Daryl Kipke - US grants

9409939 Kipke This Research Initiation Award proposes involved understanding of speech processing in the elaborate neural circuits of the lower auditory system and to apply this understanding to improving cochlear implants. The objectives are to develop computer models of the cochlear nucleus to explore central auditory processing. The specific aims are to: (1) identify anatomical and physiological parameters that are critical for single-cell responses to tones, noise, and speech using detailed models of the cochlear nucleus primary types of neurons, (2) identify parameters that are critical for describing the functional connectivity in the cochlear nucleus using network models, and (3) investigate the effects of reduced cochlear function on the processing in the cochlear nucleus. ***

9624636 Kipke Cochlear implants are small wires inserted in the inner ear that can restore limited hearing to some profoundly deaf people. However, our understanding of the neurological mechanisms by which such implants work is far from complete. While we know that auditory areas of the cerebral cortex in adults continually change in response to the sounds that are listened to and to the onset of partial deafness, comparatively little is known about how these parts of the brain respond to long-term use of cochlear implants by hearing-impaired persons. Yet, this adaptation (or plasticity) of the cerebral cortex most likely plays a critical role in determining the ultimate effectiveness of the implants, and could provide a key to unlocking the world of sound for more hearing-disabled people. This project involves novel experiments and the development of new computer models to investigate the dynamics (extent and rate) of plasticity in auditory-related areas of the cerebral cortex in response to long-term electrical stimulation using cochlear implants. Array of hair-sized wire electrodes are implanted into the cerebral cortex of deafened animals that have been fitted with a cochlear implant. These electrodes allow monitoring of local neurological responses as the animals learn to "listen" via their cochlear implant. These responses are correlated with behavioral performance to gain insight into the brain's responses elicited by the implants and their functional significance. Concurrently developed computer models of the relevant brain areas and of the cochlear implant provide important analytical and visualization tools for understanding the complex mechanisms involved in cerebral cortex plasticity driven by the implants. This research is complemented by an education plan in which a graduate-level student internship is developed with a leading cochlear implant company. This internship extends beyond the conventional walls of academia by providing an opport unity for bioengineering students to gain substantive experience in a high- tech industrial setting. It is a mechanism for training students in science and engineering to contribute to advances in the U.S. medical device industry. This project provides critical new insight into how the brain adapts to long-term use of cochlear implants. A better understanding of cerebral cortex plasticity may lead to important new advances in cochlear implant design and patient training procedures. The project also provides important new opportunities for attracting talented bioengineering students who are interested in neural prostheses. Together these activities will ultimately, help increasingly larger numbers of hearing- impaired people regain the ability to enjoy the sounds of the world. ***

The major thrust of this Center proposal is to enable research investigators in systems neurobiology, neuroprosthesis designers and other electrophysiologists to communicate with excitable tissue using multichannel thin-film devices constructed on silicon substrates. One, two and three dimensional arrays with tens to hundreds of recording or stimulation sites can be custom designed to fit the needs of specific tissue communication applications. There is a significant service and technology transfer component to this center. The Center educates investigators on the technology and its use through a number of media. New users are first given stock devices found in a catalog published by the Center and proceed to working with the Center staff to design new probes and matching an interconnect technology to their application. The service component and the research projects of the Center are designed to move the technology in three major directions over the next five years: 1) make the design of probes more rational by developing a data base and models will quantitatively guide researchers and designers, 2) broaden the distribution offerings of the Center include fluid delivery probes, probes with active circuits, probes coated with bioactive materials and three dimensional probes and 3) move the fabrication from University Laboratories to commercial fabrication facilities. Three internal research projects drive these thrusts. These projects cover extensions of the device technology, through experimentation and modeling, understand more fully the recording and stimulation characteristics of the devices, and development of methods by which exact geometrical relationships between tissue and devices can be confirmed postmortem. In addition to these projects there are several collaborative projects with investigators in universities and industry involving all of our major application areas.

