Takashi Daniel Yoshida Kozai, PhD - US grants

? DESCRIPTION (provided by applicant): Penetrating recording microelectrode arrays are a crucial component of numerous human neuroprosthetics. Obtaining selective, high fidelity, long-lasting readouts of brain activity is a critical technology across basic and applied neuroscience that impacts learning and memory studies as well as motor, pre-motor, and visual cortex neuroprostheses and brain-computer interfaces. However, implantation of cortical microelectrodes causes a reactive tissue response, which results in a degradation of the preferred functional single-unit performance over time, thus limiting the device capabilities. Insertion of neural probes or microelectrodes inevitably disrupts the blood-brain barrier (BBB) integrity and causes microhemorrhages that have been shown to trigger the inflammatory tissue response cascade. The degree of microhemorrhaging from probe insertion has been shown to be uncontrollable and difficult to reproduce across implants, mirroring the large variability in inflammatory tissue responses and chronic recording success. We hypothesize that the level of BBB damage impacts chronic neural recording quality. This proposal aims to characterize the sustained BBB breakdown and chronic recording failure in vivo caused by the insertion induced BBB disruption and BBB occlusion by quantifying structural, cellular, and molecular level tissue response to chronic implants in the brain in real time through combining multiphoton imaging technology and neural engineering technology at the University of Pittsburgh. A dynamic understanding of the interfaces is necessary for elucidating the mechanism(s) behind neural recording failure. This work has the potential to output basic and clinical science level knowledge relevant to neural engineering, ischemia, stroke, intracortical hemorrhage, aneurysm, traumatic brain injury, and closed-loop neurostimulation.

Project Summary This R21 (PA-16-161) application aims to greatly improve basic science understanding of oligodendrocytes and oligodendrocyte progenitor cells with respect to spatial and temporal dynamic changes around chronically implanted microelectrodes and long-term recording performance. Penetrating recording microelectrode arrays are a crucial component of numerous human neuroprosthetics. Obtaining selective, high fidelity, long-lasting readouts of brain activity is a critical technology across basic and applied neuroscience that impacts learning and memory studies as well as motor, pre-motor, and visual cortex neuroprostheses and brain-computer interfaces. However, implantation of cortical microelectrodes causes a reactive tissue response, which results in a degradation of the preferred functional single-unit performance over time, thus limiting the device capabilities. While the BBB and the role of other glial cells like microglia and astrocytes have long been studied with respect to the degradation of chronic recording performance, the role of oligodendrocytes and oligodendrocyte progenitor in this foreign body response has been understudied. This proposal aims to characterize the role of oligodendrocytes and oligodendrocyte progenitor cells and chronic recording failure in vivo caused by the insertion via quantifying structural, cellular, and molecular level tissue response to chronic implants in the brain in real time through combining multiphoton imaging technology and neural engineering technology at the University of Pittsburgh. A dynamic understanding of the interfaces is necessary for elucidating the mechanism(s) behind neural recording failure. Oligodendrocytes and oligodendrocyte progenitor cells have been implicated as key players in neuronal health following brain injury and numerous neurodegenerative diseases. Therefore, this work has the potential to output basic and clinical science level knowledge relevant to neural engineering, ischemia, stroke, intracortical hemorrhage, aneurysm, traumatic brain injury, and closed-loop neurostimulation.

Project Summary This BRG R01 (PAR-16-242) application aims to greatly improved spatial and temporal resolution: Penetrating electrical stimulation arrays are a crucial component of basic neuroscience research and human neuroprosthetics. A challenge with this technology is achieving a highly localized stimulated area of the same neurons over weeks and months. However, implantation of cortical microelectrodes causes a reactive tissue response, which results in a degradation of the preferred functional performance over time, thus limiting the device capabilities. Current electrical stimulation implants are tethered to the skull, which chronically increases the impact of mechanical mismatch, causes neural degeneration around the implant, increases the chance of infection, increases the chance of mechanical trauma induced failure as well as shifting of the electrode position, and increases in electrical impedances from glial scarring. In turn, the electrical stimulation loses its effectiveness to excite neural tissue, making longevity a challenge. Simply increasing the electrical current to compensate can lead to permenant damage to the tissue and/or the electrode. This proposal proves an innovative strategy that uses leading-edge biocompatible materials to develop innovative ?Wireless Axon? electrodes that are ultra-small and untethered, with bioactive surfaces and nanostructured materials for enhanced signal transduction to electrically excitable tissue. The project aims to decouple the mechanical requirements necessary in traditional microstimulation technology and improve spatial selectivity of activated neurons for stable long-term electrical stimulation. The guiding hypothesis is that decoupling the mechanical tether will improve tissue integration, while immobilized biomolecules will effectively intervene with the reactive tissue response as well as improve electrode-neuron signal-coupling and selectivity. This project is likely to make significant contributions through developing advanced neural probes for long- term (permanent), high quality, and selective neural stimulation. These could potentially lead to paradigm shifts in both neuroscience research and clinical neuroprosthetics and neurostimulation through creating the capability of activating specific neurons for long periods of time with great precision. Our guiding hypothesis is that the product of the combined benefit is synergistic and greater than the sum of its parts. 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 as well as new paradigms for longitudinally probing neural circuits, particularly for the study of learning and plasticity. Several variations of the technology developed in this project is expected to be compatible with optogenetics. This project would impact both the neuroscience research community, and clinical scientists (neurosurgeons, neurologists, and patients) that use and benefit from neuroprosthetic- and neurostimulation-based treatments interventions.

Project Summary Electrical microstimulation has become a mainstay of fundamental neuroscience exploration and an increasingly prevalent clinical therapy. Despite the growing prevalence of neuromodulation therapies, the fundamental physiological and mechanistic properties driving the beneficial effect for the patient are poorly understood. This R01 application aims to greatly improve our understanding of how different non-neuronal cells (myeloid lineage, oligodendrocyte progenitor lineage, and vascular smooth muscle cells) respond and contribute to the electrical stimulation response. Understanding of the relationship between stimulation parameters and supporting non-neuronal cell activity, including blood flow, will help determine the impact of electrical microstimulation on chronic circuit behavior in-vivo over time. In this proposal, we use leading-edge in vivo multiphoton imaging techniques with multiple transgenic animals to systematically evaluate the relationship between stimulation parameters and the induced changes over time at the molecular, cellular, and local network. An improved understanding of the impact of electrical microstimulation on the overall tissue health, changes to the foreign body response, stimulation of tissue repair, and safety limits will help inform improved stimulation paradigms and device design for therapeutic applications and basic neuroscience research.