An external control unit implemented for stimulator ASIC testing

This paper presents the design and development of an external control unit (ECU) for a stimulator ASIC testing purposes. The ECU consists of a graphical user interface (GUI) from the PC, a data transceiver and a power transmitter. The GUI was developed using MATLAB for stimulation data setup. The data transceiver was designed using hardware description language (HDL) Verilog code and was implemented in a Virtex-II Pro FPGA board. The overall stimulator ASIC design architecture and its operation for an epiretinal implant application are briefly explained to correlate with the ECU’s design requirements. The flexible multichannel stimulator ASIC was successfully fabricated in a 0.35μm AMS HVCMOS technology. Conducted simulation and measurement results on stimulation waveform generation, supply voltage compliance and external control of supply voltage adaptation validate the functionality of the designed ECU and the stimulator ASIC.Keywords: external control unit; data transceiver; stimulator ASIC; retinal prosthesis; epiretinal implant; stimulation waveform; Manchester data; voltage compliance

A Suprachoroidal Electrical Retinal Stimulator Design for Long-Term Animal Experiments and In Vivo Assessment of Its Feasibility and Biocompatibility in Rabbits

This article reports on a retinal stimulation system for long-term use in animal electrical stimulation experiments. The presented system consisted of an implantable stimulator which provided continuous electrical stimulation, and an external component which provided preset stimulation patterns and power to the implanted stimulator via a paired radio frequency (RF) coil. A rechargeable internal battery and a parameter memory component were introduced to the implanted retinal stimulator. As a result, the external component was not necessary during the stimulation mode. The inductive coil pair was used to pass the parameter data and to recharge the battery. A switch circuit was used to separate the stimulation mode from the battery recharging mode. The implantable stimulator was implemented with IC chips and the electronics, except for the stimulation electrodes, were hermetically packaged in a biocompatible metal case. A polyimide-based gold electrode array was used. Surgical implantation into rabbits was performed to verify the functionality and safety of this newly designed system. The electrodes were implanted in the suprachoroidal space. Evoked cortical potentials were recorded during electrical stimulation of the retina. Long-term follow-up using OCT showed no chorioretinal abnormality after implantation of the electrodes

Feasibility Assessment of an Optically Powered Digital Retinal Prosthesis Architecture for Retinal Ganglion Cell Stimulation

Clinical trials previously demonstrated the notable capacity to elicit visual percepts in blind patients affected with retinal diseases by electrically stimulating the remaining neurons on the retina. However, these implants restored very limited visual acuity and required transcutaneous cables traversing the eyeball, leading to reduced reliability and complex surgery with high postoperative infection risks. To overcome the limitations imposed by cables, a retinal implant architecture in which near-infrared illumination carries both power and data through the pupil to a digital stimulation controller is presented. A high efficiency multi-junction photovoltaic cell transduces the optical power to a CMOS stimulator capable of delivering flexible interleaved sequential stimulation through a diamond microelectrode array. To demonstrate the capacity to elicit a neural response with this approach while complying with the optical irradiance limit at the pupil, fluorescence imaging with a calcium indicator is used on a degenerate rat retina. The power delivered by the laser at the permissible irradiance of 4 mW/mm2 at 850 nm is shown to be sufficient to both power the stimulator ASIC and elicit a response in retinal ganglion cells (RGCs), with the ability to generate of up to 35 000 pulses per second at the average stimulation threshold. This confirms the feasibility of generating a response in RGCs with an infrared-powered digital architecture capable of delivering complex sequential stimulation patterns at high repetition rates, albeit with some limitations.Comment: 11 pages, 13 figure

Photogenetic Retinal Prosthesis

The last few decades have witnessed an immense effort to develop working retinal implants for patients suffering from retinal degeneration diseases such as retinitis pigmentosa. However, it is becoming apparent that this approach is unable to restore levels of vision that will be sufficient to offer significant improvement in the quality of life of patients. Herein, a new type of retinal prosthesis that is based on genetic expression of microbial light sensitive ion channel, Chanelrhodopsin-2 (ChR2), and a remote light stimulation is examined. First, the dynamics of the ChR2 stimulation is characterized and it is shown that (1) the temporal resolution of ChR2-evoked spiking is limited by a continuous drop in its depolarization efficiency that is due to (a) frequency-independent desensitization process and (b) slow photocurrent shutting, which leads to a frequency-dependent post-spike depolarization and (2) the ChR2 response to light can be accurately reproduced by a four-state model consisting of two interconnected branches of open and close states. Then, a stimulation prototype is developed and its functionality is demonstrated in-vitro. The prototype uses a new micro-emissive matrix which enables generating of two-dimensional stimulation patterns with enhanced resolution compared to the conventional retinal implants. Finally, based on the micro-emitters matrix, a new technique for sub-cellular and network-level neuroscience experimentations is shown. The capacity to excite sub-cellular compartments is demonstrated and an example utility to fast map variability in dendrites conductance is shown. The outcomes of this thesis present an outline and a first proof-of-concept for a future photogenetic retinal prosthesis. In addition, they provide the emerging optogenetic technology with a detailed analysis of its temporal resolution and a tool to expand its spatial resolution, which can have immediate high impact applications in modulating the activity of sub-cellular compartments, mapping neuronal networks and studying synchrony and plasticity effects

