藉由非同步電刺激改善人工視網膜的空間解析度

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研究生：	李文庭 Li, Wun-Ting
論文名稱：	藉由非同步電刺激改善人工視網膜的空間解析度 Improving spatial resolution of retinal prosthesis with asynchronous electrical stimulation
指導教授：	焦傳金 Chiao, Chuan-Chin
口試委員:	吳重雨 Wu, Chung-Yu 林伯剛 Lin, Po-Kang
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2021
畢業學年度：	109
語文別：	中文
論文頁數：	36
中文關鍵詞：	電刺激、人工視網膜、空間解析度、串擾效應、非同步電刺激、閥值、細胞膜膜電位
外文關鍵詞：	electrical stimulation, retinal prosthesis, spatial resolution, crosstalk, asynchronous stimulation, threshold, membrane potential
相關次數：	點閱：2 下載：0
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利用人工視網膜所產生的電刺激幫助退化性視網膜疾病（如視網膜色素病變和老年性黃斑部病變）的患者是一種有前景的治療策略。在過去這幾年中，許多的人工電子眼已經在歐美國家通過了臨床試驗和商業授權。即便如此，因為涉及到人工視網膜設計、生物物理和視網膜迴路，目前仍然有數種挑戰需要去克服。例如：由於當今的人工視網膜常使用多個電極同時給予電刺激，因而造成了空間解析度不佳的問題。

同步電刺激所造成的電場疊加效應會降低空間解析度。為了避免這樣的副作用，非同步電刺激被視為一種有效降低電場交互作用的方法。在本篇研究中，兩鄰近電極給予同步電刺激或是非同步電刺激的狀況下，視網膜節狀細胞所產生的放電反應會被記錄下來以評估電場串擾的效應。使用多通道微電極陣列刺激由野生種小鼠解剖下來的視網膜組織，並透過電生理技術紀錄視網膜節狀細胞的反應。

與過去研究的結果一致，同步電刺激以及電極-細胞間的相對距離會影響到刺激視網膜節細胞的效率。另外，主導電極（細胞正下方的電極）若是先放電，有助於抑制原先來自鄰近電極刺激到細胞所造成的放電反應。再者，若是鄰近電極先放電，根據細胞電反應的不同，抑制主導電極的效果也有所不同。除此之外，在相鄰兩電極、2毫米時間間隔下的非同步電刺激，具有最佳的電場串擾效應。根據細胞膜膜電位的改變將細胞分為兩種主要類別，電刺激過後產生過極化的細胞相較於去極化的細胞其放電反應較為微弱。從藥理學實驗結果也證實了這樣的過極化反應是來自於上游γ-氨基丁酸（GABA）和甘氨酸（glycine）的抑制訊號。

總結來說，相鄰兩電極同時電刺激有助於降低刺激到視網膜節細胞所需要的閥值電壓，然而附近的細胞也會因此而被刺激到，因此降低了所謂的空間解析度。我們的結果證實了相鄰兩電極非同步地電刺激可以有效的抑制不希望的細胞放電反應，特別是那些來自於鄰近電極電刺激所產生的。在這些視網膜節細胞當中，電刺激過後維持長時間過極化反應的細胞相較去極化反應的細胞，更難以產生第二次的放電反應。

Electrical stimulation using retinal prostheses has been a promising strategy for helping patients with retinal degenerative diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Over these years, several visual prostheses have passed clinical trials and commercialized in Europe and United States. However, there are still numerous challenges involved in the integration of prostheses, biophysics and retinal circuitry. Particularly, multiple electrodes applying stimulation simultaneously in current retinal prostheses decreases the spatial resolution, which is one of the major challenges.

The electric field overlap caused by the synchronous electrical stimulation decreases the spatial resolution. To avoid the side effect, asynchronous electrical stimulation is regarded as an effective method to minimize electric field interaction from individual electrodes. In this study, we recorded the spiking response of retinal ganglion cells (RGCs) under two neighboring stimulating electrodes applying electrical stimulations either synchronously or asynchronously to assess the crosstalk effect. Multi-electrode array (MEA) was used to stimulate retina dissected from wild-type mice and the cell response of RGCs was recorded by electrophysiological technique.

