Nitish V. Thakor - US grants

The research will focus on modeling and computer simulation of cardiac action potentials, automatic detection of cardiac arrhythmia with automatic defibrillation when required, packaging for ECG monitors, and pacemakers and defibrillators on a VLSI chip for long-term implantation within the body.

I propose an integrated approach to investigations of issues connected with long-term ambulatory ECG monitoring. I envisage my research culminating in the development of microprocessor-based ambulatory and intra-cardiac arrhythmia monitors. Signal processing: I plan to carry out frequency and time domain analysis of ECG and noise signals. I will identify optimal QRS filter and detector parameters, and signal processors for high resolution ECG. ECG interpretation: I propose a significant-point extraction algorithm that carries out data reduction and pattern recognition. This technique promises to help identify P and T-waves, and S-T segments. Also, R-R and P-R interval predictors will aid in arrhythmia analysis. Electrode studies; I propose experiments on new electrode designs-including a guard-ring ECG electrode, optimal placement, study origins of skin potentials and artifacts, and skin preparations to reduce them. Intracardiac ECGs and defibrillation: In connection with pacemaker and defibrillator developments, I plan to characterize intra-cardiac ECG (including ventricular fibrillation- VFIB) signals, develop algorithms, and investigate other sensors for VFIB recognition. For effective defibrillation, I plan to study current distributions in the thorax. Evaluation: I will develop quantitative measures of performance of arrhythmia detectors (analysis of contingency table, detection curves, utility theoretic analysis, etc.). For evaluation of arrhythmia systems, studies with annotated database, volunteers, and patients are proposed. Long term goals: I hope to design patient monitors utilizing microprocessor and VLSI (very large scale integration) technologies. This research should benefit the development of Holter event-recorders, pacemakers and defibrillators with ECG interpretation capabilities, long-term monitoring and (when necessary) resuscitation of critically ill cardiac patients in their homes. Through the use of intelligent ambulatory and implantable monitors I hope to develop solutions to identification and prevention sudden death in ambulatory population.

Our pilot studies suggest that time-varying changes in the fundamental fraction, comprising the lower harmonics, of the somatosensory evoked potential (EO) may be a sensitive early indicator of cerebral hypoxia. Recently we have also acquired experimental evidence that near-infrared (NIR) spectroscopy appears to estimate noninvasively the cerebral oxygen delivery. We now have the unique ability to acquire and analyze, simultaneously and continuously, the time-varying changes in the NIR spectra and the neuroelectric signals (EP and EEG) that should allow us to assess oxygen deprivation and its effect on electrical function under the conditions of acute hypoxic or ischemic injury to the brain. The aim of the current project is to answer the questions: Is time-frequency mapping (time-varying changes in the harmonics or the spectrum) of neuroelectric signals (EP and EEG) a sensitive approach to detecting acute oxygen deprivation of the brain? Is the fundamental fraction of the neuroelectric signals a specific indicator of cerebral ischemic injury? Do the spectral changes in the neuroelectric signals correlate with oxygen delivery to the brain estimated by NIR spectroscopy? What components (oxy- and deoxy-hemoglobin, cytochrome a,a3) of the NIR spectra are sensitive to hypoxic and ischemic injuries and the associated neuroelectric response? To answer these questions, we propose the following research plan: Develop signal processing methods to obtain time-frequency distributions of EP and EEG signals by adaptive Fourier series modeling and coherence estimation techniques. Conduct experiments to determine: (i) confounding effects on the neuroelectric signals, if any, of various anesthetics, and (ii) the transient response to acute cerebral ischemia generated by temporary occlusion of cerebral arteries. Analyze, and correlate with time-frequency distributions of neuroelectric signals, the time-varying changes in the NIR spectra under conditions of altered oxygen delivery to the brain. Conduct experiments: (i) to monitor cerebral hemoglobin saturation under the conditions of global cerebral hypoxia, and (ii) to selectively evaluate the NIR response in the cytochrome band. In high risk surgeries, as well as in neurological intensive care situations, the brain may experience acute injury due to hypoxia or ischemia. Our research should help establish the noninvasive, continuous, and rapid techniques of neuroelectric signal processing and NIR spectroscopy as tools for monitoring injury to the brain at times of initial dysfunction when the insult may be reversible.

