Kensall D. Wise - US grants

Design, fabrication and testing of multielectrode probes for use in recording extracellular potentials from single cortical neurons in mammalian cerebral and cerebellar cortex.

The specific objective of this contract is research and development on thin film stimulation electrodes with the primary goal of developing modiolar auditory nerve electrodes, but with the realization that many of the techniques developed will be applicable to both recording and stimulating electrodes utilized throughout the nervous system by both basic neurophysiologists and neural prosthetic investigators.

To design, fabricate and test integrated multiplexed multiple electrode intracortical recording probes.

The objective of this contract is to design and fabricate multielectrode stimulating probes capable of stimulating small populations of neurons within the central nervous system.

This research will explore the use of single-sided bulk- silicon process technology for the realization of microelectromechanical systems (MEMS). Efforts on fundamental materials characterization, the development of new microstructure formation techniques, and the development of generic modeling and simulation capabilities for MEMS will be conducted. Research results will be applied in the fabrication of two- and three-dimensional devices, including electrostatically driven linear micromotors, laterally driven resonant microstructures, and microvalves. One device that will be considered is a fully integrated scanning thermal profilometer (STP) that operates using laterally driven resonant structures fabricated from bulk silicon. The STP will incorporate an integrated polysilicon metal thermocouple for temperature measurement, a submicron silicon tip supporting the thermocouple, electrostatic drive mechanisms, and a chip-level package realized by stacking multiple silicon levels to protect the STP from particulates and physical damage. The technology resulting from this research should complement surface micromachining techniques to extend the field of MEMS and realize new structures.

9413559 Wise This proposal requests funding to significantly upgrade the equipment for producing chemical-vapor deposited (CVD) thin dielectric films at the University of Michigan. Specifically, the proposal seeks funding to upgrade the pumping system on our existing LPCVD system for silicon nitride and silicon dioxide in order to overcome serious problems with down-time that have been experienced over the last several years. These problems have seriously impeded a number of important research programs. In addition, the proposal seeks funding to install a new CVD system for the deposition of low-temperature oxide (LTO) and phosphosilicate glass (PSG). While these processes are basic and standard throughout the microelectronics industry, they have never been available at Michigan, seriously limiting our research capabilities and the types of structures that can be addressed. The lack of these films has been a major factor limiting our research on surface micromachined microstructures, which are useful in the development of a great many integrated sensors and microactuators. Specific immediate uses of the LTO/PSG system include the conformal chip-level encapsulation of integrated sensors for use in chronically-implantable neural prostheses, the development of planarized feedthroughs for hermetically-sealed microsystems, and application in a number of microsensors and microactuators for use in transportation systems and automated semiconductor manufacturing. The proposed equipment directly affects the programs of 26 faculty and nearly 50 graduate research students at the University of Michigan; in addition, it will permit an expanded range of projects in two laboratory courses at the University and will allow structures such as those produced by surface micromachining to be introduced into the courses in a practical way. The field of sensors, microactuators, and microsystems ("MEMS") us expanding on a worldwide basis and is generally accepted as very important to areas such as health ca re, environmental CLOSEOUTDOC I T FTMON94 DOC $9 L MAY24PANDOC q ? X REIMFORTDOC WJ JIN TX8 Y f CONRAD TX8 p` i WISE TX8 +c

9713494 Wise Funds are provided to underwrite the cost of graduate student participation in the International Conference on Solid-State Sensors and Actuators to be held in Chicago in June, 1997. This conference is the world's leading forum for reporting new advances in integrated sensors, MEMS and Microsystems, and is held in the U.S. only once in every six years. ***

implant; microelectrodes; electronic recording system; brain electrical activity; biomedical equipment development; molecular film; telemetry; medical implant science; Mammalia;

technology /technique development; prosthesis; nervous system; biomedical resource; bioengineering /biomedical engineering;

