Inspiratory Muscle Activation via High Frequency Spinal Cord Stimulation

描述（由申请人提供）：许多颈脊髓损伤患者终生依赖机械通气支持。虽然电刺激技术能够使一些患者摆脱机械通气，但绝大多数患者仍然需要使用它们。考虑到这些设备的显著缺点，我们迫切需要额外的起搏选项。我们最近在初步动物实验中证明，吸气肌激活可以通过上胸高频（bbb200赫兹）脊髓刺激（HF-SCS）实现。这种方法需要刺激与吸气运动神经元池突触的脊髓束。这是一种新颖的、更加生理性的吸气肌激活方法，因为刺激发生在前运动神经元水平，允许在运动神经元池中处理刺激，从而产生更加生理性的招募模式。因此，这项技术有可能提供一种更有效的吸气肌起搏方法。然而，在临床试验之前，该技术的一些重要方面需要进一步的表征。以下目标旨在通过评估最佳刺激模式和电极位置、HF-SCS的机制、维持通气的有效性、最佳电极设计和长期安全性来评估该技术的生物学效果。在目标1中，最佳刺激模式和电极位置导致吸气肌的激活将通过吸气体积和气道压力产生的测量来确定。在目的II中，将通过吸气肌肌电图测量评估HF-SCS的机制，包括单个运动单元记录和胸腔和腹部位移测量。这些结果将使我们能够验证我们的假设，即HF-SCS导致吸气肌激活的生理模式。将进行脊髓消融研究，以确定介导吸气运动神经元池激活的通路的位置。在目标III中，电场测量将与建模技术结合使用，以确定最佳电极设计。在目的IV中，将评估HF-SCS在维持长时间通气支持方面的功效。在目标V中，我们计划采用新设计的电极，用于评估该方法在慢性动物模型中的长期安全性。每天进行18-24小时的刺激，持续3个月。长期刺激后，将对脊髓结构、脊神经和肌肉进行病理检查。这些研究的结果将解决动物实验中有关该技术的重要基础科学问题，并为人体临床试验提供框架。一种更生理性的吸气肌激活方法可能会减少依赖机械通气的四肢瘫痪患者的数量，从而提高他们的生活质量。

DESCRIPTION (provided by applicant): Many patients with cervical spinal cord injury are dependent upon lifelong mechanical ventilatory support. While electrical stimulation techniques have been able to free some patients from mechanical ventilation, the vast majority still require their use. Given the significant disadvantages of these devices, additional pacing options are badly needed. We have recently demonstrated in preliminary animal testing that inspiratory muscle activation can be achieved with upper thoracic high frequency (>200 Hz) spinal cord stimulation (HF-SCS). This method entails stimulation of spinal cord tracts which synapse with the inspiratory motoneuron pools. This is a novel and more physiologic method of inspiratory muscle activation since stimulation occurs at a pre- motoneuron level, allowing for processing of the stimulus within the motoneuron pools resulting in a more physiologic recruitment pattern. This technique therefore has the potential to provide a more effective method of inspiratory muscle pacing. Prior to clinical trials, however, there are important aspects of this technique that require further characterization. The following objectives are designed to assess the biology of this technique by evaluating the optimal stimulus paradigm and electrode location, mechanism of HF-SCS, efficacy in terms of maintaining ventilation, optimal electrode design and, long term safety. In Objective I, optimal stimulus paradigm and electrode location resulting in activation of the inspiratory muscles will be determined by measurements of inspired volume and airway pressure generation. In Objective II, the mechanism of HF-SCS will be evaluated by inspiratory muscle EMG measurements including single motor unit recordings and measurements of rib cage and abdominal displacements. These results will allow us to test our hypothesis that HF-SCS results in a physiologic pattern of inspiratory muscle activation. Spinal cord ablation studies will be performed to determine the location of pathways mediating inspiratory motoneuron pool activation. In Objective III, electric field measurements will be used in conjunction with modeling techniques to determine optimal electrode designs. In Objective IV, the efficacy of HF-SCS in maintaining ventilatory support for prolonged time periods will be assessed. In Objective V, we plan to employ newly designed electrodes which will be used to assess the long term safety of this method in a chronic animal model. Stimulation will be provided for 18-24 hrs/day for 3 months. Following long term stimulation, pathologic examination of the spinal cord structures, spinal nerves and muscles will be undertaken. The results of these studies should resolve important basic science issues concerning this technique in animals, and provide the framework for human clinical trials. A more physiologic method of inspiratory muscle activation is likely to reduce the number of tetraplegics dependent upon mechanical ventilation and thereby improve their life quality. PUBLIC HEALTH RELEVANCE: Patients with paralysis secondary to cervical spinal cord injury are often dependent upon mechanical ventilators to support their breathing. These devices restrict mobility, are uncomfortable, interfere with the production of normal speech, provoke anxiety due to fear of disconnection and thereby reduce life quality. The proposed research will investigate new electrical stimulation methods to restore breathing and eliminate the disadvantages of mechanical ventilation.