Cynthia A. Chestek, PhD - US grants

DESCRIPTION (provided by applicant): A major goal in neuroscience is to understand the computations performed by local brain circuits. A large obstacle to achieving this goal is that - at least in mammals - we currently cannot observe the spiking activity of most neurons within a circuit. A key reason is that standard electrodes are just too big, and provoke too much damage to brain tissue. If placed with high enough density to sample a majority of neurons, they would destroy the very circuit they are intended to monitor. Another important obstacle to understanding local brain computations is that circuit dynamics are rapidly and dramatically altered by chemical neuromodulators, which normally go unobserved. Real-time monitoring of critical modulators such as dopamine can be achieved using fast-scan cyclic voltammetry, but this method has not yet been effectively combined with large-scale circuit recordings. The proposed work would make important progress towards overcoming these obstacles, using ultra-dense arrays of 8µm carbon thread electrodes. These are stiff enough to insert deep into the brain, yet small enough to avoid a destructive immune response. By using an 80µm distance between electrodes, the great majority of neurons within a cortical layer would be within recording range. Furthermore, carbon thread electrodes are well-suited for chemical sensing using voltammetry. This proposal is to construct advanced new tools for neuroscientific investigation in a series of modular steps, culminating in 1024-channel, combined electrophysiological and electrochemical recording in freely-behaving rats. Aim 1 involves the development and testing of silicon frameworks that allow assembly of ultra-dense arrays, together with updated headstages that allow hundreds of channels to be monitored simultaneously. Aim 2 will exploit the ability of carbon thread electrodes to be sliced in situ during histological processing. This greatly facilitates the ability to localize individual recordig sites within microcircuit architecture, and to identify individual recorded neurons. Aim 3 involves further optimization of carbon thread electrodes for chemical sensing, and joint single-unit recording and fast-scan cyclic voltammetry across many electrodes simultaneously. Overall this project combines expertise in electrical engineering, neurophysiology, and neurochemistry to create innovative, powerful devices that will be widely disseminated and may have transformational impact for our understanding of how our brains work.

DESCRIPTION (provided by applicant): A major goal in neuroscience is to understand the computations performed by local brain circuits. A large obstacle to achieving this goal is that - at least in mammals - we currently cannot observe the spiking activity of most neurons within a circuit. A key reason is that standard electrodes are just too big, and provoke too much damage to brain tissue. If placed with high enough density to sample a majority of neurons, they would destroy the very circuit they are intended to monitor. Another important obstacle to understanding local brain computations is that circuit dynamics are rapidly and dramatically altered by chemical neuromodulators, which normally go unobserved. Real-time monitoring of critical modulators such as dopamine can be achieved using fast-scan cyclic voltammetry, but this method has not yet been effectively combined with large-scale circuit recordings. The proposed work would make important progress towards overcoming these obstacles, using ultra-dense arrays of 8µm carbon thread electrodes. These are stiff enough to insert deep into the brain, yet small enough to avoid a destructive immune response. By using an 80µm distance between electrodes, the great majority of neurons within a cortical layer would be within recording range. Furthermore, carbon thread electrodes are well-suited for chemical sensing using voltammetry. This proposal is to construct advanced new tools for neuroscientific investigation in a series of modular steps, culminating in 1024-channel, combined electrophysiological and electrochemical recording in freely-behaving rats. Aim 1 involves the development and testing of silicon frameworks that allow assembly of ultra-dense arrays, together with updated headstages that allow hundreds of channels to be monitored simultaneously. Aim 2 will exploit the ability of carbon thread electrodes to be sliced in situ during histological processing. This greatly facilitates the ability to localize individual recordig sites within microcircuit architecture, and to identify individual recorded neurons. Aim 3 involves further optimization of carbon thread electrodes for chemical sensing, and joint single-unit recording and fast-scan cyclic voltammetry across many electrodes simultaneously. Overall this project combines expertise in electrical engineering, neurophysiology, and neurochemistry to create innovative, powerful devices that will be widely disseminated and may have transformational impact for our understanding of how our brains work.

Project Summary A neural interface is needed that will allow for monitoring the diverse neural anatomy in chronic, behaving animal experiments. The state-of-the-art tools including both flexible surface arrays and stiff penetrating arrays have well-known limitations including low signal-to-noise and unstable recordings over time. The goal of this project is to develop and test a novel device concept that combines stretchable substrates with high-density needles to penetrate through the epineurium of ganglia and peripheral nerves. Nothing in this scale has been demonstrated or attempted to date. This approach has the potential to mitigate the poor fidelity of surface arrays and eliminate damage induced from larger penetrating arrays. Initial validation testing on ganglionic and nerve interfaces will yield a variety of control signals from the sympathetic, parasympathetic, and somatic motor and sensory pathways that innervate the bladder and lower urinary tract. Although bladder dysfunction is a significant healthcare problem, the underlying neural control is not well understood. This shortfall of knowledge results in only partially effective therapies, including drugs and neurostimulators. In Aim 1, microneedle array design and fabrication will yield several device iterations will be evaluated in benchtop phantom experiments to demonstrate insertion effectiveness and ease-of-use. In Aim 2, acute and short-term chronic in vivo experiments will allow us to further evaluate and improve usability, demonstrate signal fidelity, and perform histological evaluation. We expect that this technology and subsequent learning opportunities will lead to significant improvements in neuromodulation devices.