Doctor of Philosophy

dissertationMagnetic fields are permeable to the biological tissues and can induce electric field in the conductive structures. Some medical devices take advantage of this ability to transfer energy from the source to the receiving site without direct contact. Prosthetic devices such as retinal implants use time-varying magnetic field to achieve wireless power transfer to the implanted magnetic coil. However, devices such as magnetic stimulators use the induction principle to create an electric field at the stimulation site. Efficiency of these devices is primarily dependent on the design of the magnetic coils. Therefore, in this work, we designed and validated efficient magnetic coils for wireless power transfer to implanted devices and magnetic stimulation of the peripheral nerves. Typical wireless power transfer (WPT) systems uses two-coil based design to achieve contactless power transfer to the implanted electronics. These systems achieve low power transfer efficiency (< 30%) and frequency bandwidth. Moreover, efficient wireless system requires high coupling and load variation tolerance during device operation. To design an electromagnetic safe WPT system, the power absorbed by the tissue and radiated field due to the proximal magnetic coils needs to be minimized. In this work, we proposed a multi-coil power transfer system which solves some of the current challenges. The proposed multi-coil WPT system achieves more than twice the power transfer efficiency, controllable voltage gain, wider frequency bandwidth, higher tolerance to coupling and load variations, lower absorbed power in the tissue and lower radiated field from the magnetic coil than a comparable two-coil system. In this work, we have developed analytic models of the multi-coil WPT system and validated the accuracy of the solutions using experiments. Magnetic coils play an important role in controlling the distribution of induced electric field inside the nerve during magnetic stimulation. In the past, homogeneous models were used to estimate the field profile inside conductive tissue due to the time varying current in the magnetic coil. Moreover, the effect of the surrounding media and stimulation mechanisms was understudied, which limits the optimization accuracy of the magnetic coils. In this work, we developed anatomically correct tissue models to study the effect of tissue heterogeneity and the surrounding media on the induced electric field. We also developed an optimization algorithm for designing energy efficient cm-size magnetic coils, that were then used for ex-vivo magnetic stimulation of the frog's sciatic nerve

A Multi-Channel Stimulator With High-Resolution Time-to-Current Conversion for Vagal-Cardiac Neuromodulation

This paper presents an integrated stimulator for a cardiac neuroprosthesis aiming to restore the parasympathetic control after heart transplantation. The stimulator is based on time-to-current conversion. Instead of the conventional current mode digital-to-analog converter (DAC) that uses ten of microamp for biasing, the proposed design uses a novel capacitor time-based DAC offering close to 10 bit of current amplitude resolution while using only a bias current 250 nA. The stimulator chip was design in a 0.18 m CMOS high-voltage (HV) technology. It consists of 16 independent channels, each capable of delivering 550 A stimulus current under a HV output stage that can be operated up to 30 V. Featuring both power efficiency and high-resolution current amplitude stimulation, the design is suitable for multi-channel neural simulation applications

Zapping the Retina - Understanding electrical responsiveness and electrical desensitization in mouse retinal ganglion cells

