Control of the Diaphragm by Motor Cortical Areas

 描述（由申请人提供）：呼吸是人类生命所必需的，以及声音和言语的产生。膈肌是吸气的主要肌肉，其功能在许多疾病中受损，例如肌萎缩性侧索硬化症、颈脊髓损伤和多发性硬化症。由此对呼吸和通讯造成的打击所带来的医疗保健费用是惊人的。到目前为止，还没有确定皮质治疗靶点来解决横膈膜功能障碍。事实上，尽管对猫的生理学研究和对人类的宏观解剖学研究，“横膈膜运动皮层”的实际位置仍然未知。 描述横膈膜的皮质表征的能力不仅对掌握呼吸的意志控制很重要，而且对理解发声控制也很重要。隔膜的运动是导致发声和说话的复杂事件链中的第一个。这些运动与完成即将到来的通信任务所需的空气量成正比。换句话说，灵感的深度必须受到大脑皮层的精心准备控制。对于能够产生相对复杂的发声的动物，如猴子，可能存在直接从大脑到控制横膈膜的运动神经元的神经通路。已知猴子具有从手部区域的皮质运动区到脊髓的这些直接（皮质-运动神经元）通路，这赋予它们产生分次手指运动的能力。猴子的声音和呼吸功能比其他通常研究的动物更接近人类。因此，该项目有可能（a）勾勒出膈肌运动皮层的精确位置，（B）进一步揭示 其他涉及横膈膜控制的运动前区，以及（c）提供关于是否存在用于横膈膜控制的皮质运动神经元投射的见解。 此外，该项目代表了澄清横膈膜的两个解剖学和功能不同的部分是否各自由大脑皮层唯一控制的第一步。这两个部分-肋和小腿肌-似乎不仅在呼吸中起着不同的作用，而且在胃食管运输中也起着不同的作用。这个项目将作为更好地理解隔膜这两个部分的运动控制的独特神经通路的基础。 我们建议使用狂犬病毒作为逆行transneuronal示踪剂，以表征的皮质代表性的食蟹猴肋膈。拟议的调查将填补一个关键的差距，我们的隔膜功能的神经基板的理解，可以作为一个跳板，为患者确定治疗方案与隔膜功能障碍和失败，并将提供一个宝贵的奖学金培训机会。

 DESCRIPTION (provided by applicant): Breathing is essential to human life, as well as voice and speech production. The diaphragm is the primary muscle of inspiration and its function is impaired in many diseases, such as amyotrophic lateral sclerosis, cervical spinal cord injury, and multiple sclerosis. Health care costs associated with the resultant blow to respiration and communication are staggering. As yet, no cortical therapeutic target has yet been identified to address diaphragm dysfunction. In fact, despite physiologic studies in cats and macroanatomical work in humans, the actual location of "diaphragm motor cortex" remains unknown. The ability to describe the cortical representation of the diaphragm is not only important for grasping volitional control of breathing, but also for understanding vocal control. Movements of the diaphragm are the first in a complex chain of events leading to vocalization and speech. These movements are in direct proportion to the amount of air needed to accomplish the upcoming communication task. Stated differently, the depth of an inspiration must come under exquisite preparatory control by the cerebral cortex. For animals capable of producing relatively sophisticated vocalizations, such as monkeys, it is possible that neural pathways directly from the brain to the motor neurons controlling the diaphragm exist. Monkeys are known to have these direct (cortico- motoneuronal) pathways from cortical motor areas in the hand region to the spinal cord, which bestow them with the ability to produce fractionated finger movements. Monkeys demonstrate voice and respiratory functions that are more closely analogous to that of humans than are other commonly studied animals. Thus, this project has the potential to (a) outline the precise location of the diaphragm motor cortex, (b) further reveal other premotor areas involved in diaphragm control, and (c) give insight regarding whether corticomotoneuronal projections exist for diaphragm control. Further, this project represents the first step toward clarifying whether two anatomically and functionally different parts of the diaphragm are each controlled uniquely by the cerebral cortex. The two parts-the costal and crural diaphragm-seem to play distinct roles not only in breathing, but also in gastroesophageal transport. This project will serve as a foundation for better understanding the unique neural pathways underlying the motor control of these two parts of the diaphragm. We propose to use rabies virus as a retrograde transneuronal tracer in order to characterize the cortical representation of the costal diaphragm in cynomolgous monkeys. The proposed investigations will fill a critical gap in our understanding of the neural substrates of diaphragm function, may serve as a springboard for identifying treatment options for patients with diaphragm dysfunction and failure, and will provide an invaluable fellowship training opportunity.