Chemotherapy effect on brain structure, neurophysiology and psychomotor behavior

描述（由申请方提供）：辅助化疗（CTh）是一种既定的术后治疗，通常用于癌症患者以降低复发风险。然而，很大比例的患者报告经历与CTh相关的认知、精神和其他功能障碍。一些症状可能在治疗后持续数年，并可能对癌症幸存者的生活质量产生严重影响。尽管许多研究报告了CTh治疗期间/之后的各种症状，但这些症状的潜在机制尚不清楚。最近的动物和人脑成像研究表明，CTh可能对脑，特别是脑白色物质（WM）具有直接的神经毒性作用。然而，迄今为止，还没有纵向研究已经完成，以检查CTh对人类患者的皮质/皮质下WM完整性的影响。此外，还没有努力将给定的WM结构与其相应的神经生理功能（NPF）和行为相关联。本研究提出在诊断为乳腺癌的女性中进行纵向实验，以检查CTh对胼胝体（CC）和皮质脊髓束（CST）的影响（目的1），对直接依赖于CC/CST结构质量的NPF的影响，以及对严重依赖于CC/CST功能（传导性）的精神行为的影响（目的2）。CC/CST结构完整性与其相应的NPF和心理行为之间的关系也将被检查（目标3）。本研究的基本假设是：（1）CTh对CC和CST具有直接的神经毒性作用，导致微结构变性;（2）CC和CST的结构损伤会损害相关的神经生理功能和行为。这项研究预计将产生关于与Cth相关的副作用的神经结构和生理原因的重要信息;已知这些信息将有助于更有效地管理症状。通过展示CTh对中枢神经系统有害后果的直接证据，希望这些证据将鼓励制药公司开发更安全的癌症治疗药物。 公共卫生相关性：大多数癌症幸存者遭受化疗副作用，包括认知和精神功能障碍，降低了他们的生活质量。本研究的目的是探讨目前广泛使用的化疗药物对脑神经纤维结构和功能的影响以及相关的精神行为。这些发现预计将有助于揭示癌症治疗副作用的原因，并更好地管理它们，并通过显示化疗对神经系统的有害影响来促进更安全的癌症治疗药物的开发。

DESCRIPTION (provided by applicant): Adjuvant chemotherapy (CTh) is an established postoperative treatment often prescribed to cancer patients to reduce risk of relapse. However, a great proportion of patients report experiencing cognitive, psychomotor, and other functional impairments associated with CTh. Some symptoms may persist for years after treatment and can have dramatic consequences on cancer survivors' quality of life. Despite numerous studies reporting various symptoms during/after CTh treatment, mechanisms underlying these symptoms are not well understood. Recent animal and human brain imaging studies suggest that CTh may have direct neurotoxic effects on the brain, in particular on brain white matter (WM). However, to date, no longitudinal studies have been done to examine the effects of CTh on cortical/subcortical WM integrity in human patients. Furthermore, no effort has yet been made to correlate a given WM structure with its corresponding neurophysiological function (NPF) and behavior. This study proposes longitudinal experiments in women diagnosed with breast cancer to examine the effects of CTh on the corpus callosum (CC) and corticospinal tract (CST) (Aim 1), on NPF that directly depends on the quality of CC/CST structure, and on psychomotor behavior critically relying on CC/CST function (conductivity) (Aim 2). The relationship between CC/CST structural integrity and their corresponding NPF and psychomotor behavior will also be examined (Aim 3). The general underlying hypotheses of the study are that (1) CTh has a direct neurotoxic effect on the CC and CST, resulting in microstructural degeneration and (2) structural damage to the CC and CST impairs relevant neurophysiological function and behavior. This research is expected to yield significant information regarding neural structural and physiological causes of CTh-related side effects; known this information would help more effectively manage the symptoms. By demonstrating direct evidence of detrimental consequences of CTh on the central nervous system, it is hoped that the evidence would encourage pharmaceutical companies to develop safer cancer treatment drugs. PUBLIC HEALTH RELEVANCE: A majority of cancer survivors suffer chemotherapy side effects, including cognitive and psychomotor function impairment that diminishes their quality of life. The goal of this research is to investigate how currently widely used chemotherapy drugs affect structure and function of brain nerve fibers and relevant psychomotor behavior. The findings are expected to help uncover the cause of cancer treatment side effects and better manage them and facilitate development of safer cancer treatment drugs by showing harmful effects of chemotherapy on the nervous system.