This project is designed to extend the basic passive probe technology to make the probes more versatile by giving them more ways to interact with the cells which surround them. We have developed and successfully implemented a process which allows the inclusion of chemical delivery channels on the same substrate as the conductive electrode sites. This permits multipoint drug delivery and multichannel recording and/or stimulation with minimal tissue disruption. Successful packaging techniques for the chemical delivery probes have been developed which permit handling and use in the normal context of acute pharmacological characterization of neuronal activity. In vitro tests have verified the passage of quantified doses of fluid to a surrounding medium. In vivo tests of simultaneous chemical delivery and extracellular recordings in guinea pig inferior and superior colliculus are demonstrating results consistent with conventional approaches. Data presented at meetings including that of the 1998 Association for Research in Otolaryngology has generated much interest in the device by the neuroscience community. New devices have been fabricated which have configurations relevant to specific neurophysiological studies to be carried out in Dr. Bledsoe's laboratory. Developments during the past year include the development of an in-line flowmeter for monitoring of the dose chemical delivered.

Many potential neural prostheses, including visual, auditory, and motor prostheses, will not be feasible until microelectrode arrays are developed that allow multiple, small clusters of neurons to be independently stimulated. This project will involve research and development on thin-film microelectrode arrays capable of independently stimulating as many as 512 such small clusters of cells. Specifically, these microelectrode arrays are being designed to provide microstimulation at multiple sites in the visual cortex, the cochlear nucleus and the lumbrosacral spinal cord. Micromachining of silicon, combined with integration of electronic circuits on the micromachined structure, permits fabrication of active circuit microelectrodes with multiple stimulating sites on multiple shanks. Microelectrode arrays currently under development have 64 stimulation sites placed along 8 or 16 penetrating shanks. These 64-site, two-dimensional microelectrode arrays can be assembled into a 3-dimensional array with 512 stimulating sites. These thin- film stimulating microelectrodes have several advantages over more conventional wire bundle microelectrodes for multiple site, highly selective stimulation. Their stimulating site density is at least an order of magnitude greater than wire bundle electrodes and permits stimulation site spacing with dimensions comparable to the dimensions of neurons. The designs provide circuitry which permits extracorporeally generated stimulus instructions for many neural stimulating sites to be combined into a single signal and then decoded by integrated electronics on the implant. The integrated electronics also permit the arrays to be designed with integrated telemetry, eliminating the need for tethering cables.

The Engineering Research Center (ERC) for Wireless Integrated Microsystems is focused on miniature low-cost integrated microsystems capable of measuring or controlling a variety of physical parameters, interpreting the data, and communicating with a host system over a bi-directional wireless link. The ERC is targeted at the intersection of micropower electronics, wireless communications, and microelectromechanical systems (MEMS). The resulting devices are expected to become pervasive in society during the next two decades, with applications ranging from environmental monitoring (weather, global warming, air and water quality) to improved health care (wearable and implantable biomedical systems). The ERC brings together faculty from the University of Michigan, Michigan State University, Michigan Technology University, with expertise in VLSI design and computer architecture, wireless communications, packaging, medicine, and MEMS. The Center is supported by the State of Michigan and over twenty companies having vital interest in these areas.
The four research thrusts of the ERC focus on micropower circuits, wireless interfaces, sensors and microinstruments, and micropackaging. The work will extend existing micropower circuit techniques and sensor-driven controller architectures, develop single-chip communication transceivers based on micromechanical structures and MEMS microesonators, explore a variety of self-testing microinstruments (including chemical, mechanical, and thermal devices), and develop hermetic wafer-level packaging using deposited thin films and fused vacuum cavities. The goal is to develop systems that are rapidly configurable, reconfigurable, and self-testing. Work in these four thrust areas will be coordinated by focusing on two application testbed systems: an rf-powered implantable microsystem (initially a cochlear prosthesis for the profoundly deaf, with subsequent extension to devices for treating epilepsy and Parkinson's disease), and a battery-powered environmental monitoring system capable of gas analysis as well as the measurement of barometric pressure, temperature, humidity, and other variables. These testbeds are intended to emphasize the challenges that will be found in microsystems generally.
Industrial programs, including technology transfer and jobs creation, are important components of the ERC and will be addressed through joint efforts, personnel exchanges, and prototype fabrication. The multidisciplinary nature of microsystems makes them ideal tools for exploring innovative approaches to engineering education, including electives that cut across traditional disciplinary boundaries. The ability to mix students with different backgrounds in team-oriented research is critical in the training of future engineers. The educational thrusts in this ERC extend from high school through the graduate level. In high school, working with science coordinators and teachers, MEMS will be used to illustrate important principles and encourage students to pursue exciting careers in engineering. This will include special efforts with underrepresented minority students. In the undergraduate and graduate programs, multi-university multidisciplinary distance learning and virtual-laboratory experiences will be employed in the development of new course sequences in MEMS and microsystems. Finally, the ERC will explore the broader societal implications of these microsystems and their associated technology.
This award provides $2.5 million for the first year of NSF support to the ERC through a fice-year cooperative agreement, which is renewable in year three and six.