This proposal is for the acquisition of a new 400 kV, research-grade ion implanter to replace an aging 200 kV commercial unit and to significantly expand capability. In the past 10 years, over 30 research groups, from within the U of M, other universities and industry have used the current ion implanter. This research has resulted in dozens of publications, some of which are referenced in the project description. Over 40 graduate students have used the implanter for a significant portion of their thesis research. The new implanter will be an essential part of 14 research programs across campus, especially in the areas of 1) nanoparticle formation in metals and ceramics, 2) semiconductor nanostructures and heterostructures, 3) atomic and molecular structure modification, and 4) biomedical device materials. It will also play the lead role in providing surface modification capability to users of the NSF National Nanotechnology Infrastructure Network (NNIN) through the Michigan node. This instrument will support research programs of 28 faculty spanning 9 departments across the University (Materials Science & Engineering, Nuclear Engineering and Radiological Sciences, Biomedical Engineering, Electrical Engineering and Computer Sciences, Mechanical Engineering, Aerospace Engineering, Physics, Chemistry, and Geological Sciences), 5 other universities (Michigan State University, Wayne State University, Ohio State, U. Arkansas, University of Cork) and involving 55 graduate students, undergraduate students and post-docs, not including participation from NNIN. The programs outlined in the proposal narrative are some of the principal research programs at UM relying on ion implantation at MIBL.


Ion implantation is a technique of using a beam of charged atoms (ions) to introduce a new atomic type into a material. This method is widely used in the semiconductor industry, where it is a fundamental tool in fabricating all modern electronic devices. The new implanter funded in this proposal will allow researchers in nine different departments to introduce students to research using this instrument. We are replacing an earlier instrument that has been operational for years, and very productive, but which is now obsolete. Dozens of students have been trained with the earlier instrument and a very broad set of research programs started. We will extend that work to an even wider audience, including collaborations with 5 other universities, and have research programs underway that involve 55 graduate, undergraduate and postdoctoral students. The new implanter will be used in several educational programs specifically aimed at undergraduate and high schools students trhough the NASA Summer High School Apprenticeship Program (SHARP).

DESCRIPTION (provided by applicant): Our long-term research goal is to develop implantable neurotechnologies for long-term and high fidelity microscale electrical and chemical interfaces to the central nervous system. The objective of this two-year project is to develop a new type of multi-modal neural probe by integrating chemical sensors on microfabricated thin-film silicon devices that are presently used for neural recording, stimulation, and microscale drug injection. The first specific aim is to develop and characterize integrated chemical sensing of two electroactive neurochemicals (dopamine and serotonin), along with concurrent electrophysiological recording. The primary tasks include developing electrode site materials, integrating a reference electrode onto the probe substrate, and characterizing 'electrode site spacing for concurrent neurochemical sensing and electrophysiological recording. The second specific aim is to develop arid characterize integrated chemical sensing of two non-electroactive neurochemicals (acetylcholine and glutamate), along with concurrent electrophysiological recording and microfluidic delivery of pharmacological agents. The primary tasks of this aim include developing polymer wells and conductive polymer coatings for enzyme entrapment and characterizing sensor performance. In both aims, the multi-modal devices will be quantitatively evaluated and systematically refined through bench top testing and in vivo acute experiments. This project significantly extends the state-of-the-art for microscale neural interfaces by developing a new technology that combines precise, high-resolution neurochemical sensing with high-fidelity neural recording and targeted drug delivery. This technology is likely to provide a solid foundation for developing a new class of implantable device that will enable next-generation, closed-loop neuroprostheses and neuromodulation systems for improved treatments of neurological disease and injury, such as Parkinson's Disease and severe movement disorders.

