Impaired sensory filtering as a mechanism of Parkinson's disease

感觉过滤受损是帕金森病的机制

• 批准号: 10668521
• 负责人: Zachary Thomas Irwin
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668521
• 关键词: Acceleration; Affect; Age; Automobile Driving; Basal Ganglia; Behavioral; Biological Markers; Bradykinesia; Brain; Clinical Management; Conscious; Data; Deep Brain Stimulation; Development; Disease; Disease Outcome; Feedback; Frequencies; Functional disorder; Future; Generations; Goals; Human; Impairment; Individual; Lead; Maps; Measures; Modeling; Motor; Motor output; Movement; Muscle; Muscle Hypertonia; Neurodegenerative Disorders; Noise; Operative Surgical Procedures; Outcome; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Postoperative Period; Prediction of Response to Therapy; Process; Production; Property; Provider; Reaction; Reflex action; Research; Rest; Role; Sensory; Sensory Ganglia; Specific qualifier value; Symptoms; System; Technology; Testing; Therapeutic; Time; Treatment Efficacy; Tremor; arm; arm movement; associated symptom; clinical biomarkers; clinical practice; disability; implantation; improved; improved outcome; innovation; insight; limb movement; mortality; motor symptom; neural; neural circuit; neuromechanism; novel; novel therapeutics; prevent; response; sensory feedback; sensory input; sensory integration

PROJECT SUMMARY Conventional models of Parkinson’s disease (PD) dysfunction do not account for sensory feedback, which is both clearly represented in the basal ganglia and clearly impaired in PD. Despite the critical importance of this feedback to normal movement, the contribution of impaired sensory processing to PD pathophysiology is unknown. Our long-term goal is to clarify the role of sensory feedback in the production of pathological motor commands in PD. This research could help reveal the neural basis of both PD pathology and its treatment, leading to more efficient clinical practices, driving the development of novel therapeutic technologies, and helping to alleviate the enormous burdens of PD on patients and providers. In healthy people, the motor system will automatically ignore sensory feedback that is not directly relevant to the current behavioral goal. In this proposal, we seek to determine whether the basal ganglia participate in this goal-directed sensory filtering, and whether this process is impaired in PD. This phenomenon could potentially provide a framework to explain PD motor symptoms with a single underlying cause: normal sensory feedback is not filtered appropriately, which reduces the ability of the motor system to produce normal commands. Underdamped sensory feedback could produce excessive transcortical reflexes in rigidity, corrupt the brain’s internal models and interfere with movement planning in bradykinesia, and even produce tremor via stochastic resonance (a phenomenon common in nonlinear neural systems in which a sub-threshold oscillation is amplified by noise). Whether or not our specific hypotheses are supported, the experimental paradigms of this study will generate unparalleled data and insights into sensorimotor integration in the human brain. If our hypotheses are correct, however, we will further provide a framework for an unprecedented mechanistic model of PD symptom generation and a roadmap towards improved treatment.

项目概要 帕金森病 (PD) 功能障碍的传统模型并未考虑感觉反馈，即 尽管这一点至关重要，但两者都明显出现在基底神经节中，并且在 PD 中明显受损。 反馈到正常运动，感觉处理受损对 PD 病理生理学的贡献是 我们的长期目标是阐明感觉反馈在病理运动产生中的作用。 这项研究有助于揭示 PD 病理学及其治疗的神经基础， 带来更有效的临床实践，推动新型治疗技术的发展，并帮助 减轻帕金森病给患者和提供者带来的巨大负担。 对于健康人来说，运动系统会自动忽略与运动不直接相关的感觉反馈。 在本提案中，我们试图确定基底神经节是否参与其中。 目标导向的感觉过滤，以及这一过程在帕金森病中是否受到损害。 提供一个框架来解释帕金森病运动症状的单一根本原因：正常的感觉反馈是 没有适当过滤，这会降低运动系统产生正常命令的能力。 阻尼不足的感觉反馈可能会产生过度的僵化跨皮层反射，破坏大脑的 内部模型并干扰运动迟缓的运动计划，甚至通过随机产生震颤 共振（非线性神经系统中常见的现象，其中亚阈值振荡被放大 通过噪音）。 无论我们的具体假设是否得到支持，本研究的实验范式都将 如果我们的假设是的话，就会产生关于人脑感觉运动整合的无与伦比的数据和见解。 然而，正确的是，我们将进一步为 PD 症状的前所未有的机械模型提供一个框架 一代和改善治疗的路线图。