Current abstract still valid.

The objective of this proposal is to have a workshop on the subject of "From Macro to Nano: Challenges and Opportunities in Integrative Complex Systems Engineering". This workshop will attempt to define broadly integrative complex systems in terms of common threads, helping the ECS Division to focus future funding programs and initiatives in research and education in areas that will enable progress in the important areas of systems research. Integrated complex systems, configured as networks of information-gathering devices, are viewed as critical in meeting a broad range of societal challenges, including those associated with global warming, health care, transportation, manufacturing productivity, environmental quality, and homeland security. Such systems will extend the electronic connectivity represented by personal communications and the worldwide web to information provided directly by the environment.

Intellectual merit and broader impact: The workshop proceedings will highlight the challenges of integrative systems, and will define key research topics for the coming decade. The workshop will define what are the macro, micro, and nano systems and it will identify some key examples in support of these systems. The outcome of this workshop will help define future areas of IS emphasis for the ECS Division and the new IS research topics will impact the interdisciplinary and IS education. And will provide new and additional opportunities for encouraging more of our young people to pursue careers in science and engineering.

Abstract


Objective

This objective of this proposal is to request funding to support a workshop aimed at speeding the development of micro/nanoelectronic devices for improved healthcare. The workshop will be held at the Interdisciplinary Microelectronics Center (IMEC) in Leuven, Belgium on September 25-26, 2008. The workshop will bring together leading researchers from the microsystem and nanobiotechnology communities to identify grand challenges, promote collaborations, and recommend research needed to speed the use of these technologies in biology and biomedicine. This workshop will bring together scientists and engineers from micr/nano communities and biology and biomedicine and will try to identify devices and systems that could be used for in-vivo and in-vitro applications. The two disciplines seem destined to meet at cellular dimensions, and this workshop seeks to bridge the gap between them.

Intellectual Merit:
After nearly four decades, many of the microelectronic technologies needed for health care are now emerging. Sophisticated signal processing tasks involving millions of transistors can be performed on a single chip at microwatt levels. Wireless technology has created global communication networks and is being reduced to single chips capable of working in-vivo. MEMS-based sensors now exist for many physiological parameters, and hermetic wafer-level packaging techniques suitable for use in implants are emerging. Structures based on nanotechnology are being combined with microfluidics and being developed to analyze DNA and screen for proteomic biomarkers of Alzheimer?s disease, heart disease, and cancer. But many challenges remain. Improved power sources are needed, some perhaps based on energy scavenging, and the critical interface between the biological environment and physical monitoring devices must be much better understood. True advances in health care will likely require the integration of both.

Broader impact:
Health care is one of the most important problems confronting the 21st century. In 2000, life expectancies ranged from 35 years in Sierra Leone to 77 in the U.S. and 83 in Japan, and in U.S. the cost of health care represented 13% of GDP. About 630 million people worldwide were over the age of 60, but by 2050 this number will increase to over two billion, an increase of 330%. Clearly something must be done to avoid catastrophic health care cost. Diagnostic devices based on cellular/molecular analysis and implantable microsystems for treating many of our most serious chronic disorders are among the most promising approaches for meeting these challenges.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

The objective of this project is to acquire an electron-beam lithography system for the University of Michigan. This system will be used to facilitate research on a broad array of new technology, materials, structures, and devices, including nanolithography, negative-index materials, polymer-based photovoltaics, nanotube applications, quantum devices, nanomechanical terahertz antennas, fluidic systems for disease diagnostics, and chemical gas analyzers.

