A CMOS-based neural implantable optrode for optogenetic stimulation and electrical recording

This paper presents a novel integrated optrode for simultaneous optical stimulation and electrical recording for closed -loop optogenetic neuro-prosthetic applications. The design has been implemented in a commercially available 0.35μm CMOS process. The system includes circuits for controlling the optical stimulations; recording local field potentials (LFPs); and onboard diagnostics. The neural interface has two clusters of stimulation and recording sites. Each stimulation site has a bonding point for connecting a micro light emitting diode (μLED) to deliver light to the targeted area of brain tissue. Each recording site is designed to be post-processed with electrode materials to provide monitoring of neural activity. On-chip diagnostic sensing has been included to provide real-time diagnostics for post-implantation and during normal operation

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

Evolution of optogenetic microdevices

Implementation of optogenetic techniques is a recent addition to the neuroscientists\u27 preclinical research arsenal, helping to expose the intricate connectivity of the brain and allowing for on-demand direct modulation of specific neural pathways. Developing an optogenetic system requires thorough investigation of the optogenetic technique and of previously fabricated devices, which this review accommodates. Many experiments utilize bench-top systems that are bulky, expensive, and necessitate tethering to the animal. However, these bench-top systems can make use of power-demanding technologies, such as concurrent electrical recording. Newer portable microdevices and implantable systems carried by freely moving animals are being fabricated that take advantage of wireless energy harvesting to power a system and allow for natural movements that are vital for behavioral testing and analysis. An investigation of the evolution of tethered, portable, and implantable optogenetic microdevices is presented, and an analysis of benefits and detriments of each system, including optical power output, device dimensions, electrode width, and weight is given. Opsins, light sources, and optical fiber coupling are also discussed to optimize device parameters and maximize efficiency from the light source to the fiber, respectively. These attributes are important considerations when designing and developing improved optogenetic microdevices

A scalable optoelectronic neural probe architecture with self-diagnostic capability

There is a growing demand for the development of new types of implantable optoelectronics to support both basic neuroscience and optogenetic treatments for neurological disorders. Target specification requirements include multi-site optical stimulation, programmable radiance profile, safe operation, and miniaturization. It is also preferable to have a simple serial interface rather than large numbers of control lines. This paper demonstrates an optrode structure comprising of a standard complementary metal-oxide-semiconductor process with 18 optical stimulation drivers. Furthermore, diagnostic sensing circuitry is incorporated to determine the long-term functionality of the photonic elements. A digital control system is incorporated to allow independent multisite control and serial communication with external control units

Optogenetics in Silicon: A Neural Processor for Predicting Optically Active Neural Networks

We present a reconfigurable neural processor for real-time simulation and prediction of opto-neural behaviour. We combined a detailed Hodgkin-Huxley CA3 neuron integrated with a four-state Channelrhodopsin-2 (ChR2) model into reconfigurable silicon hardware. Our architecture consists of a Field Programmable Gated Array (FPGA) with a custom-built computing data-path, a separate data management system and a memory approach based router. Advancements over previous work include the incorporation of short and long-term calcium and light-dependent ion channels in reconfigurable hardware. Also, the developed processor is computationally efficient, requiring only 0.03 ms processing time per sub-frame for a single neuron and 9.7 ms for a fully connected network of 500 neurons with a given FPGA frequency of 56.7 MHz. It can therefore be utilized for exploration of closed loop processing and tuning of biologically realistic optogenetic circuitry

Optogenetics in silicon: A neural processor for predicting optically active neural networks

We present a reconfigurable neural processor for real-time simulation and prediction of opto-neural behaviour. We combined a detailed Hodgkin-Huxley CA3 neuron integrated with a four-state Channelrhodopsin-2 (ChR2) model into reconfigurable silicon hardware. Our architecture consists of a Field Programmable Gated Array (FPGA) with a custom-built computing data-path, a separate data management system and a memory approach based router. Advancements over previous work include the incorporation of short and long-term calcium and light-dependent ion channels in reconfigurable hardware. Also, the developed processor is computationally efficient, requiring only 0.03 ms processing time per sub-frame for a single neuron and 9.7 ms for a fully connected network of 500 neurons with a given FPGA frequency of 56.7 MHz. It can therefore be utilized for exploration of closed loop processing and tuning of biologically realistic optogenetic circuitry