In order to understand how neural signals propagate to conduct specific functions in behaving animals and how individual neurons are physically connected in the context of behavior, advanced tools should be available at the hands of neuroscientists. The Multimodal Integrated Neural Technologies (MINT) hub aims to develop and provide tools that are able to read from and modulate neurons at multiple sites independently at high spatial and temporal resolutions. The hub will disseminate tools and methods to correlate the recorded cell activity with the structural connection. In this way, the connectivity of active cells can be visualized, labeled, and traced for detailed functional mapping. The mission of the MINT hub is to provide a collection of tools, synergistically developed, integrated, and available to the neuroscience community, to address one theme: connecting neurophysiology and structural analysis with a greater scale and resolution. The synergistic integration of these neurotechnology tools at the MINT Hub would accelerate the rate of discovery in neuroscience. This in turn can be expected to pave the way to improved treatments for neurological disorders and to breakthroughs in artificial intelligence, especially neuromorphic computing. The MINT hub will provide annual training workshops for new users to be familiar with new technologies and able to use them effectively. To achieve sustainability, the hardware tools will be actively marketed to the community and those with sustainable volume will be transitioned to commercialization partners. Importantly, this program will cross-train neuroscience and technology personnel during the course of this program, resulting in preparation of a new generation of multi-disciplinary engineers and scientists.

This hub uniquely combines high-density electrodes, chemical sensing, optical stimulation, and cell labeling. Fiberless high-density optoelectrodes can allow optical stimulation of individual or few neurons with high specificity and selectivity using monolithically integrated micro-LEDs or optical waveguides on multi-shank silicon probes. Carbon microthreads will be used to create advanced arrays that will dramatically increase the ability to record from interconnected neurons and label those cells with high accuracy. Advanced metal alloys will also be used to greatly enhance the signal-to-noise ratio of miniaturized electrodes. The MINT hub will innovate viral vector delivery and tissue clearing in the nervous system and combine these with multispectral labeling for intact cell phenotyping. Furthermore, an open-source software will be developed to improve the accuracy and efficiency of anatomical reconstruction for creating connectivity maps. The MINT hub will validate the developed tools and methods in three in-vivo experiments to exemplify what can be accomplished when the proposed modalities and methods are synergistically integrated. This NeuroTechnology Hub award is co-funded by the Division of Emerging Frontiers within the Directorate for Biological Sciences, and the Division of Chemical, Bioengineering, Environmental & Transport Systems within the Directorate for Engineering as part of the BRAIN Initiative and NSF's Understanding the Brain activities.

Project Summary/Abstract There are approximately 50,000 people in the US with complete amputation of the hand, and many more with debilitating partial hand amputations. Treatments have not changed substantially since the body powered hook was invented during the civil war. While electrical signals from residual muscle can provide some function, every amputee is missing muscles, and therefore missing a variety of important functions. Attempts to record these signals from the nerves have suffered from low amplitude, low longevity, or both. Recently our group has demonstrated a novel method for obtaining signals from independent nerve fascicles in rats and NHPs, which we call the Regenerative Peripheral Nerve Interface (RPNI). Multiple dissected residual nerve branches are each placed in a 1x3 cm free muscle graft. The small muscle grafts degenerate, regenerate, revascularize, and reinnervate utilizing natural biologic processes. Upon completion of this regenerative process, the neurotized free muscle graft then amplifies a 5 ?V cuff ENG into a >250 ?V EMG signal. Most recently, we have replicated these results in 3 humans with upper limb amputation, routinely recording signals above 100 ?V that correspond to individual finger movements. Our long-term goal is to provide intuitive high fidelity control of individual prosthetic fingers and enable naturalistic sensory feedback. The objective of the present application, which represents our proposed next step, is a pilot clinical trial of safety and bidirectional prosthetic control efficacy using the RPNI in 6 subjects. Our team includes the original developers of the RPNI concept, Drs. Cederna and Kung, who have since placed human RPNI implants in 65 patients for the control of neuroma pain. The team also includes two engineers, Drs. Chestek and Gillespie with complementary expertise in neural signal processing and prosthetic control. Dr. Chestek also has extensive experience in neuroprosthetic human clinical trials. Three specific aims have been constructed to address independent aspects of safety and efficacy of RPNis in humans during a 5 year study. In Aim 1, 6 participants will be implanted with multiple grafts on each severed nerve, following by indwelling EMG electrodes in a later procedure. Multiple validated instruments will be used to monitor pain and other potential adverse events during this process. In Aim 2, we will evaluate the amplitude, specificity, and longevity of the result neural signals for up to 12 months. In Aim 3, we will quantitatively determine whether enhanced finger control ultimately enables higher performance on tasks of daily living and embodiment with the prosthetic limb. The results of these aims will provide critical safety and efficacy data, and strongly motivate a larger, perhaps pivotal clinical trial across multiple years, using a wireless implantable neural recording device for EMG.