The electron-beam lithography system will enable research in the emerging areas of science and engineering. Research on new materials will include tunable light sources, spintronics, and high efficiency photovoltaics. Research in nanobiotechnology will include DNA analysis, protein patterning, and biophotonic flow cytometry. Research on nanodevices will include 250Gb/cm2 crossbar memories, nanoscale gas analyzers, and terahertz antennas. These discoveries will push our understanding of materials and devices well beyond current levels into the new frontier of atomic-scale nanotechnology.

This system allows generation of new sources for secure broadband communications, high-efficiency lighting, renewable energy, wristwatch-size sensors for global environmental monitoring and security, and breakthroughs in prostheses for deafness, blindness, paralysis and Parkinson's disease. The research enabled by this tool thus tackles some of the most critical challenges in energy, security, environmental quality, and health care facing us in the 21st century. In addition, it will also be utilized in undergraduate and graduate classes, in technical workshops for engineers, in outreach activities to convey the excitement of science and engineering careers to students at the pre-college level, and as a resource to researchers from academia and industry through the NSF National Nanofabrication Infrastructure Network.

The object of this research is to develop a new platform concept, BioBolt, as a distributed wireless neural interface for minimally-invasive, fully-implantable epidural recording. The approach is to implement a stand-alone wireless link for a number of microelectrodes, which can be easily placed on the dura mater through a small hole in the skull by simple operation procedure.

The technical challenge is to implement an extremely low-power wireless link in a small form factor. The proposed system consists of multiple BioBolts and MasterBolt. Spatially distributed BioBolts in the region of interest record the neural activities and send signals to MasterBolt. We explore the intra-skin wireless communication between BioBolt nodes and MasterBolt, which allows extremely low power signal transmission under 5?ÝW. MasterBolt transmits all the collected neural signals from the neighboring BioBolts using single-channel FM modulation with a power budget of <1mW. This system gives flexibility and expandability for long-term chronic monitoring of neural signals.

Fully-implanted distributed wireless microsystems for epidural neural recording will provide a new tool to study and understand the collective brain activities for practical interface with computer, prosthetic devices and control of impaired body. The completed system developed in this project will expand the potential applications for brain-to-computer interfaces beyond simple cursor control and offer people with motor disabilities a good alternative to natural communication and movement. This project will train graduate and undergraduate students across the different disciplines to implement an important interface between brain and electronics.

The objective of this program is to define a hierarchical integration architecture that allows all
the heterogeneous components required for electrical and optical interface with neurons can be
directly integrated on a micromachined probe substrate with a low-rise profile for high-density
studies of neural networks in behaving animals. The implemented microsystem aims to be a
generic platform technology for scalable, adaptable and reconfigurable hybrid integration.
The intellectual merit is in a number of important areas, including the formation of highdensity
interconnects to hybrid electronic chips, hermetic encapsulation of these chips on
micromachined platforms, the use of magnetically-aligned anisotropic conductive adhesives for
high-density lead transfers, the monolithic integration of highly-flexible parylene cables into
probes formed using completely dry-etched process flows, and the development of hermetic,
low-profile packages that are compatible with both the cables and the hybrid circuitry.
The broader impacts are in realizing tools to permit revolutionary progress in our
understanding of neural circuits and systems. The work will also provide a platform for realizing
improved prostheses designed to overcome disorders such as severe epilepsy, Parkinson?s
disease, and, perhaps, paralysis. Though important these breakthroughs in health care will be, the
impact of the work should be much broader, especially in combining MEMS-based sensors with
embedded computing and wireless connectivity, as the next major frontier in microelectronics,
coupling it to the non-electronic world.

