HRS targeting of ON and OFF ganglion cells

描述（由申请人提供）：视网膜修复术致力于恢复视力的外部视网膜疾病，如黄斑变性和视网膜色素变性失明。 近年来，有报道称，先前失明的受试者能够识别家居物品，以有限的方式在不熟悉的景观中导航，甚至阅读，这方面取得了相当大的进展。 然而，尽管取得了这些进展，但诱发视觉的总体质量仍然有些有限。 例如，即使是最快的受试者每分钟也只能阅读几个简单的单词，所有受试者的平均阅读速度要低得多。 此外，这些设备的分辨率通常远低于电极间距所预测的分辨率。 被认为降低人工视觉质量的因素之一是用于刺激视网膜神经元的方法。 在健康的视网膜中，大约有十几种不同类型的神经节细胞（视网膜输出神经元）各自利用不同的信号模式与大脑进行通信。 例如，ON神经节细胞在光刺激开始时产生尖峰脉冲，而OFF细胞沉默或甚至减少尖峰脉冲（如果存在非零基线速率）。 相比之下，来自假体电极的刺激被认为在许多神经节细胞中产生高度相似的尖峰模式，包括同时开启和关闭神经节细胞，从而将非生理性的信号传输到大脑。 最近，我们测试了一系列调幅波形：2000脉冲每秒（PPS）恒定幅度序列，偶尔增加振幅（或降低），即从50 uA增加在150 ms的过程中将电流（基线）增加到60 uA，然后在随后的150 ms中返回到40 uA。正如预期的那样，这种波形在每次出现瞬时增加时在ON BT小区中引起尖峰脉冲。 然而，令人惊讶的是，在OFF BT细胞的反应是完全不同的，包括减少尖峰在刺激幅度的瞬时增加。 因此，相同的刺激波形在ON轻快瞬变（BT）细胞中引起尖峰增加，并且在OFF BT细胞中引起尖峰同时减少。 这与这两种细胞类型的生理反应模式密切匹配，从而提高了这种方法可能优于现有刺激方法的可能性。 我们在这个建议中的目标是通过探索它们对刺激参数的敏感性来进一步研究这些差异，以优化潜在的刺激过程。 额外的初步实验表明，对2000 PPS的反应起源于神经节细胞（即它不是由突触电路介导的）。 因此，我们假设，反应的差异引起的内在差异，神经节细胞类型可能在轴突起始段（AIS）的差异。 因此，我们将研究不同类型的AIS差异，以开发准确的计算模型，用于理解并希望进一步增强响应差异。 最后，我们还将研究如何响应以及潜在的生物物理特性的变化，视网膜退化。

DESCRIPTION (provided by applicant): Retinal prosthetics strive to restore vision to those blinded by outer retinal diseases such as macular degeneration and retinitis pigmentosa. There has been considerable progress in recent years with reports of previously-blind subjects identifying household objects, navigating in limited ways through unfamiliar landscapes and even reading. Despite this progress however, the overall quality of elicited vision is still remais somewhat limited. For example, even the fastest subjects can only read a few simple words per minute and the average reading rate across all subjects is considerably lower. In addition, the resolution from these devices is typically much lower than that predicted by electrode spacing. One of the factors thought to reduce the quality of prosthetic vision is the methods utilized to stimulate retinal neurons. In the healthy retina, approximately a dozen different types of ganglion cells (retinal output neurons) each utilize different signaling patterns to communicate with the brain. For example, ON ganglion cells generate bursts of spiking at the onset of a light stimulus while OFF cells are silent or even reduce spiking (if a non-zero baseline rate is present). In contrast, stimulation from prosthetic electrodes is thought to create highly similar patterns of spiking in many ganglion cells, including both ON and OFF ganglion cells simultaneously and thus transmit a signal to the brain that is non-physiological. Recently, we tested a series of amplitude-modulated waveforms: 2000 pulse per second (PPS) constant-amplitude train with an occasional increase (or decrease) in amplitude, i.e. an increase from 50 uA (baseline) to 60 uA over the course of 150 ms followed by a return to 40 uA over the subsequent 150 ms. As expected, such waveforms elicited bursts of spikes in ON BT cells for each occurrence of the transient increase. Surprisingly however, responses in OFF BT cells were quite different and consisted of a reduction in spiking during the transient increase in stimulus amplitude. Thus the same stimulus waveform elicits an increase in spiking in ON brisk transient (BT) cells and a simultaneous decrease in spiking in OFF BT cells. This closely matches the physiological response pattern for these two cell types raising the possibility that this approach may have advantages over existing stimulation methods. Our goal in this proposal is to investigate these differences further by exploring their sensitivity to the parameters of stimulation with the goal of optimizing the underlying stimulation process. Additional preliminary experiments indicate that the response to 2000 PPS originates in the ganglion cell (i.e. it is not mediated by the synaptic circuitry). Therefore, we hypothesize that the response differences arise from intrinsic differences across ganglion cell types probably differences within the axon initial segment (AIS). Therefore, we will study the AIS differences across types in order to develop accurate computational models that can be used to understand and hopefully further enhance the response differences. Finally, we will also study how both responses as well as the underlying biophysical features change as the retina degenerates.