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The mechanism by which electric stimulation activates retinal neurons

电刺激激活视网膜神经元的机制

基本信息

批准号：
8599463
负责人：
Shelley Fried
金额：
$ 36.52万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-12-31
项目状态：
已结题

项目摘要

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 precisely 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.

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令人瞩目的成就临床结果。例如，脑深部刺激(DBS)现在被常规用于治疗帕金森氏症震颤和人工耳蜗术刺激听神经恢复高严重失聪的人的听力水平。然而，并不是所有的设备都实现了同样的效果成功的程度。例如，视网膜假体并不可靠地引起复合体(甚至简单)空间知觉，即使单个电极可以持续地引起焦点感受器(膦)。即使是更成功的申请有时也可以前后不一致，并产生了不受欢迎的副作用。为了改善结果与视网膜(和其他神经)假体相关的，我们正在研究基础电刺激与靶向神经元之间的相互作用电生理学、解剖学和计算建模。在视网膜神经元中，我们发现对电刺激反应的最低阈值出现在刺激电极位于轴突的近端部分(靠近胞体)。这一地区低阈值与密集的电压门控钠通道带精确对准经免疫化学鉴定。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。这意味着频段差异是阈值差异的原因，我们建议调查发生这种情况的详细信息。很可能这条带子也是尖峰出现的地方已启动，但尚未得到证实；在此，我们建议进行几个实验确定该波段是否为实际站点。对棘波起始部位的认识使我们能够系统地研究外加电场的变化(由刺激脉冲)改变神经反应。我们的初步数据表明类似于刺激轴突，感应电压的二次空间导数沿频带的轮廓是脉冲疗效的一个很好的预测指标。在时间域中，我们我想确定哪种刺激模式对激活不同元素最有效在神经元内。我们还在探索特定的类或子类是否神经元对不同的刺激频率有优先反应。我们的希望是到了解应对机制的基本要素，包括不同类型神经元的反应差异，我们可以开发出更有效的刺激方法将导致更好的临床结果。