Companies dealing with profound hearing loss, chronic pain, Parkinson's disease, and epilepsy must rely on expensive and technologically-limited hand-assembled electrode arrays in their neurostimulators. These devices are costly due to low throughput and yield; the complexity is limited by what can be achieved with the human hand; and quality assurance is difficult to maintain in the presence of human error. By using lithographically-based technology for the automated manufacturing of arrays, this project has the potential to significantly reduce their cost while improving their reproducibility and performance. The microelectromechanical arrays has the potential to enable medical device manufacturers to increase the number of electrodes on their leads by 5X, reduce the size of the electrodes by greater than 30X, reduce the overall size of the leads by 92%, and easily define the mechanical properties of the arrays. And by utilizing this technology to eventually add position sensing and actuation, the team believes that the insertion of the arrays can be largely automated, reducing surgical placement time and cost while allowing better placement and improved performance.

There is a rise in the incidence of neurological diseases and disorders in the US. Conditions such as hearing loss, Parkinson's disease, and epilepsy are more prevalent now than ever, and pharmaceutical solutions are lacking in both effectiveness and safety. Neurostimulation implants have been developed to treat such conditions, however, their performance and costs are lacking, due to hand-assembly manufacturing. In the case of hearing loss, over 150,000 cochlear prosthetics have been implanted worldwide to date; however, over 250 million people worldwide are estimated to be disabled due to hearing loss. Many of these people are in developing countries and lack the funds necessary to take advantage of current prostheses, both due to the cost of the systems themselves and due to the cost of the associated surgery. By using lithographically-based technology for the neurostimulation arrays, the team has the potential to significantly reduce their cost while improving their surgical safety and performance. The enabling technology will also promote the creation of new neurostimulation devices (e.g., for blindness and paralysis) whose size and complexity is not currently achievable with hand-assembly. The technology being proposed promised to result in a significant leap forward in the practical treatment of neurological disorders and diseases on a worldwide scale and thus possesses the potential for significant impact.

Significance: A number of scientific questions, especially in local circuit analysis, require manipulating neurons in vivo at multiple sites independently at high spatial and temporal resolutions by perturbing a controlled number and simultaneously recorded neurons. Optogenetic stimulation is cell-type specific which has proven to be the most powerful means of circuit control. Several laboratories have developed solutions to deliver optical stimulation to deep brain structures whilst simultaneously recording neurons. However, stimulation through light sources placed on the surface of the brain or large fibers placed in the brain parenchyma a few hundred ?mu?m from the recording sites inevitably activate many un-monitored neurons, making the separation of direct and population-mediated effects impossible. Moreover, the high intensity used for the activation of deep neurons may generate superposition of multiple spike waveforms and considerable light artifacts. There is an unmeet need to provide an adequate tool to enable local circuit stimulation to the level of single neurons and closed-loop interactions with excitation/inhibition patterns. The objective of this application is to develop high-density optoelectrode probes for enabling highly specific neural circuit control. Based upon our previous experience with waveguides, coupling technology, and high-density neural probes, we will implement a fiber-less, multi-channel, multi-wavelength platform for simultaneous, low-noise electrical recording and optical stimulation. Validation of multiple configurations will occur in vivo in rodents against clearly defined benchmarks. Preliminary Data: We have demonstrated the feasibility of the monolithic integration of optical waveguides with Michigan neural probes, delivering light from an aligned optical fiber to the stimulation site. We have also implemented both polymer (SU-8) and oxynitride waveguides in various configurations as optical mixers and splitters to guide light in lithographically-defined patterns. We implanted the fabricated probe in a rat and have successfully recorded neural spiking responses to optical stimulation (lambda=473nm) from the hippocampus CA1 region. Specific Aims: In aim 1, we will develop an efficient coupling scheme from the light source through novel reflector design and high-confinement waveguide implementation. We will optimize the waveguide and reflector efficiency through parametric and free-form optical modeling. In aim 2, we will fabricate and assemble the multi-channel multi-site optoelectrode array to achieve 60-?mu?W output from the low-profile waveguide for simultaneous, low-noise recording and optical stimulation. The tasks include microfabrication, thermal optimization, on-chip driver, low-noise optimization, assembly refinement and verification testing. In aim 3, the fabricated probes will be validated by two in-vivo experiments: one is activating few or single neurons at extremely low power (3-10?mu?W) and the other is closed-loop optogenetic interaction with identified neuron types using multi-color control.