The field of science and technology has come a long way since the famous 70’s science fiction series “The Six Million Dollar Man,” where a disabled pilot was transformed into a bionic superhero after receiving artificial implants. What was indeed once a science fiction has now turned into a science fact with the development of various electronic devices interfacing the human neurons in the brain, retina, and limbs. One such advancement was the development of retinal implants. Over the past two decades, the field of retinal prosthetics has made significant advancement in restoring functional vision in patients blinded by diseases such as Retinitis pigmentosa (RP) and Age-related macular degeneration (AMD). RP and AMD are the two leading cause of degenerative blindness. While there is still no definitive cure for either of these diseases, various treatment strategies are currently being explored. Of the various options, the most successful one has been the retinal implants. Retinal implants are small microelectrode or photodiode arrays, which are implanted in the eye of a patient, to stimulate the degenerating retina electrically. They are broadly classified into three types depending on the placement ̶ epiretinal (close proximity to retinal ganglion cells, RGCs) , subretinal (close proximity to bipolar cells, BP) and suprachoroidal (close proximity to choroid). While the ongoing human trials have shown promising results, there remains a considerable variability among patients concerning the quality of visual percepts which limits the working potential of these implants. One such limitation often reported by the implanted patients is “ fading” of visual percepts. Fading refers to the limited ability to elicit temporally stable visual percepts. While, this is not a primary concern for epiretinal implants , it is often observed in subretinal and suprachoroidal implants which use the remaining retinal network to control the temporal spiking pattern of the ganglion cells. The neural correlate of fading is often referred to as “electrical desensitization”, which is the reduction of ganglion cell responses to repetitive electrical stimulation . While much is known about the temporal component of desensitization ( time constant, τ), the spatial aspects (space constant, λ) has not been well characterized. Further, how both these aspects interact to generate spiking responses, remains poorly understood. These crucial questions formed the critical components of my thesis. To address these questions, we stimulated the retinal network electrically, with voltage and current pulses and recorded the corresponding spiking activity using the microelectrode arrays (MEAs). While addressing the primary question of my thesis, we were able to address few idiosyncrasies which has currently stymied the field of retinal prosthetics. At a conceptual level, we have developed an experimental and analysis framework by which one can identify the single stimulus that will activate the most ganglion cells (Chapter 2, Part 1). This stimulus is optimal for ‘blind’ experiments where the specific response properties of each cell are unknown. Furthermore, we attempted to understand the correspondence between the electrical response patterns and visual response types (Chapter 2, Part2). In Chapter 3, we sought to understand better how the visual responses parameters change during ongoing electrical stimulation. We demonstrated that apart from the adaptation occurring due to visual stimulation and invitro experimental conditions, the electrical stimulation alters the RGC visual responses, suggesting the requirement for stimulation-induced changes to be incorporated in the designing of stimulation paradigms for the implant. Finally addressing the primary question (Chapter 4) of my thesis with which we started, we were able to demonstrate, that the electrical desensitization requires the interaction of both time and distance and is not a global phenomenon of the retina. In the final chapter (Chapter 5) we summarize the results of the thesis, discuss the key outcomes and its relevance to the prosthetic field and other vision restoration strategies and the potential future directions of this research. Therefore, in future, to improve the efficacy of retinal prostheses and patient outcomes, it is crucial to have an in-depth understanding of the responsiveness of the retinal circuitry to electrical stimulation

Current Stimulator IC for Retinal Prosthesis Using Nanowire FET Switch Array and in vitro Experiment with rd1 Mouse