DESCRIPTION (provided by applicant): Microfabricated implantable neural probes are an enabling technology for neuroscience. The demand for these devices comes from diverse scientific directions and presents challenging technical requirements. The mission of the Center for Neural Communication Technology is to develop and provide microscale neural probe technologies for chronic, high-fidelity neural interfaces to the CNS. We will fulfill this mission by establishing a systematic, sequenced research and development program that integrates leading-edge neurotechnologies and techniques with pioneering neuroscience applications. The Center has four objectives: Objective 1 is to develop microscale neural probes, treatments, and methodologies for long-term, multichannel electrical and chemical neural interfaces with targeted areas of the brain. Objective 2 is to integrate these components into implantable devices and characterize their long-term biocompatibility and performance in diverse experimental applications. Objective 3 is to provide service and training to Center participants that will enable them to fully understand and use the Center's devices and methodologies in their research. Objective 4 is to disseminate research and technology outcomes to Center participants, the neuroscience and neural engineering communities, and the broader national research community. We will work closely with collaborators to define, refine, and test new devices and techniques that are directed at providing more powerful neural interfaces to extend their research. We will also work with larger groups of invited users to further validate the devices for broader applications. Our approach is to systematically extend our core platform neural interface technology in directions that will systematically overcome the biocompatibility issues and device limitations that presently limit long-lasting microscale electrical and chemical neural interfaces. We will combine our R&D program with an equal effort in in training and dissemination in order to maximize the Center's impact on the national research community. The Center's organization and operations provide a means to efficiently coordinate and manage its four programs to meet its objectives. Each program has an identified leader who is responsible for its overall performance. Each program is milestone driven with realistic operational processes and measurable outcomes. Synergy among the Center's programs is highly valued and will be facilitated by aligning research goals across core and collaborative projects, and by establishing cross-cutting work groups to address specific research, service, training, and dissemination problems.

[unreadable] DESCRIPTION (provided by applicant): Cortical control is emerging as an important area in neuroprosthetic research. The different types of neural signals that are being investigated as control signals depend on the volume of brain tissue that is sampled and the invasiveness of the recording electrode. In particular, multi-channel neuronal spike recordings and local field potentials have been separately considered for real-time cortical control applications. While these signals are both intracortical extracellular potentials that are recorded simultaneously using implantable microelectrode arrays, the relationship between these signals in the context of providing optimized cortical control has not yet been explored. The objective of this project is to investigate the information content of multi-channel spike recordings and local field potentials used either in isolation or in concert in a real-time cortical control paradigm. This integrated look at the control aspects of spike recordings and local field potentials seeks to understand the degree to which combining these signals can be used to optimize the cortical control signal. This project has two specific aims. Specific aim 1 is directed at quantitatively determining the shared information between multi-channel local field potentials and spike recordings. Animals will be operantly conditioned to modulate either multiple local field potential signals only or multiple spike recordings only, with both types of signals being recorded. Offline analysis will investigate the degree to which information about the target states is distributed between and within the two types of signals. Specific aim 2 is directed at investigating the relative contribution of local field potentials and spike recordings when subjects perform an operant conditioning task that utilizes both types of signals. Subjects will be provided the opportunity to use both (or either) local field potentials and ensemble spike activity to perform a behavioral task. The relative decoding filters for both signals will be compared to determine subject preference. Task difficulty will then be varied in order to study the interplay between task difficulty and modality preference. This project investigates a novel use of intracortical signal combinations for neuroprosthetic control and it is likely to contribute to the development of future clinical neuroprostheses. [unreadable] [unreadable]

