人工視網膜系統目前正積極開發以冀恢復視網膜色素病變以及老年性黃斑部病變患者們的視力。然而在人工視網膜系統的開發過程中遇到了諸多挑戰，其中之一為人工視網膜的能源提供效率有限，因而無法在高畫素的系統下提供足夠的刺激電流;另一個挑戰為:由於較長時間的電流脈波，造成因電極過度極化而產生的電解水反應。藉由與交通大學吳重雨教授團隊的合作，應用時間整合的原理，本論文將分別研究分區供電系統，與脈波次數調變兩種方案來解決上述的兩大挑戰。
藉由在每一個時間區段，將來自於電源的所有電力供應給部分像素，並由快速的轉換來整合出影像，藉此集中電力的方案稱之為分區供電系統。此方案雖然大幅的提升電力的使用效率，但卻有可能會降低對植入患者的空間與時間解析度。本研究藉由心理物理學的方式系統性的探討時間與空間整合在各種分區供電參數下的表現，透過Arduino控制16x16畫素的LED陣列，作為模擬植入採用分區供電系統的人工視網膜患者所看到的影像，並藉由改變不同的更新頻率來量化受測者對於不同參數的辨識表現。結果顯示，觀看視角、背景照度、顯示順序與圖形分區數皆不會影響到分區供電的表現，然而藉由分區供電呈現正與負片的圖像，受測者的表現將會顯著的受到影響。
脈波次數調變為透過雙向脈波刺激的次數，來達到調控視網膜細胞反應的目的。由於較短且較弱的雙向刺激不會造成電極的過度極化，因此不會產生影響植入者安全的電解反應。本研究利用多電極陣列刺激與記錄視網膜感光細胞退化小鼠的視網膜，系統性的探討時間整合在脈波次數調變方案上的表現。雖然脈波次數調變其刺激效率並不如脈波強度調變與脈波長度調變，但本研究仍驗證了脈波次數調變確實可以整合多個雙向刺激，來達到調變細胞反應的成效;再者，藉由比較不同脈波的間距對細胞造成的反應，也證明改變較長脈波的間距並不會影響到視網膜細胞對脈波次數調變刺激的反應。最後更透過藥理學實驗驗證了時間整合的反應是來自視網膜節細胞上游的整合，而非視網膜節細胞本身的反應。
總結而言，此篇論文研究分別從心理物理學及電生理的方式驗證了分區供電系統以及脈波次數調變方案皆有潛力運用於人工視網膜，除了在視覺的時間整合領域上得以有更一步的發展外，更使我們對於人工視網膜的開發有更深的理解，也希望能藉由此研究成果，能加速新一代人工視網膜開發，讓更多盲人得以重現光明。

The retinal prosthesis is currently under studied aiming to restoring vision of patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). There are still many challenges remained during development. One of them is the limitation of power efficiency that makes the high-pixel retinal prosthesis difficult to provide sufficient electrical stimulation. The other issue is when increasing the duration of the stimulating pulse for activating retinal cells, it is very easy to reach the limitation of water window. In collaboration with Prof. Chung-Yu Wu at the NCTU, we conquer these two challenges by applying the concept of temporal integration to study the divisional power supply scheme (DPSS) and the pulse number modulation in the retinal prosthesis design.
The DPSS system, which provides electricity to only a subset of electrodes at any moment in time with its total power, can significantly increase the power efficiency for each electrode, but may potentially reduce the spatiotemporal resolution of retinal prosthesis in human patients. The present study was to systematically characterize the performance of spatiotemporal integration in various DPSS conditions for human subjects using a psychophysical approach. A 16x16 pixels LED array controlled by Arduino was used to simulate the output signal of the DPSS design, and human performance corresponding to different visual stimulations at various update frequencies was used to assess the spatiotemporal resolution of retinal prosthesis. The results showed that the contrast polarity of the image influenced the optimal update frequency of the DPSS system, while the visual angle, ambient light level, order in each sub-region, and division number did not affect the performance of pattern recognitions.
Electrical stimulation in the pulse number modulation, which fixes the total amount of charge injection and varies the strength of the stimulus only by the number of pulses, can significantly prevent the redox reaction from exceeding the water window by reducing the charge accumulation with shorter and smaller bi-phasic pulses. The present study was to systematically characterize the performance of temporal integration in the pulse number modulation with electrophysiological recording of the retinal ganglion cells (RGCs). Multi-electrode array (MEA) was used to stimulate and record the retina from rd1 mice. The results showed that the charges of repeated bi-phasic pluses in the pulse number modulation were integrated over time and evoked RGC responses successfully, even though the pulse number modulation was not as efficient as the amplitude and pulse width modulations. Moreover, it was found that longer inter-pulse intervals did not affect the temporal integration of electrical stimulation of multiple repeated pulses in driving RGC responses. Finally, the effect of temporal integration of multi-pulse electrical stimulation on RGC responses was likely originated from the upstream retinal neurons, not from stimulating RGCs directly.
In conclusion, electrical stimulation with the DPSS and pulse number modulation has great potentials in the retinal prosthesis design. These findings not only demonstrate the effect of temporal integration on visual prosthesis, but also provide an insight into the optimization of the photovoltaic retinal prosthesis. These strategies could be developed into an improved prosthesis device able to restore vision in the future.

致謝 4
摘要 5
Abstract 7
Chapter 1. Introduction 9
1-1 Retinal prosthesis 9
1-2 Visual persistence 9
1-3 Challenges of retinal prosthesis 10
1-4 Divisional power supply scheme 11
1-5 Multi-pulse electrical stimulation 11
1-6 Specific aims 12
Chapter 2. Materials and methods 14
2-1 Psychophysical experiments 14
2-2 Electrophysiological experiments 19
Chapter 3. Spatiotemporal integration of visual stimuli in the divisional power supply scheme of the retinal prosthesis 22
3-1 Results 22
3-2 Discussion 25
Chapter 4. Temporal Integration of repeated electrical stimuli in pulse number modulation of the retinal prosthesis 30
4-1 Results 30
4-2 Discussion 32
Chapter 5. Conclusion and general discussion 36
References 38
Table 48
Figures 49
Supplementary figure 64

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