Prosthetic hands controlled directly by the nervous system have been the subject of science fiction for decades, and could lead to dramatic quality of life improvements for people with upper limb amputations or paralysis. The brain is the only known controller capable of moving a 5-fingered robot with high precision to use a wide variety of tools and objects. While we know a lot about the control signals in the brain and movement of the fingers, we do not have a good idea of how one gives rise to the other. Here, we will generate an enormous dataset, which will be publicly distributed to students and other scientists everywhere. It will include many channels of brain activity simultaneously with muscle activity to help work out the transformation between the two, and attempt to replicate this control system using artificial neural networks. A strong demonstration of brain controlled prostheses could lead to human studies, and a clinical system that could impact the quality of life for hundreds of thousands of people with amputations or paralysis, as well generating insights for smarter robotic systems. Beyond the direct output of the research, brain machine interfaces have the capability to inspire a large number of students, including those from underrepresented groups, into careers in science and technology, by showing clearly to a young audience how this kind of education can help people.

This project proposes to record data simultaneously from the brain, muscles, and kinematics of the primate hand during complex finger movements, in order to replicate this control system. Specifically, the objective of this particular application is to establish the first such dataset in a nonhuman primate, recording 200 channels from motor cortex, 12 channels of EMG from the muscles, and precise kinematics during the acquisition of finger targets from 4 different degrees of freedom. Our central hypothesis is that firing rates can be transformed to EMG using a single layer neural nonlinearity followed by a regularized linear regression, and then transformed into finger kinematics through non-linear but well-characterized anatomy. This differs from upper limb signals, which can appear to be linearly modulated by endpoint velocity regardless of posture. We will complete this project with three objectives. In Objective 1, we will establish a world-class surgical team to create a nonhuman primate animal model with simultaneous chronic brain recording and EMG recording. In Objective 2, we will develop an algorithmic approach to map motor cortex firing rates to EMG as well as kinematics, with both offline and online testing. In Objective 3, we will explore low power circuitry to extract this information in real time, at a power consumption that would be appropriate for an implantable medical device. The overall scientific philosophy of this project is that the brain provides an example of a low power neural network, which is relatively shallow between motor cortex and EMG, for controlling a complex soft robotic system. Uncovering this relationship will enable us to use this approach for brain machine interfaces for paralysis as well as guiding future human made robotic approaches.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

The broader impact/commercial potential of this I-Corps project is the development of a nerve interface that will provide patients with intuitive prosthetic control. The global market for advanced upper-limb prosthetics is expected to be valued at $0.87 billion in the year 2024. However, despite their high cost, patient satisfaction for these devices remains low. Current solutions do not provide reliable or intuitive control of robotic hands and arms while creating a burden on the prosthetist trying to provide patients with a comfortable and functional prostheses. The I-Corps project will explore the commercial potential of a nerve interfacing technology by testing the hypotheses around these customer and end-user needs, as well as the needs of other stakeholders in the ecosystem such as physicians, surgeons, occupational therapists, and insurers. Beyond this application, the customer discovery model can be used to validate similar products for other patient populations who need to control prosthetic, rehabilitative, or digital devices. This technology may not only improve the well-being of patients, but also reduce employment shifts that are common after disabilities. It further advances a field that is vital for the United States to maintain a productive and competitive workforce.

This I-Corps project is based on the development of the regenerative peripheral nerve interface (RPNI). The proposed RPNI technology is built by grafting small muscles on the ends of severed nerve branches that reinnervate the grafts. This technique has three key benefits. First, the muscle grafts naturally amplify small nerve signals into large amplitude electromyography. Second, it reduces limb pain by preventing the formation of neuromas. Third, it allows us to use muscle as a biological cuff to implanting electrodes for a prosthetic interface. Control signals may be read from the nerve with higher functional specificity, strength, and stability than current technologies. This technique has been validated in rodent and primate models and is currently being evaluated in a clinical trial. Research has demonstrated intuitive control of individual finger and grasp movements without the need for frequent controller adjustments or recalibration. Should this technology be commercialized, people with amputations may no longer require a certain amount of remaining musculature or a high gadget tolerance to benefit from a multi-articulating prosthetic hands.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.