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DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (13): Smart Biomaterials - Theranostics, and specific Challenge Topic, 13-NS-101: Developing novel biomaterials to interfaces with neural activity. Implantable neural interface devices are a critical component to a broad class of emerging neuroprosthetic and neurostimulation systems, in both research and clinical settings. In almost all cases, the performance of the system hinges to a large degree on the performance of the device to record and/or stimulate within quality, stability, and longevity requirements. Recording quality, longevity and stability is highly variable according to numerous reports, and the reactive tissue response that occurs to devices following implantation is a likely key contributing factor. The fundamental challenge is to develop advanced materials and implantable structures that will enable neural interface devices to be implanted in target areas of the brain and remain functional for as long as needed, sometimes stretching into years and decades. This proposal provides an innovative strategy that uses leading-edge biocompatible polymers to develop innovative 'microthread neural probes'that are ultra-small and flexible, with bioactive surfaces and nanostructured electrode sites for enhanced signal transduction. We will create these microthread probes using advanced carbon nanotube (CNT) and bioactive polymer coating technologies. We will focus on the problem of chronic neural recording of spike activity because this is considered to be the most sensitive assay of neural interface material performance. Aim 1 is to develop base versions of microthread neural probes for chronic neural recording. This aim will establish a technology foundation and set of validation benchmarks for microthread neural probes. The primary tasks will be to integrate CNT and functionalized polymer coating technologies into microthread neural probes that can be reliably inserted into the brain and used for chronic recording. The design space includes size, flexibility, strength, conductivity, site electrical characteristics, insulating coating, insertion techniques, and electrode size. Aim 2 will develop functionalized microthread neural probes for targeted intervention in chronic tissue responses. The guiding hypothesis is that immobilized biomolecules on the microthread probe surface be effective for intervening with specific reactive tissue responses, including biofouling, inflammation, and neurotoxicity. This proposal is innovative in its biologically inspired strategies and use of leading-edge biomaterials to develop chronic neural probes that are small (sub-cellular), flexible, and strong with excellent electrical and transduction properties, and have sophisticated surfaces tailored for specific biological processes. This project is likely to make significant contributions through developing advanced neural probes for long-term (permanent), high quality and selective neural recording. The outcomes of this project are also likely to establish new biologically inspired paradigms for creating long-lasting, high-fidelity neural interfaces with biomimetic materials. This project will impact both the neuroscience research community, and clinical communities (neurosurgeons, neurologists, and patients) that use and benefit from neuroprosthetic- and neurostimulation-based treatments interventions. The public health relevance of this project is to improve neural prosthetic and neural stimulation devices for treatment of neurological diseases or injury.

DESCRIPTION (provided by applicant): Next generation neural probe technology must enable neuroscientists to bridge the gap between neurons and neuronal pools to fully understand the orchestrated 'temporal dynamics'of the brain. This will require high-density, stable recordings in longitudinal experiments. Similarly, next generation brain machine interfaces (BMI) must improve longevity and reliability of the recorded neural signals if translation of the research technology to the clinical realm is to be successful. Long-term signal degradation is widely believed to be directly related to cellular reactivity in the presence of the neural probe. The sub-cellular edge electrode array (or "SEE" probe) was designed to mitigate the cellular reactivity evident in conventional microelectrode designs and thereby address the longevity and stability issues of recording technology. The SEE design concept hypothesized that if a structural feature size is smaller than a reactive cell body (<7