학위논문 (석사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 2. 조동일.망막 색소 변성 (Retinitis pigmentosa) 및 노인성 황반 변성 (Age-related macular degeneration) 은 난치성 망막 변성 질환으로서 발병 후 수 년 내에 시력을 완전히 상실하게 한다. 이러한 망막 변성 질환을 치료하기 위해 전기 자극으로 시각 신경 신호를 발생시키는 인공망막 장치가 개발되어 왔다. 최근에는 세계 각지의 연구 그룹에서 자극 해상도를 1,000 픽셀 이상으로 높여 보다 뚜렷한 시각 정보를 전달하려는 시도를 하고 있다. 그러나 기존의 one-to-one interconnection 방식으로 전극과 자극기 회로를 연결할 경우, 배선이 복잡해져 유연한 인공망막 장치를 개발하기 어렵다. 이에 따라 본 연구진에서는 32 × 32 픽셀의 나노와이어 field-effect transistor (FET) 스위치 array 를 이용하여 배선의 복잡성을 줄인 고해상도 인공망막 장치를 개발하고 있다. 본 논문에서는 나노와이어 FET 스위치 기반의 인공망막 자극기 구동을 위한 자극기 회로에 대해 다루고 있다. 본 자극기 회로는 12 V 의 자극 전압을 사용하여, 0 ~ 100 μA 의 자극 전류를 주입할 수 있도록 설계하였다. 또한 나노와이어 FET 스위치 기반의 인공망막 자극 시스템 구동을 위한 디지털 인터페이스 회로를 포함하고 있다. 본 자극기 회로는 12 V 의 고전압 자극을 인가하기 위해 0.35 μm bipolar-CMOS (Complementary Metal-Oxide-Semiconductor)-DMOS (Double Diffused Metal-Oxide-Semiconductor) 공정을 이용하여 제작하였다. 자극기 회로의 기능 검증을 위해 전류 주입 실험 및 in vitro 실험을 진행하였다. 전류 주입 실험 결과 입력 신호에 따라 자극 전류의 세기가 적절히 변화하였으며, 시뮬레이션과 5% 내외의 오차를 보였다. 또한 in vitro 실험을 통해 전류 자극 세기에 따라 신경 반응이 조절되는 유효한 신경 자극을 인가할 수 있음을 확인하였다.Retina pigmentosa (RP) and Age-related macular degeneration (ARMD) are incurable retinal degenerative diseases that cause vision loss in several years after disease onset. Retinal prosthetic devices using electrical stimulations have been developed to restore vision of people blinded from the RP and ARMD. Recently, many research efforts have been tried to achieve a high-spatial resolution with more than 1,000 pixels. However, it is difficult to achieve the high-spatial resolution with the conventional one-to-one interconnection method that requires excessive wiring complexities. In our research group, a high-resolution retinal prosthetic system using a nanowire field-effect transistor (FET) switch integrated 32 × 32 microelectrode array (MEA) has been developed to resolve the wiring problem. In this paper, a current stimulator integrated circuit (IC) to operate the nanowire FET switch integrated MEA is presented. The stimulator circuit generates a biphasic stimulation current in a range of 0 to 100 μA using a high stimulation voltage of 12 V. The digital interface circuits are also integrated in the stimulator IC to operate the MEA. For the high voltage stimulation of 12 V, the stimulator IC is fabricated using a 0.35 μm bipolar-CMOS (Complementary Metal-Oxid-Semiconductor)-DMOS (Double Diffused Metal-Oxide-Semiconductor) process. Experimental results show that the amplitude of the stimulation current is properly modulated according to the level of the input signal. Errors between the measured current amplitudes and the simulated levels are approximately 5%. An in vitro experiment is also conducted to evaluate the neural stimulating function of the fabricated stimulator IC. In the in vitro experiment, the neural responses are successfully evoked by the current stimulation from the stimulator IC.제 1 장 서 론 1 제 1 절 연구의 배경 1 제 1 항 망막 변성 질환 1 제 2 항 시각 보철의 종류 5 제 3 항 인공망막 장치의 분류 7 제 4 항 인공망막 장치 연구 동향 12 제 5 항 고해상도 인공망막 자극기 개발의 필요성 15 제 6 항 고해상도 자극을 위한 나노와이어 FET 스위치 array 기반 인공망막 자극 시스템 17 제 2 장 본 론 19 제 1 절 설계 개념 19 제 1 항 나노와이어 FET 스위치 array 기반 인공망막 자극 시스템의 동작 개념 19 제 2 항 나노와이어 FET 스위치 array 기반 인공망막 자극기 회로의 동작 조건 21 제 2 절 설계 및 시뮬레이션 25 제 1 항 자극기 회로 전체 구성 25 제 2 항 Analog block 설계 27 제 3 항 Digital block 설계 36 제 4 항 Layout 43 제 3 절 시스템 구현 45 제 1 항 자극 시스템 구현을 위한 PCB 제작 45 제 4 절 실험 및 검증 48 제 1 항 전기적 특성 평가 48 제 2 항 in vitro 동물 실험 56 제 3 장 결 론 65 제 1 절 자극기 회로의 기능성 평가 65 제 2 절 향후 계획 67 참고문헌 68 ABSTRACT 74Maste

Information transmission in normal vision and optogenetically resensitised dystrophic retinas

Phd ThesisThe retina is a sophisticated image processing machine, transforming the visual scene as detected by the photoreceptors into a pattern of action potentials that is sent to the brain by the retinal ganglion cells (RGCs), where it is further processed to help us understand and navigate the world. Understanding this encoding process is important on a number of levels. First, it informs the study of upstream visual processing by elucidating the signals higher visual areas receive as input and how they relate to the outside world. Second, it is important for the development of treatments for retinal blindness, such as retinal prosthetics. In this thesis, I present work using multielectrode array (MEA) recordings of RGC populations from ex-vivo retinal wholemounts to study various aspects of retinal information processing. My results fall into two main themes. In the rst part, in collaboration with Dr Geo rey Portelli and Dr Pierre Kornprobst of INRIA, I use ashed gratings of varying spatial frequency and phase to compare di erent coding strategies that the retina might use. These results show that information is encoded synergistically by pairs of neurons and that, of the codes tested, a Rank Order Code based on the relative order of ring of the rst spikes of a population of neurons following a stimulus provides information about the stimulus faster and more e ciently than other codes. In the later parts, I use optogenetic stimulation of RGCs in congenitally blind retinas to study how visual information is corrupted by the spontaneous hyperactivity that arises as a result of photoreceptor degeneration. I show that by dampening this activity with the gap junction blocker meclofenamic acid, I can improve the signal-to-noise ratio, spatial acuity and contrast sensitivity of prosthetically evoked responses. Taken together, this work provides important insights for the future development of retinal prostheses