ECCS Prop. No. 1407977

Proposal Title:
High-Density Neural Recording Arrays with Monolithically-Integrated Nanopillar LEDs for Multi-Wavelength Optical Stimulation

Award Goal
This research aims to achieve monolithic integration of full-color micro-LED arrays directly on silicon-based neural probes
such that optical stimulation of single neurons can be specifically tailored by wavelength and intensity.


Nontechnical Abstract

The objective of this work is to design, fabricate and test an implantable neural probe capable of simultaneous optical stimulation and chronic electrical recording in animals. Recent advancement in optogenetics (optical stimulation of neurons) promises new possibilities for selectively exciting or inhibiting individual neurons. However, to this date there is still an unmet need for reliable implantable tools to precisely deliver light to target neurons and simultaneously record from corresponding single neurons in a behaving animal. In the proposed work, we will develop an implantable probe with light emitting devices directly integrated on the lithographically defined probe shank. The size of light emitting devices and the recording electrodes have a dimension (~10 micrometers) similar to that of a neuron, offering unmatched resolution for single-cell manipulation.
The outcome of this result will be significant because the developed probe can allow high precision, local stimulation of multiple, spatially distinct inputs to a single neuron. Also, it will mitigate tethering problems and minimize hindering to the animal movement as compared to the previous optical fiber approaches, allowing practical scaling of light sources for a behavioral study. To realize the monolithic integration of multiple light sources on the probe shank, we adapt the display device technologies developed for solid-state lighting. Wavelength of the light emitting devices can be tailored by implementing nanopillar structures on the emitting surface.
This research will leads into the development of generic tools to access individual neurons in the target region of brain with high specificity for simultaneously recording and stimulation. The developed probes will open new windows into understanding the function and organization of the brain in the areas of brain mapping, memory storage, retrieval and plasticity in chronic behavioral neuroscience. There is good reason to hope that these advances will lead to dramatic improvements in our ability to treat some of mankind's most debilitating diseases such as Parkinson's disease, epilepsy and paralysis.
Technical Abstract
Recent advances in optogenetics provide a new capability to control action potential patterns by selectively exciting or inhibiting the targeted neurons by light at specific wavelengths. However, to date there is still an unmet need for reliable implantable tools to precisely deliver multiple wavelengths of light to manipulate neural activities at the cellular level and monitor the response of affected neurons simultaneously. This research aims to achieve monolithic integration of full-color micro-LED arrays directly on silicon-based neural probes such that optical stimulation of single neurons can be specifically tailored by wavelength and intensity. Monolithic integration allows precise alignment between the recording electrodes and the LED array with submicron accuracy. Multiple micro-LEDs in a cellular dimension (10 x15 micro-m2) allow precise local delivery of light to the target neurons at single cell resolution. The fabricate probe will be implanted in mice to perform a unique experiment that will elucidate how memories are formed and maintained.

This project entitled "International Program for the Advancement of Neurotechnology (IPAN)" is about understanding the complexity and mysteries of the brain. It is cited by many as the biggest scientific challenge of this century. In this International Program for the Advancement of Neurotechnology (IPAN), the researchers are creating a holistic system for studying brain activity by closely integrating hardware from leading neurotechnologists with novel software from leading neuroscientists. Enabling this large-scale collaboration should accelerate the rate of discovery in neuroscience. This in turn will pave the way to improved treatments for neurological disorders and to breakthroughs in artificial intelligence in the next decade. The PIRE team will also provide advanced educational opportunities for undergraduates with the express purpose of recruiting future U.S. STEM (science, technology, engineering and mathematics) researchers. Graduate students and postdocs will also be enrolled in a unique cross-training program between neuroscience and neurotechnology laboratories. The resulting experience will prepare a new generation of globally-connected multi-disciplinary engineers and scientists while driving critical advances in neurotechnology.

