The mechanism by which electric stimulation activates retinal neurons

描述(由申请人提供)： 在过去的十年里，几种基于中枢神经系统的神经假体已经取得了显著的临床效果。例如，脑深部刺激(DBS)现在被常规用于治疗帕金森氏症震颤，人工耳蜗术刺激听神经，使严重失聪的人恢复高水平听力。然而，并不是所有的设备都取得了相同程度的成功。例如，视网膜假体不能可靠地引起复杂的(甚至是简单的)空间知觉，即使单个电极可以持续地引起焦点知觉(膦)。即使是更成功的应用程序有时也可能不一致，并产生了不想要的副作用。为了改善与视网膜(和其他神经)假体相关的结果，我们结合电生理学、解剖学和计算建模，研究电刺激和靶向神经元之间的基本相互作用。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(靠近胞体)时，对电刺激的反应阈值最低。这一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准。不同类型的视网膜神经元有不同的条带(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，我们建议调查这种差异发生的细节。很可能该带也是启动棘波的位置，但这一点尚未得到证实；在这里，我们提出几个实验来确定该带是否确实是该位置。对棘波起始位置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，类似于对轴突的刺激，感应电压沿频带的第二空间导数是一个很好的脉冲疗效预测因子。在时间域中，我们想要确定哪种刺激模式对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亚类别的神经元是否优先对不同的刺激频率做出反应。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，从而导致更好的临床结果。 公共卫生相关性： 尽管一些基于中枢神经系统的神经假体取得了显著的进展，但针对中枢神经系统其他区域的装置尚未取得令人满意的临床效果。作为开发更有效的视网膜假体刺激方法的一步，我们正在研究电刺激和靶向视网膜神经元之间的基本相互作用。因为在这些研究中获得的知识与一般的激活机制有关，所以它很可能既适用于视网膜假体，也适用于广泛的其他基于中枢神经系统的设备。

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.