous system; response; taxane; theories; treatment as usual

PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting toxicity that affects over 65% of the roughly 250,000 patients per year receiving neurotoxic chemotherapy (e.g., taxane-, platinum-, vinca alkaloid-based), which is widely used for breast, prostate, lung, colorectal, and blood cancers among others. Not only does CIPN increase mortality by limiting the dose of chemotherapy, CIPN affects walking, writing, eating, and dressing via numbness, tingling, pain, cold sensitivity, and cramping in the hands and feet. There are no FDA-approved treatments for CIPN because we need a greater understanding of the pathophysiology of CIPN and mechanisms of action of promising treatments for CIPN. To date, most research on CIPN pathophysiology has focused on peripheral sensory nerve damage. This project is motivated by an innovative perspective that CIPN symptoms are not due simply to peripheral nerve damage, but rather that CIPN symptoms are worsened by damage to the interoceptive brain system (i.e., the brain’s reaction to peripheral nerve damage). The long-term vision for this project is mechanism-based CIPN sub-typing and mechanism- based treatments for CIPN informed by brain fMRI, as has been done in other brain-mediated conditions such as chronic pain and depression. This is a Phase II randomized clinical trial to assess CIPN and fMRI brain connectivity in the interoceptive brain system in 66 patients with CIPN from neurotoxic chemotherapy before and after 6 weeks of exercise vs. usual care. This study will be included as part of the clinical trial URCC 19075. The specific aims of this project are (1) to obtain preliminary estimates of the relationships between CIPN and functional connectivity in the interoceptive brain system in patients with CIPN, and (2) to obtain preliminary estimates of the effects of exercise vs. no exercise on both CIPN severity and functional connectivity in the interoceptive brain system in patients with CIPN. This is the first study to examine the interoceptive brain system in the pathophysiology and treatment of CIPN. Results from this study will inform an R01 application to more definitively assess this theory of CIPN and exercise. If this work is successful, it will reveal a novel objective biomarker of CIPN—functional connectivity in the interoceptive brain system—to improve prediction, tracking, sub-typing, and treatment of CIPN using exercise or other interventions that affect this brain system. This will ultimately help alleviate the burden of chemotherapy on treating patients with cancer. Chair: Ian Kleckner

项目摘要/摘要 化学疗法诱导的周围神经病（CIPN）是一种严重的剂量限制毒性，影响超过65％ 每年大约有25万名患者接受神经毒性化疗（例如，紫杉烷，铂 - ，Vinca 基于生物碱），广泛用于乳房，前列腺，肺，结直肠和血液癌。 CIPN不仅通过限制化学疗法的剂量来增加死亡率，CIPN会影响步行，写作， 饮食和穿衣服，通过麻木，刺痛，疼痛，敏感性和束缚在手和脚上。那里 没有FDA批准的CIPN治疗方法，因为我们需要对病理生理学有更多的了解 CIPN和CIPN承诺处理的作用机制。迄今为止，大多数有关CIPN的研究 病理生理学专注于周围感觉神经损伤。该项目是由创新的动机 CIPN症状的观点不仅是由于周围神经损害，而是CIPN 症状会因对互感的大脑系统的损害而遗忘（即大脑对周围的反应 神经损伤）。该项目的长期视觉是基于机制的CIPN亚型和机制 - 在其他脑介导的疾病中所做的，基于大脑fMRI告知CIPN的治疗方法 作为慢性疼痛和抑郁。 这是一项II期随机临床试验，用于评估感受性大脑中的CIPN和fMRI脑连接性 在运动前后，66例神经毒性化学疗法的CIPN患者在6周之前和之后 关心。这项研究将作为19075年临床试验的一部分。该项目的具体目的是 （1）获得CIPN与功能连接之间关系的初步估计 CIPN患者的感受性大脑系统，（2）获得有关的初步估计。 练习与在CIPN的严重程度和功能连接性中没有练习 CIPN患者。 这是第一个研究CIPN病理生理学和治疗中的感受性脑系统的研究。 这项研究的结果将为R01应用程序提供信息，以更明确地评估CIPN和 锻炼。如果这项工作成功，它将揭示CIPN的新型客观生物标志物 - 功能连接 感知性的大脑系统 - 改善使用CIPN的预测，跟踪，亚型和处理 运动或其他影响该大脑系统的干预措施。这最终将有助于减轻燃烧 治疗癌症患者的化学疗法。 主席：伊恩·克莱克纳（Ian Kleckner）