Doctor of Philosophy

dissertationOptical methods are well-established in the fields of neuroscience, medical imaging, and diagnostics, etc. Optogenetics, for example, enables molecular specificity in optical neural stimulation and recording and has been named the "Method of the Year 2010" by Nature Methods. A novel microdevice was designed, fabricated, developed, and tested to facilitate three-dimensional (3D) deep-tissue light penetration with the capacity to accommodate spatiotemporal modulation of one or more wavelengths to advance a broad range of applications for optical neural interfaces. A 3D optrode array consisting of optically transparent "needles" can penetrate >1 mm directly into tissue, thereby creating multiple independent paths for light propagation that avoid attenuation due to tissue absorption and scattering, providing a high level of selectivity and comprehensive access to tissue not available in current interfaces. Arrays were developed based upon silicon and glass. The silicon optrode array is based upon the well-established Utah electrode array architectures and is suitable for near-infrared (NIR) applications; glass optrodes are appropriate waveguides for both visible and NIR wavelengths. Arrays were bulk-micromachined with high-aspect ratio, a process that has not been reported to be applied to glass previously. In addition to device fabrication, extensive laboratory testing was performed with various optical sources to determine loss mechanisms and emitted beam profiles in tissue across the relevant wavelength ranges, with particular focus on performance metrics for optogenetic and infrared neural stimulation applications. Optrode arrays were determined to be amenable to integration with typical neural stimulation and imaging light delivery mechanisms such as optical fibers and microscopes. Glass optrodes were able to transmit light at ~90% efficiency through depths many times greater than the tissue attenuation length, with negligible light in-coupling loss. Si optrodes were determined to be only ~40% efficient with losses mostly from high index contrast, tip backreflection, and taper radiation. The in-coupling technique and optrode geometry may be modified to produce illumination volumes appropriate for various experimental paradigms. While the focus of this work is on optical neural stimulation, optrode array devices have application in basic neuroscience research, highly selective photodynamic therapy, and deep tissue imaging for diagnostics and therapy

FPGA design and implementation of a framework for optogenetic retinal prosthesis

PhD ThesisThere are 285 million people worldwide with a visual impairment, 39 million of whom are completely blind and 246 million partially blind, known as low vision patients. In the UK and other developed countries of the west, retinal dystrophy diseases represent the primary cause of blindness, especially Age Related Macular Degeneration (AMD), diabetic retinopathy and Retinitis Pigmentosa (RP). There are various treatments and aids that can help these visual disorders, such as low vision aids, gene therapy and retinal prosthesis. Retinal prostheses consist of four main stages: the input stage (Image Acquisition), the high level processing stage (Image preparation and retinal encoding), low level processing stage (Stimulation controller) and the output stage (Image displaying on the opto-electronic micro-LEDs array). Up to now, a limited number of full hardware implementations have been available for retinal prosthesis. In this work, a photonic stimulation controller was designed and implemented. The main rule of this controller is to enhance framework results in terms of power and time. It involves, first, an even power distributor, which was used to evenly distribute the power through image sub-frames, to avoid a large surge of power, especially with large arrays. Therefore, the overall framework power results are improved. Second, a pulse encoder was used to select different modes of operation for the opto-electronic micro-LEDs array, and as a result of this the overall time for the framework was improved. The implementation is completed using reconfigurable hardware devices, i.e. Field Programmable Gate Arrays (FPGAs), to achieve high performance at an economical price. Moreover, this FPGA-based framework for an optogenetic retinal prosthesis aims to control the opto-electronic micro-LED array in an efficient way, and to interface and link between the opto-electronic micro-LED array hardware architecture and the previously developed high level retinal prosthesis image processing algorithms.University of Jorda

Self-diagnosis implantable optrode for optogenetic stimulation

PhD ThesisAs a cell type-specific neuromodulation method, optogenetic technique holds remarkable potential for the realisation of advanced neuroprostheses. By genetically expressing light-sensitive proteins such as channelrhodopsin-2 (ChR2) in cell membranes, targeted neurons could be controlled by blue light. This new neuromodulation technique could then be applied into extensive brain networks and be utilised to provide effective therapies for neurological disorders. However, the development of novel optogenetic implants is still a key challenge in the field. The major requirements include small device dimensions, suitable spatial resolution, high safety, and strong controllability. In particular, appropriate implantable electronics are expected to be built into the device, accomplishing a new-generation intelligent optogenetic implant. To date, different microfabrication techniques, such as wave-guided laser/light-emitting diode (LED) structure and μLED-on-optrode structure, have been widely explored to create and miniaturise optogenetic implants. However, although these existing devices meet the requirements to some extent, there is still considerable room for improvement. In this thesis, a Complementary Metal-Oxide-Semiconductor (CMOS)-driven μLED approach is proposed to develop an advanced implantable optrode. This design is based on the μLED-on-optrode structure, where Gallium Nitride (GaN) μLEDs can be directly bonded to provide precise local light delivery and multi-layer stimulation. Moreover, an in-built diagnostic sensing circuitry is designed to monitor optrode integrity and degradation. This self-diagnosis function greatly improves system reliability and safety. Furthermore, in-situ temperature sensors are incorporated to monitor the local thermal effects of light emitters. This ensures both circuitry stability and tissue health. More importantly, external neural recording circuitry is integrated into the implant, which could observe local neural signals in the vicinity of the stimulation sites. Therefore, a CMOS-based multi-sensor optogenetic implant is achieved, and this closed-loop neural interface is capable of performing multichannel optical neural stimulation and electrical neural recording simultaneously. This optrode is expected to represent a promising neural interface for broad neuroprosthesis applications