Operant conditioning of sensory evoked potentials to reduce phantom limb pain

摘要/项目摘要 在200万失去肢体的美国人中，包括96，519名退伍军人，60-90%的人有一个 截肢时的疼痛感-称为幻肢痛（PLP）。PLP可以持续数年，并导致 药物依赖、失业和生活质量低下。截肢导致感觉和运动异常 皮质重组，这与PLP有关。恢复更正常的皮质组织是 与PLP降低有关。目前的疗法旨在恢复运动皮层的组织， 很少关注感觉处理，这对有效运动也至关重要。这些都取得了成功，但 它们的功效仍不清楚。我们假设，恢复躯体感觉皮层组织将是至关重要的， 降低PLP。感觉丧失与记录的脑信号中的小或延迟的诱发电位相关， 头皮我们将开发和测试一种新的非侵入性非药物治疗，其工作原理是通过训练， 人增加他们的体感诱发电位（SEP）。这种有针对性的神经可塑性方案是 基于操作性条件反射，由我们的研究小组在过去的40年里开发， 神经系统中特定部位的可塑性。我们已经证明，其他人也证实，这些 有针对性的神经可塑性方案可以增强人和动物的脊髓功能恢复 损伤、中风和其他疾病。SEP也可以是条件性的，并影响功能，如图所示。 几项研究。 我们的目标是开发一个协议，为上空调SEP，与我们有针对性的条件反射的方法，在人 治疗幻肢痛，期望它能改善感觉皮层的皮层组织， 并帮助减轻疼痛，具有更持久的效果。我们将首先优化调理方案并进行测试 在10名健康的退伍军人中，然后将其应用于20名患有PLP的退伍军人。幻肢的SEP将是 引起非疼痛的触觉刺激，与众所周知的镜像效应，即将刺激施加到完整的 肢体及其反射在镜子中被看到，在躯体感觉中引起电诱发反应。 幻肢对侧的皮层我们的初步测试在人与完整的手臂和人与 截肢表明这是可能的该研究将评估退伍军人干预的可行性 与PLP，在26个一小时的会议，超过9周（3次会议/周）。他们将被随机分配到一个 调节组或对照组，每组10人;其中对照组将接受等量的 刺激作为条件反射组，但没有条件反射反馈。本次干预将与我们的 一个完善的诱发电位操作条件反射系统（EPOCS），已经开发和使用 在过去的十年里，我们和其他人成功地进行了类似的条件反射研究。 我们将评估SEP调节对功能疼痛、生活质量、触觉敏锐度的影响， 注意力/认知，以及生理学-感觉和运动皮层组织，兴奋性和功能 连通性。我们预计SEP调节将减轻疼痛并改善感觉运动皮质 组织，兴奋性和感觉运动功能连接的幻肢。它还可以改善 触觉敏锐度、生活质量和注意力-作为探索性结局进行评估。这些改进将持续 至少6个月。相对于对照组，条件组的这些影响更大。 我们希望这些初步结果将为后续更大规模的研究提供支持，使我们能够 进一步评估SEP上调对降低PLP，改善皮质骨的治疗效果， 组织，减少药物依赖，提高截肢退伍军人的生活质量。这将 还推进了影响许多退伍军人的其他中枢神经系统疾病的疼痛研究方法的开发（例如， 中风、脊髓损伤、慢性中枢性疼痛、背痛）。

Abstract/ project summary Among the two million Americans who have lost a limb, including 96,519 Veterans, 60-90% have a sensation of pain in the amputated limb– called phantom limb pain (PLP). PLP can last for years and lead to drug dependence, job loss, and poor quality of life. Limb amputation leads to abnormal sensory and motor cortex reorganization, which is associated with PLP. Restoration of more normal cortical organization is associated with reduced PLP. Current therapies have aimed to restore organization in the motor cortex with little focus on sensory processing, which is also crucial in effective movement. These have shown success, but their efficacy remains unclear. We hypothesize that restoring somatosensory cortex organization will be vital in reducing PLP. Sensory loss correlates with a small or delayed evoked potential in brain signals recorded from the scalp. We will develop and test a novel noninvasive non-pharmacological therapy which works by training a person to increase their somatosensory evoked potentials (SEPs). This targeted neuroplasticity protocol is based on operant conditioning, and was developed by our research group, over the past 40 years, to target plasticity to specific sites in the nervous system. We have shown, and others have confirmed, that these targeted neuroplasticity protocols can enhance recovery of function in people and animals with spinal cord injury, stroke, and other disorders. SEPs can also be conditioned, and affect function, as has been shown in few studies. We aim to develop a protocol for up-conditioning SEPs, with our targeted conditioning approach, in people with phantom limb pain, with the expectation that it will improve the cortical organization of the sensory cortex and help reduce the pain, with longer lasting effects. We will first optimize the conditioning protocol and test it in 10 healthy Veterans, and then apply it in 20 Veterans with PLP. The SEPs for the phantom limb will be elicited for non-painful tactile stimuli, with the well-known mirror effect–i.e. the stimuli is applied to the intact limb and its reflection is viewed in the mirror, evoking an electrical evoked response in the somatosensory cortex contralateral to the phantom limb. Our preliminary tests in person with intact arms and a person with amputated arm, shows that this is possible. The study will assess the feasibility of the intervention in Veterans with PLP, across 26 one-hr sessions, over 9-weeks (3 sess/week). They will be randomly assigned to a Conditioning or a Control group, 10 people per group; where Control group will receive equal amount of stimulation as the conditioning group, but no conditioning feedback. This intervention will be performed with our well established Evoked Potential Operant Conditioning System (EPOCS), that has been developed and used successfully, by us and others, over the past decade, for similar conditioning studies. We will assess the impact of SEP conditioning on function–pain, quality of life, tactile acuity, attention/cognition, and physiology–sensory and motor cortical organization, excitability and functional connectivity. We expect that SEP conditioning will reduce pain, and improve the sensory-motor cortical organization, excitability and sensorimotor functional connectivity for the phantom limb. It may also improve tactile acuity, QoL and attention –assessed as exploratory outcomes. These improvements will persist for at least 6 months. These effects will be larger for the Conditioning group, relative to the Control group. We expect that these initial results will provide support for subsequent larger studies that enable us to further assess the therapeutic efficacy of SEP up-conditioning for reducing PLP, improving cortical organization, reducing medication dependence, and enhancing QoL in Veterans with amputations. This would also advance method development for pain research for other CNS disorders that affect many Veterans (e.g., stroke, spinal cord injury, chronic central pain, back pain).