Consistent with previous studies, the results indicate synchronous electrical stimulation and the distance between the stimulating electrode and RGC influence the efficiency of stimulating RGCs. Furthermore, the dominated electrode (under the recorded cell, abbreviated as the ‘D electrode’) stimulating first reduced the spiking response resulting originally from the subordinated stimulating electrode (the neighbor electrode, abbreviated as the ‘S electrode’). Moreover, the S electrode stimulating at the early phase caused different extent of inhibition based on the cell type. Besides, the electrical crosstalk of two neighboring electrodes had a constructive effect with time interval of 2 ms. By separating these recorded RGCs into two groups based on their membrane potential (MP) changes, the cells with hyperpolarized MP after stimulation had weaker spiking responses than the cells with depolarized MP after stimulation. The data showed that the hyperpolarized response was resulted from the upstream inhibitory signals such as GABA and glycine.

In conclusion, both neighboring electrodes stimulating the RGC synchronously can decrease the threshold voltage, nearby cells were also stimulated by the neighboring electrodes, and this would reduce the spatial resolution of electrical stimulation. We demonstrated that two neighboring electrodes stimulating the RGC asynchronously could effectively prevent cells from generating unwanted spikes, especially for the subordinated stimulating electrode. Among these RGCs, cells that exhibited long-term hyperpolarization after stimulation were more difficult to generate the second spike by the neighboring electrode stimulating asynchronously.

摘要 ................................................................................................................................. i
Abstract ........................................................................................................................ iii
Chapter 1. Introduction............................................................................................... 1
1-1 Retinal prosthesis system .................................................................................. 1
1-2 Challenges in retinal prosthesis ........................................................................ 1
1-3 Resolution ........................................................................................................... 2
1-4 Synchronous and asynchronous electrical stimulation .................................. 2
1-5 Network-mediated activation ............................................................................ 3
1-6 Goals and approaches ........................................................................................ 3
Chapter 2. Materials and methods ............................................................................. 5
2-1 Animals and retina preparation ....................................................................... 5
2-2 Electrophysiological recording ......................................................................... 5
2-3 Light stimulation ................................................................................................ 6
2-4 Electrical stimulation ......................................................................................... 6
2-5 Pharmacological treatment ............................................................................... 7
2-6 Data analysis ....................................................................................................... 7
Chapter 3. Results ........................................................................................................ 8
3-1 Synchronous electrical stimulation and the distance influence the efficiency of directly stimulating RGCs ................................................................. 8
3-2 The electrical response of recorded RGCs can be divided into two major groups after electrical stimulation and this division is independent of light response. .................................................................................................................... 8
3-3 The dominated electrode stimulating first reduces the spiking response of direct stimulation originally resulting from the neighboring electrode. ......... 9
3-4 The neighboring electrode stimulating at the early phase causes different strength of inhibition on second stimulation based on the cell type. ................... 9
3-5 The electrical crosstalk of two neighboring electrodes has a constructive effect with certain time parameter. ...................................................................... 10
3-6 The relationship of direct and network-mediated activation on electrical stimulation with subretinal electrodes. ................................................................. 11
3-7 The spiking response of indirect stimulation from the dominated electrode would not affected by the neighboring electrode stimulating later. .. 11
3-8 The later stimulation by the dominated electrode reduced the spiking response of indirect stimulation from the neighboring electrode with short time interval. ........................................................................................................... 12
3-9 The effect of the delaying electrode was reduced by the activated leading electrode with longer time interval. ...................................................................... 12
3-10 The activation of the inhibitory neurons containing GABAergic and glycinergic cells contributed to the hyperpolarization of RGCs. ....................... 13
Chapter 4. Discussions ............................................................................................... 14
4-1 Pros and cons of synchronous and asynchronous electrical stimulation . 14
4-2 The influence of time interval parameter on short-latency response with asynchronous electrical stimulation ..................................................................... 14
4-3 Temporal interactions under asynchronous electrical stimulation ......... 15
4-4 Spatial interactions under asynchronous electrical stimulation .............. 16
4-5 The neural network involved in post-stimulation response of RGCs ..... 17
References ................................................................................................................... 18
Figures ......................................................................................................................... 23
                                

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