? DESCRIPTION (provided by applicant): The cardiac neuronal hierarchy is made up of interdependent feedback loops comprising somata located in i) intrinsic cardiac ganglia, ii) intrathoracic extracardiac (stellate, middle cervical) as well as iii) the spinal cord, iv) brainstm and v) higher centers (up to the insular cortex). Each of these processing center contains afferent, efferent and interactive (local circuit ones in peripheral ganglia) neurons which interac locally and in an interdependent fashion with other levels to coordinate regional cardiac indices on a beat-to-beat basis. It is now recognized that autonomic dysregulation is central to the evolution of heart failure and arrhythmias. With respect to heart disease and the cardiac nervous system, there is an upregulation of the sympathetic nervous system and a corresponding decrease in parasympathetic activity. Many of these changes are driven by alterations in afferent transduction and processing of that information at multiple levels of the cardiac nervous system. There is little understanding of how such neural systems adapt during disease progression. There are two critical unmet needs in the field of cardio-neural mapping: 1) Development and optimization of 2D and 3D electrode arrays for chronic, high-fidelity neural recording from peripheral ganglia and 2) Integration of neural recordings with chronic high-fidelity recording of cardiac electrophysiological function. To address this need three aims are proposed. Specific aim 1: To develop 2D and 3D microelectrode arrays and systems for chronic, high-fidelity neural recording from intrinsic cardiac ganglia. Proposed methods include development of thin-film based flexible microelectrode arrays with up to 256 electrode contacts. Once proof of concept is established in the acute setting, chronic packages and fixation techniques will be developed to enable chronic recordings from large animal models. Specific aim 2: To develop 3D electrode arrays and systems for chronic, high-fidelity neural recording in peripheral encapsulated sympathetic (stellate) and sensory (nodose) ganglia. Proposed methods include development of thin-film based 3D penetrating microelectrode arrays (up to 256 electrode contacts). Once proof of concept is established in the acute setting, chronic packages and fixation techniques will be developed to enable chronic recordings from encapsulated peripheral ganglia from large animal models. Specific aim 3: To develop conformal high-definition grid electrodes for chronic, high-resolution electrophysiological mapping from atrial and ventricular epicardial surfaces. These `HD grid electrodes' will have up to 512 sites. Similar to and in conjunction with Aims 1 and 2, chronic packages and fixation techniques will be developed to enable chronic high-fidelity cardiac-neural mapping for up to 28 days. New Knowledge and Innovation: Creation of a distributed electrode system for chronic and continuous high fidelity cardio-neural mapping in normal and pathological states.

Project Summary/Abstract Cardiovascular disease, such as heart failure, atrial and ventricular arrhythmias, hypertensive and valvular heart disease is the leading cause of morbidity and mortality in the USA and the world. Importantly, over 500,000 cardiac surgeries and procedures, which require detailed cardiac diagnostics and intense monitoring, are performed to treat arrhythmias and structural heart disease in the US each year, which together carry a morbidity and mortality risk of 1-30%, depending on a patient's comorbidities. Cardiovascular specialists are required to monitor the heart routinely during interventions and almost exclusively rely on surface ECG and pressure measurements from the heart and vascular compartments and in selected cases electrical mapping of the heart. Current state-of-art technologies for cardiac electrophysiological and surgical therapies for management of complex atrial and ventricular arrhythmias provide limited and time-disparate data to guide interventions and monitor patients, primarily relying on hemodynamic parameters, gross and time-consuming point-by-point electrophysiological mapping techniques, and intermittent evaluation of blood chemistries. At present these data, in addition to being limited, often have substantial time delays from sampling to usable readouts leading to increase intraoperative and post-operative recovery time. This proposal outlines development of a conceptually new approach to cardiac monitoring that can impact diagnostics, therapeutics, and ultimately lead to closed-loop bioelectronics control of the heart. For Quantum Phase 1, three aims are proposed: Aim 1: Development of bioelectronic interfaces, platforms/modules, and analytical tools for real-time assessments of the cardiac interstitial and vascular parameters (catecholamine levels, acid-base and metabolic indices), along with high-density thin-film microarrays for mapping of cardiac electrical function and recording of peripheral cardiac autonomic neural activity. Aim 2: Integration of monitoring platforms, technologies, and analytics for cardiac electrophysiological mapping, multi-point cardiac pacing, hemodynamics, autonomic function, and real-time assessments of interstitial (and plasma) neurotransmitters and neuropeptide levels, acid-base levels, and metabolic factors. Aim 3: Discovery and validation of critical autonomic, metabolic, and electrophysiological parameters that precede and predict adverse cardiac events in infarcted porcine hearts and initial proof-of-concept human studies. Developing and optimizing new mapping arrays and systems for real-time measurement and evaluation of multiple electrophysiological parameters simultaneously with instantaneous ?read-outs? of regional autonomic function (neural and cardiac interstitial neurotransmitters) has the potential to revolutionize the practice of medicine and patient care.