IPAN is an explicit partnership of leading neuroscientists and technologists to develop and deliver a hardware and software system that fundamentally simplifies the ability of a neuroscientist to (i) identify recorded neuron types, (ii) reconstruct local neural circuits, and (iii) deliver biomimetic or synthetic inputs in a cell-specific targeted manner. This project teams the University of Michigan, New York University, Howard Hughes Medical Institute, and the University of Puerto Rico with the University of Freiburg, the University of Hamburg-Eppendorf, the Korea Institute of Science and Technology, Singapore?s Institute for Microelectronics, and University College London. Complementary strengths, world-class infrastructures, and strong student exchange programs are an important part of this IPAN team, with major thrusts in Technology, Neuroscience, and Education. The enabling technology to meet these three system goals (i-iii) will be next-generation neural probes equipped with novel optoelectronics, high-density recording interfaces, and low-noise multiplexed digital outputs. The neuroscience thrust will help define the technology from the onset and are developing novel software tools to accelerate the analysis of large neurophysiological data sets. The team includes leading system neuroscientists with unique capabilities specializing in memory, sensory, fear, and development, and will work with technologists to validate both the technology and the software tools in distinctive neuroscience applications.

? DESCRIPTION (provided by applicant): A number of scientific questions, especially in local circuit analysis, require manipulating neurons in vivo at multiple sites independently at high spatial and temporal resolutions by perturbing a controlled number and simultaneously recorded neurons. Optogenetic stimulation is cell-type specific which has proven to be the most powerful means of circuit control. Several laboratories have developed solutions to deliver optical stimulation to deep brain structures whilst simultaneously recording neurons. However, stimulation through light sources placed on the surface of the brain or large fibers placed in the brain parenchyma a few hundred ¿m from the recording sites inevitably activate many un-monitored neurons, making the separation of direct and population-mediated effects impossible. Moreover, the high intensity used for the activation of deep neurons may generate superposition of multiple spike waveforms and considerable light artifacts. There is an unmeet need to provide an adequate tool to enable local circuit stimulation to the level of single neurons and closed-loop interactions with excitation/inhibition patterns. The objective of this application is to develop high-density optoelectrode probes for enabling highly specific neural circuit control. Based upon our previous experience with waveguides, coupling technology, and high-density neural probes, we will implement a fiber-less, multi-channel, multi-wavelength platform for simultaneous, low-noise electrical recording and optical stimulation. Validation of multiple configurations will occu in vivo in rodents against clearly defined benchmarks. Preliminary Data: We have demonstrated the feasibility of the monolithic integration of optical waveguides with Michigan neural probes, delivering light from an aligned optical fiber to the stimulation site. We have also implemented both polymer (SU-8) and oxynitride waveguides in various configurations as optical mixers and splitters to guide light in lithographically-defined patterns. We implanted the fabricated probe in a rat and have successfully recorded neural spiking responses to optical stimulation (¿=473nm) from the hippocampus CA1 region. Specific Aims: In aim 1, we will develop an efficient coupling scheme from the LED light source through novel reflector design and high-confinement waveguide implementation. A compact, elliptic reflector will be made with one layer of photo-defined transparent medium. We will optimize the waveguide and reflector efficiency through parametric and free-form optical modeling. In aim 2, we will fabricate and assemble the multi-channel multi-site optoelectrode array to achieve 60-¿W output from the low-profile waveguide for simultaneous, low-noise recording and optical stimulation. The tasks include microfabrication, thermal optimization, on-chip driver, low-noise optimization, assembly refinement and verification testing. In aim 3, the fabricated probes will be validated by two in-vivo experiments: one is activating few or single neurons at extremely low power (3-10¿W) and the other is closed-loop optogenetic interaction with identified neuron types using multi-color control.