Electrical Stimulation to Restore Three Dimensional Vestibular Sensation

描述(申请人提供)：由于耳毒性损伤或对双侧迷路的其他侮辱，导致双侧前庭感觉丧失。受影响的人长期身体不平衡，摔倒的风险增加，在步行和驾驶等常见日常活动中的头部运动中视力不稳定。大多数轻度或中度损失的人最终会通过增强残留功能的康复练习进行补偿，但那些严重损失但未能补偿的人没有好的治疗选择。在许多这种情况下，前庭神经是完整的，所以植入的刺激器编码来自头戴式运动传感器的信号可以兴奋前庭神经--如果它在神经的五个分支上创造了正确的活动模式--恢复头部的运动感(就像植入人工耳蜗恢复声音的感觉一样)。这项建议建立在我们已经为实现这一目标而取得的实质性进展的基础上，包括：(1)表征庆大霉素治疗后耳毒性损伤动物的三维前庭-眼反射(3D VOR)、前庭神经活动和内耳组织学；(2)开发一种多通道前庭假体(MVP)，通过电刺激支配半规管(SCCs)的三个壶腹神经分支来编码头部旋转；(3)证明MVP可以显著恢复双侧前庭缺陷(BVD)啮齿类动物和恒河猴的3D VOR，同时保持听力；(4)开发强大的计算策略，以最小化MVP诱发的和理想的3D VOR反应之间的差异；以及(5)确认中枢神经系统(CNS)迅速适应以纠正大部分剩余错误。在产生这些有希望的结果的同时，我们发现了三个主要的剩余挑战：(1)VOR错位(由于电流传播激活了前庭神经目标分支外的非靶神经纤维)，(2)VOR不对称(由于MVP在尝试编码抑制性头部运动时无法抑制自发的神经元活动)以及(3)缺乏椭圆形和球囊输入(因为我们专注于刺激壶腹神经以恢复SCC和角VOR功能，并且尚未尝试对黄斑[椭圆形和球囊]神经进行假体刺激以恢复倾斜和 他们通常驾驶的翻译VOR反射)。在这个项目中，我们将研究如何使用独特的技术组合来克服这些挑战，包括双目3D VOR测量，警觉的啮齿动物和恒河猴的单位记录，编码旋转和平移运动的新的MVP，植入迷宫的强大计算模型，电诱发复合动作电位(ECAPs)，新型康复范例，以及控制神经元活动的高度创新的方法。这些研究将产生新的电极设计、刺激优化方案、计算机辅助设计工具、外科技术和康复范例，为成功部署MVP用于临床治疗数万名因前庭感觉丧失而慢性残疾的患者奠定基础。

DESCRIPTION (provided by applicant): Bilateral loss of vestibular sensation due to ototoxic injury or other insults to both labyrinths is disabling. Affected individuals suffer chronic disequilibrium, increased risk of falls and unstable vision during head movements typical of common daily activities like walking and driving. Most individuals with mild or moderate loss eventually compensate through rehabilitative exercises that augment residual function, but those with profound loss who fail to compensate have no good treatment options. The vestibular nerves are intact in many such cases, so an implanted stimulator encoding signals from a head-mounted motion sensor can excite the vestibular nerve and - if it creates the right patterns of activity on the nerve's five branches - restore sensation of head movement (much as a cochlear implant restores sensation of sound). This proposal builds on substantial progress we have already made toward that goal, including: (1) characterization of the three dimensional vestibulo-ocular reflex (3D VOR), vestibular nerve activity, and inner ear histology in animals with ototoxic injury after gentamicin treatment; (2) development of a multi-channel vestibular prosthesis (MVP) that encodes head rotation via electrical stimulation of the three ampullary nerve branches innervating the semicircular canals (SCCs); (3) demonstration that the MVP can significantly restore the 3D VOR in rodents and rhesus monkeys with bilateral vestibular deficiency (BVD) while preserving hearing; (4) development of powerful computational strategies for minimizing the difference between MVP-evoked and ideal 3D VOR responses; and (5) confirmation that the central nervous system (CNS) rapidly adapts to correct much of the remaining error. While generating these promising results, we identified three major remaining challenges: (1) VOR misalignment (due to current spread activating nontarget nerve fibers outside the targeted branch of the vestibular nerve), (2) VOR asymmetry (due to the MVP's inability to suppress spontaneous neuronal activity when trying to encode inhibitory head movements) and (3) lack of utricle and saccule input (because we have focused effort on stimulating the ampullary nerves to restore SCC and angular VOR function and have not yet attempted prosthetic stimulation of the macular [utricular and saccular] nerves to restore tilt and translational VOR reflexes they normally drive). In this project, we will study ways to overcome these challenges using a unique combination of techniques including binocular 3D VOR measurements, single- unit recording in alert rodents and rhesus monkeys, a new MVP that encodes both rotational and translational movement, a powerful computational model of the implanted labyrinth, electrically-evoked compound action potentials (eCAPs), a novel rehabilitation paradigm, and a highly innovative method for controlling neuronal activity. These studies will yield new electrode designs, stimulus optimization protocols, computer-aided design tools, surgical techniques and rehab paradigms that set the stage for successful deployment of MVPs for clinical treatment of tens of thousands of individuals chronically disabled by loss of vestibular sensation.