There is a considerable need for alternative techniques for the rapid separation of biological macromolecules. The PI proposes using the principle of Lorentz forces (i.e., a combination of electrical and magnetic fields) to effect a separation. While the theoretical basis for Lorentz forces is well known, its applicability to biological macromolecules has not been examined. This proposal seeks to test experimental conditions to demonstrate the feasibility of using Lorentz forces for biological separations.

The long-term goal of this research program is to develop the t technology for evaluating and treating brain injury. Analysis of the unique elements of the brain's neuroelectric signals should produce a clear characterization of the sequence and extent of injury, and the likelihood of recovery. This study will use models of two major types of brain injury (complete focal and complete global ischemia) that are applicable to a wide range of other brain diseases. The overall strategy is to investigate brain's electrical activity in three phases of ischemia; (1) acute insult, (2) delayed excitotoxic injury, and (3) recovery and restoration of function. The specific research aims are: Phase 1: To test the hypotheses that, during the acute insult stage of ischemic injury, (a) the first changes in electrical response are a loss of high-frequency content of somatosensory evoked potentials (EP) signals, as measured by adaptive Fourier series modeling, and a decline in power of the dominant high frequencies of electroencephalogram (EEG); (b) a threshold of electrical dysfunction is reached because of failure of electrogenic pump causing a rise in extracellular potassium. Phase 2: To test the hypotheses that, during the delayed excitotoxic injury stage after the ischemic insult, (a) injury can be measured as a loss of coherence of EP signals and spectral dispersion of EEG signals; (b) the spectral measures of injury will correlate with post-mortem histological evaluation of the cortical mantle, and (c) the excitotoxic neuroelectric response and athe post-mortem histology will show improvement when brain is treatment with the glutamate antagonist MK801 or the NO- synthase inhibitor L-NAME. Phase 3: To test the hypotheses that, during the recovery stage, (a) the electrical activity is gradually restored by bursting or seizure-like EEG patterns , as measured by bispectral and bicoherence analysis of EEG; (b) the recovery of electrical function correlates with the neurologic performance of surviving animals; and (c) administration of NBQX, a AMPA/Kainate blocker, and BW1003C87, an anti-seizure drug analog, helps suppress neuronal excitability during recovery and improves the neurologic function. This research will provide new quantitative measures of EEG and EP signals referenced to physiologic events during three phases of ischemic injury postulated in this proposal. These measures will identify the neuroelectric signal parameters that are essential to improve (1) rapid clinical diagnosis of ischemic injury, (2) timing and dosing of therapeutic interventions, and (3) prediction of behavioral outcome after ischemic injury.

Hypoxic ischemia (HI) injury to brain results in both oxidative and excitotoxic stresses that provoke numerous pathophysiological and discrete electrical functional changes. Our prior brain research has led to methods that can calibrate the magnitude an duration of injury by using electrical indicators of EEG and evoked potentials (EP). The overall goal of the present proposal is to evaluate cerebral electrical signaling to provide even more important information about the response of brain to delayed injury stresses as well as recovery. The central hypothesis is that mathematical and experimental evaluation of cerebral electrical signaling will provide novel mechanistic insights into the precise temporal profile of recovery from HI injury in terms of delayed injury, early recovery, and later recovery. Aim 1 will focus on delayed injury. Cortical neuroelectric signals will be quantitatively evaluated to determine recovery of low frequencies and coarse shape details in the EP signals and an irregular recovery of the dominant frequencies of EEG. Multi-unit recording in the dorsal thalamus and reticular thalamus will test their possible central role in initiating recovery via the thalamocortical circuit. Since delayed injury is marked by excess excitatory neurotransmitter activity, the role of glutamate release inhibition and glutamate transporter knockdown on modulating the degenerative changes will be assayed neurochemically. Aim 2 will examine early recovery. Cortical signals will be characterized for the return of high frequencies and fine details in EP signals as well as spindling and burst suppression in the EEG signals. Cellular studies will determine the post-HI response to somatosensory stimuli and spindle oscillations in the thalamic relay neurons co- incident with animal's recovery. Electrophysiological investigations of somatosensory pathway and molecular manipulation of receptor density and synaptic transmission during restoration of thalamocortical circuit function will define the mechanisms of early recovery. Aim 3 will explore the late recovery by evaluating the subject's survival and any neurological deficits after therapies initiated in the earlier phases. Restoration of EP and EEG signal features will be quantified by a combined linear and non-linear modeling scheme. Effects on extended recovery of cortical and thalamic electrical signals will be compared to two contrasting manipulations: inhibition of synaptic glutamate release versus glutamate transporter knockdown. Immunochemical analysis will identify structural modifications resulting in regenerative changes and good functional recovery in thalamocortical pathways and the somatosensory cortex. The innovative use of quantitative analysis of cortical and thalamic signals coupled with novel neurochemical validation of injury and recovery mechanisms should led to the discovery of basic electrophysiological mechanisms differentiating various phases of global HI injury. The long-term benefits should be improved diagnosis and novel therapeutic strategies targeted to each phase of recovery from HI injury.

