Electrical Stimulation to Restore Three Dimensional Vestibular Sensation

描述（由申请人提供）：由于耳毒性损伤或对双侧前庭的其他损伤导致双侧前庭感觉丧失，导致残疾。受影响的个体遭受慢性不平衡，增加的福尔斯风险和在常见的日常活动（如步行和驾驶）中典型的头部运动期间的不稳定视力。大多数轻度或中度损失的人最终通过康复锻炼来补偿，以增加残余功能，但那些无法补偿的严重损失的人没有很好的治疗选择。在许多这样的情况下，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刺激前庭神经，如果它在神经的五个分支上产生正确的活动模式，就可以恢复头部运动的感觉（就像耳蜗植入物恢复声音的感觉一样）。本研究建立在我们已经取得的实质性进展的基础上，包括：（1）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特征;（2）多通道前庭假体的研制通过电刺激支配半规管（SCC）的三个壶腹神经分支编码头部旋转;（3）证明MVP可以显著恢复双侧前庭功能障碍（BVD）的啮齿动物和恒河猴的3D VOR，同时保留听力;（4）开发强大的计算策略，以最大限度地减少MVP诱发和理想的3D VOR响应之间的差异;（5）确认中枢神经系统（CNS）迅速适应，以纠正大部分剩余的错误。在取得这些令人鼓舞的成果的同时，我们确定了三个主要的剩余挑战：（1）VOR失准（由于电流扩散激活前庭神经的目标分支外的非目标神经纤维），（2）VOR不对称（由于MVP在试图编码抑制性头部运动时无法抑制自发神经元活动）和（3）缺乏椭圆囊和球囊输入（因为我们已经集中精力刺激壶腹神经以恢复SCC和角VOR功能，并且尚未尝试人工刺激黄斑[椭圆囊和囊]神经以恢复倾斜， 它们通常驱动的平移VOR反射）。在这个项目中，我们将研究如何克服这些挑战，使用独特的技术组合，包括双目3D VOR测量，在警觉啮齿动物和恒河猴中的单单位记录，编码旋转和平移运动的新MVP，植入迷宫的强大计算模型，电诱发复合动作电位（eCAP），一种新的康复范式，以及一种高度创新的控制神经元活动的方法。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、手术技术和康复范例，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个体奠定基础。

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.