Informing the Sub-Retinal Approach to Stimualation of the Retina.

描述(由申请人提供)： 为了让约150,000名因视网膜退行性疾病(如黄斑变性或视网膜色素变性)而失明的退伍军人恢复视力，我们团队和其他人正在积极开发一种视网膜假体，这是一种通过电刺激视网膜内部神经元来恢复视力的设备，已被证明其中大量神经元在变性过程中幸存下来。最近的临床试验提供了强有力的证据表明，这种设备可以恢复盲人的高水平视力(例如阅读)。然而，临床结果仍然高度不一致，感知质量仍然有些粗糙。由于视觉诱发的质量被认为直接来自视网膜中诱发的神经活动模式，我们正在开发新的刺激方法，以创建特定的活动模式。来自视网膜下植入物的电极被放置在双极细胞附近(在先前被光感受器占据的空间内)。虽然双极细胞被认为是视网膜下刺激的目标，但关于这些神经元对刺激的反应，以及不同的刺激参数是否会改变它们的反应，人们知之甚少。此外，抑制性无长突细胞也位于刺激电极附近，因此也可能被刺激激活。无长突细胞的激活被认为抑制了视网膜对进一步刺激的反应。膜片钳测量是研究这种反应的有力工具，因为它们允许测量诱发反应的两个重要组成部分：(1)可以直接测量对神经节细胞的兴奋性(或抑制性)输入(一种测量双极或无长突细胞激活的指标)；(2)可以测量神经节细胞中的单个峰-药物操作使能够区分双极细胞激活产生的峰。因此，我们可以直接测量双极或无长突细胞对不同类型刺激的激活程度。我们的实验室有很多进行这类测量的经验，初步结果表明，不同类型的刺激波形可以极大地影响双极细胞的反应。此外，了解双极细胞在视网膜退化时是否仍对刺激有反应是很重要的。因此，我们将研究rd10小鼠视网膜变性不同阶段视网膜神经元对刺激的反应性。这项研究的结果将为我们自己的设备以及其他研究小组的设备的刺激方法提供参考，并将导致诱发视觉质量的改善。 公共卫生相关性： 据估计，超过15万名退伍军人因黄斑变性(AMD)或视网膜色素变性等视网膜退行性疾病而失明。这些疾病在老年退伍军人中更为普遍，因此，随着新一代士兵的年龄增长，与失明相关的问题可能会持续存在，甚至会变得更糟。为了恢复这类患者的视力，我们团队正在开发一种视网膜假体--一种植入视网膜内的设备，可以电刺激存活的神经元。这些设备已经成功地在盲人中诱导了视觉感知，但它们的质量仍然不一致，而且在某种程度上受到限制。由于知觉质量被认为是视网膜中神经活动模式的结果，我们正在研究如何获得更有效的模式。为了进一步评估有效性，将在对照动物和RD10进行测试，RD10是一种公认的视网膜变性大鼠模型。

DESCRIPTION (provided by applicant): To restore sight to ~150,000 veterans that are blind as the result of retinal degenerative diseases (e.g. macular degeneration or retinitis pigmentosa), our group and others are actively 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. Recent clinical trials provide strong evidence that such devices can restore high levels of vision (e.g. reading) to the blind. However, clinical results are still highly inconsistent and percept quality remains somewhat crude. Because the quality of elicited vision is thought to arise directly from the pattern of neural activity elicited in the retina, we are developing new stimulation methods that create specific patterns of activity. Electrodes from the sub-retinal implant are positioned adjacent to bipolar cells (in the space previously occupied by the photoreceptors). While bipolar cells are thought to be the target of sub-retinal stimulation, little is known about how these neurons respond to stimulation, and, whether different parameters of stimulation alter their response. In addition, inhibitory amacrine cells are also closely situated to the stimulating electrodes and, as a result, may also be activated by stimulation. Activation of amacrine cells is thought to suppress the retinal response to further stimulation. Patch clamp measurements are a powerful tool for studying this kind of response as they allow two important components of the elicited response to be measured: (1) the excitatory (or inhibitory) input to ganglion cells can be measured directly (a measure of bipolar or amacrine cell activation), and (2) individual spikes can be measured in ganglion cells - pharmacological manipulation allows the spikes arising from bipolar cell activation to be distinguished. Thus, we can directly measure the activation levels of bipolar or amacrine cells to different types of stimulation. Our lab has much experience making these sorts of measurements and preliminary results suggest that different types of stimulus waveforms can greatly affect the bipolar cell response. In addition, it is important to understand whether bipolar cells remain responsive to stimulation as the retina degenerates. Therefore, we will study the responsiveness of retinal neurons to stimulation at various stages of retinal degeneration in the rd10 mouse. Findings from this study will inform the stimulation methods of our own device as well as by the devices of other research groups and will lead to improvements in the quality of elicited vision. PUBLIC HEALTH RELEVANCE: It is estimated that over 150,000 veterans are blind as the result of retinal degenerative diseases such as macular degeneration (AMD) or retinitis pigmentosa. These diseases are more prevalent in the older veteran population and, as a result, the problems associated with blindness are likely to persist, or even get worse, as a new generation of soldiers age. To restore sight to such patients, our group is developing a retinal prosthetic - a device implanted within the retina that electrically stimulates surviving neurons. Visual percepts have been successfully elicited in the blind with these devices but their quality remains inconsistent and somewhat limited. Since percept quality is thought to result from the pattern of neural activity elicited in the retina, we are studying how to elicit more effective patterns. To further evaluate effectiveness, testing will be performed in control animals as well as in rd10, a well-established rat model of retinal degeneration.