Towards improved efficacy of retinal prosthetics

 描述（由申请人提供）： 为了使因视网膜变性疾病（例如黄斑变性或视网膜色素变性）而失明的约150，000名退伍军人（和其他人）恢复视力，几个世界范围内的团体正在开发视网膜假体-一种旨在通过电刺激内部视网膜神经元来恢复视力的设备，其中大量神经元已被证明在变性过程中存活。正在进行的临床试验提供了强有力的证据，证明这种设备有可能恢复盲人的高水平视力，例如，它们能够识别形状，改善视力，甚至允许一些有限的阅读。最近的监管批准允许商业销售这些设备中的两个，使这种方法成为可行的治疗选择。然而，不幸的是，临床结果一直不一致，在大多数患者中引起的感知的质量仍然是粗糙的。因为视觉诱发的质量被认为 直接来自视网膜中引起的神经活动模式，我们研究并比较了 由不同形式的刺激引起的神经活动模式，目的是开发更有效的刺激方法。用电刺激靶向双极细胞（视网膜中间神经元）通常被认为是有利的，因为它利用幸存的视网膜电路来产生神经活动，这可能与正常（生理）信号模式更接近，因此更容易被大脑解释。虽然大多数现有的设备被认为是针对双极细胞，但这种方法的实际好处并没有 这一点已经过评估，并将成为第一个目标的重点。视网膜变性可以改变形成双极介导模式的突触通路，因此我们还将评估在变性过程中疗效如何变化。我们实验室的其他工作表明，临床使用期间报告的感知减弱可能与视网膜网络重复激活（即双极细胞激活）引起的灵敏度丧失有关。我们有新的初步结果，显示损失量的变化相当大，并表明一些被认为介导有意识视觉的细胞类型可能是对重复刺激最敏感的细胞。我们在目标2中的目标是确定所有关键细胞类型的灵敏度，并评估灵敏度的损失是否可以通过替代（重复）刺激方案来减轻。最后的目标将着眼于小电极产生生理信号模式的有效性。我们的初步结果表明，小电极在激活网络方面效果较差，我们将研究它们在健康和退化视网膜中的有效性。为了最大限度地提高我们工作的转化价值，所有测试都将使用市售设备之一的克隆进行-Retina Implant，AG的Alpha-IMS。

 DESCRIPTION (provided by applicant): To restore sight to ~150,000 veterans (and others) that are blind as the result of retinal degenerative diseases (e.g. macular degeneration or retinitis pigmentosa), several worldwide groups are developing a retinal prosthetic - a device designed to restore vision by electrically stimulating inner retinal neurons, large numbers of which have been shown to survive the degeneration process. Ongoing clinical testing provides strong evidence that such devices have the potential to restore high levels of vision to the blind e.g. they enable shape recognition, improved ambulation and even allow some limited reading. Recent regulatory approval allows commercial sale of two of these devices, making this approach a viable treatment option. Unfortunately however, clinical results have been inconsistent and the quality of elicited percepts still remains crude in most patients. Because the quality of elicited vision is thought to arise directly from the pattern of neural activity elicited in the retina, we study and compare the patterns of neural activity that arise from different forms of stimulation with the goal of developing more effective stimulation methods. Targeting bipolar cells (retinal interneurons) with electric stimulation is thought to generally be advantageous because it utilizes the surviving retinal circuitry to create neural activity that presumably is a closer match to normal (physiological) signaling patterns, and therefore, easier for the brain to interpret. While most existing devices are thought to target bipolar cells, the actual benefits of this approach have not been evaluated previously and will be the focus of the first aim. Retinal degeneration can alter the synaptic pathways that shape bipolar-mediated patterns and we will therefore also evaluate how efficacy changes during the course of degeneration. Additional work from our lab suggests that the fading of percepts reported during clinical use may be tied to a loss of sensitivity that arises in response to repetitive activation of the retinal network (i.e. from bipolar cell activatin). We have new preliminary results that show considerable variability in the amount of loss and suggest that some of the cell types thought to mediate conscious vision may be the ones most sensitive to repetitive stimulation. Our goal in Aim 2 is to determine the sensitivity of all key cll types and evaluate whether the loss in sensitivity can be mitigated by alternative (repetitive) stimulation schemes. The final aim will look at the effectiveness with which small electrodes create physio- logical signaling patterns. Our preliminary results suggest small electrodes are less effective in activating the network and we will study their effectiveness in both the healthy and degenerate retinas. To maximize the translational value of our work, all testing will be performed with a clone of one of the commercially available devices - the Alpha-IMS from Retina Implant, AG.