The mechanism by which electric stimulation activates retinal neurons

描述（由申请人提供）： 在过去的十年中，几个基于CNS的神经假体取得了显着的临床效果。例如，脑深部电刺激（DBS）现在通常用于治疗帕金森震颤，人工耳蜗刺激听觉神经，以恢复深度耳聋患者的高水平听力。然而，并不是所有的设备都取得了同样的成功。例如，视网膜修复术不能可靠地引起复杂的（甚至简单的）空间感知，即使单个电极可以一致地引起焦点感知（光幻视）。即使是更成功的应用程序有时也会不一致，并产生不必要的副作用。为了改善与视网膜（和其他神经）假体相关的结果，我们正在研究电刺激和目标神经元之间的基本相互作用，使用电生理学，解剖学和计算建模的组合。在视网膜神经元中，我们发现当刺激电极位于轴突的近端部分（靠近索马）时，对电刺激的响应阈值最低。该低阈值区域与免疫化学鉴定的电压门控钠通道的致密带精确对齐。不同类型的视网膜神经元具有不同的带（长度和位置）以及不同的绝对（最低）阈值。这意味着，频带差异有助于阈值差异，我们建议调查的细节，这种情况发生。这条带很可能也是尖峰信号起始的位点，但这一点尚未得到证实;在这里，我们提出了几个实验来确定这条带是否确实是位点。对尖峰起始位点的了解使我们能够系统地研究外加电场（由刺激脉冲引起）的变化如何改变神经反应。我们的初步数据表明，类似于轴突的刺激，诱导电压曲线的二阶空间导数沿着带是脉冲功效的良好预测因子。在时间域中，我们想要确定哪种刺激模式对于激活神经元内的不同元素最有效。我们还在探索特定类别或子类的神经元是否优先响应不同的刺激频率。我们希望通过了解反应机制的基本要素，包括不同类型神经元之间反应差异的原因，我们可以开发出更有效的刺激方法，从而获得更好的临床结果。 公共卫生相关性： 尽管一些基于CNS的神经假体取得了显着进展，但针对CNS其他区域的设备尚未取得令人满意的临床结果。作为开发更有效的视网膜修复刺激方法的一步，我们正在研究电刺激和目标视网膜神经元之间的基本相互作用。由于这些研究中获得的知识与一般激活机制有关，因此可能适用于视网膜假体以及各种其他基于CNS的器械。

DESCRIPTION (provided by applicant): In the past decade, several CNS-based neural prosthetics have achieved remarkable clinical outcomes. For example, deep brain stimulation (DBS) is now routinely used to treat Parkinsonian tremors and cochlear prosthetics stimulate the auditory nerve to restore high levels of hearing to the profoundly deaf. However, not all devices have achieved the same level of success. For example, retinal prosthetics do not reliably elicit complex (or even simple) spatial percepts even though individual electrodes can consistently elicit focal percepts (phosphenes). Even the more successful applications can sometimes be inconsistent and have created unwanted side effects. To improve the outcomes associated with retinal (and other neural) prosthetics, we are studying the fundamental interactions between electric stimulation and targeted neurons using a combination of electrophysiology, anatomy and computational modeling. In retinal neurons, we found that the lowest thresholds in response to electric stimulation occur when the stimulating electrode is positioned over the proximal portion of the axon (near the soma). This region of low threshold is precise aligned with a dense band of voltage-gated sodium channels identified immunochemically. Different types of retinal neurons have different bands (lengths and locations) as well as different absolute (lowest) thresholds. This implies that band differences contribute to threshold differences and we propose to investigate the details by which this occurs. It is likely that the band is also the site in which spikes are initiated but this has not yet been confirmed; here, we propose several experiments to determine whether the band is in fact the site. Knowledge of the site of spike initiation enables us to systematically study how changes to the applied electric field (arising from the stimulus pulse) alter the neural response. Our preliminary data suggests that analogous to stimulation of axons, the second spatial derivative of the induced voltage profile along the band is a good predictor of pulse efficacy. In the temporal domain, we want to determine which stimulus profile is most effective for activating different elements within the neuron. We are also exploring whether specific classes or sub-classes of neurons respond preferentially to different stimulus frequencies. Our hope is that by understanding the basic elements of the response mechanism, including the cause of response differences between different types of neurons, we can develop more effective stimulation methods that will lead to better clinical outcomes. PUBLIC HEALTH RELEVANCE: Despite remarkable progress with some CNS-based neural prosthetics, devices that target other regions of the CNS have not yet achieved satisfactory clinical results. As a step towards developing more effective stimulation methods for retinal prosthetics, we are studying the fundamental interactions between electric stimulation and targeted retinal neurons. Because the knowledge acquired in these studies pertains to general activation mechanisms, it is likely to be applicable to both the retinal prosthetic as well as a wide range of other CNS- based devices.