Chemotherapy effect on brain structure, neurophysiology and psychomotor behavior

描述（由申请人提供）：辅助化疗（CTh）是一种既定的术后治疗方法，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、精神运动和其他功能障碍。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，但这些症状的机制尚不清楚。最近的动物和人类脑成像研究表明，CTh可能对大脑有直接的神经毒性作用，特别是对脑白质（WM）。然而，到目前为止，还没有纵向研究来检验CTh对人类患者皮质/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）和行为联系起来。本研究建议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，以及对主要依赖于CC/CST功能（电导率）的精神运动行为的影响（目的2）。CC/CST结构完整性与其相应的NPF和精神运动行为之间的关系也将被检验（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的结构损伤损害相关的神经生理功能和行为。这项研究有望获得有关cth相关副作用的神经结构和生理原因的重要信息；了解这些信息将有助于更有效地控制症状。通过展示CTh对中枢神经系统有害后果的直接证据，希望这些证据能鼓励制药公司开发更安全的癌症治疗药物。

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.