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HRS targeting of ON and OFF ganglion cells

HRS 靶向 ON 和 OFF 神经节细胞

基本信息

批准号：
9113664
负责人：
Shelley Fried
金额：
$ 34.18万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：视网膜假体致力于恢复因黄斑变性和视网膜色素变性等视网膜外疾病致盲的患者的视力。近年来，研究取得了相当大的进展，有报道称，以前失明的受试者可以识别家居物品，在不熟悉的风景中以有限的方式导航，甚至阅读。然而，尽管取得了这些进展，但人工视觉的整体质量仍然有些有限。例如，即使是速度最快的受试者每分钟也只能读几个简单的单词，而且所有受试者的平均阅读速度都要低得多。此外，这些设备的分辨率通常比电极间距预测的要低得多。其中一个因素认为，降低质量的假肢视觉是使用的方法，以刺激视网膜神经元。在健康的视网膜中，大约有12种不同类型的神经节细胞（视网膜输出神经元）利用不同的信号模式与大脑交流。例如，在光刺激开始时，ON神经节细胞产生脉冲，而OFF细胞则沉默或甚至减少峰值（如果存在非零基线率）。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，包括同时打开和关闭神经节细胞，从而向大脑传递非生理性的信号。最近，我们测试了一系列调幅波形：2000脉冲每秒（PPS）恒定振幅序列，振幅偶尔增加（或减少），即在150毫秒的过程中从50 uA（基线）增加到60 uA，然后在随后的150毫秒内返回到40 uA。正如预期的那样，这种波形在每次瞬时增加时都会在ON BT细胞中引起尖峰的爆发。然而，令人惊讶的是，OFF BT细胞的反应是完全不同的，包括在刺激幅度短暂增加时尖峰的减少。因此，同样的刺激波形引起开启的瞬时活跃细胞（BT）的尖峰增加，而关闭的瞬时活跃细胞（BT）的尖峰同时减少。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比现有刺激方法具有优势的可能性。我们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。另外的初步实验表明，对2000 PPS的反应起源于神经节细胞（即它不是由突触回路介导的）。因此，我们假设反应差异是由神经节细胞类型的内在差异引起的，可能是轴突初始段（AIS）内的差异。因此，我们将研究不同类型的AIS差异，以便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，我们还将研究这两种反应以及潜在的生物物理特征如何随着视网膜变性而变化。