DESCRIPTION (provided by applicant): An emerging trend in neuroscience and neurophysiology is the movement towards understanding the fundamental behavior of neurons at the ensemble or population level by studying individual neurons at multiple sites. Electrophysiology of populations of neurons is greatly aided by the development of multi-channel or array electrodes by integrated circuit (IC) technology. However, there is considerable heterogeneity in the distribution and function of neurochemical elements as well. Therefore, a technology that enables simultaneous monitoring of neurochemical activity at different locations in the brain promises to make fundamental discoveries in regional heterogeneity and specialization of neurochemistry of brain tissue. Further, if the electrical activity of a population of neurons as well as the complementary neurotransmitter activity could be localized and measured concurrently, it could unify two important domains: electrophysiology and neurochemistry/pharmacology. The central goal of this proposal is to develop a novel microsensor technology for providing real time, continuous measurement of both neurotransmitter and neuronal electrical activity. The underlying novel idea is to construct a carbon-based microsensor array that will capture neurotransmitter and electrical activity from multiple neurons. Specifically, the microsensor array will be developed for measuring the diffusible messenger nitric oxide (NO) and the neuronal electrical response accompanying NO activity. The sensor will be tested in an in vitro model (hippocampai brain slice) in which the distribution of NO and its role in modulating the excitability of neurons in different regions of the slice will be studied. Fundamental technical barriers that must be overcome are: 1) Development of a carbon-based microsensor technology by utilizing novel screen printing and photolithographic processing techniques. 2) Combining electrical and electrochemical sensing on a single substrate and interfacing this sensor array to the brain tissue. This technology offers a revolutionary advance in neurophysiology research: it will potentially break down the barrier that exists in neuroscience, between the fields of pharmacological neuroscience and electrophysiologic neuroscience. The coupling of these two basic neural responses, electrical and chemical, would shift the prevailing paradigm of neuroscience research pertaining to neurological diseases or mental health.

DESCRIPTION (provided by applicant): In the basic and clinical research on brain's response to injury, cortical electrical signals from the brain, namely EEG, may be useful in providing an immediate indication of the dysfunction. As such, we hypothesize that quantitative EEG would be a powerful tool for basic research on brain injury and, eventually, clinical diagnosis. A novel approach to analyzing brain's early response to injury, based on the method of "multiresolution wavelet entropy (MRWE)" is proposed. Since the recovery of brain rhythms in response to injury occurs in different stages involving transition of rhythmic activities in different frequency bands, we propose to monitor and quantify the variations in entropy that occur within each clinical band. We hypothesize that a) following global ischemic brain injury, the time domain entropy of EEG would form a sensitive indicator of the level of injury and that the MRWE of EEG in each clinical band would identify features related to the bursting characteristics of EEG in the immediate post-ischemic recovery periods, and b) the corresponding entropy measure derived from the cortical field potentials would have cellular origins (firing pattern of neurons) in cortical and subcortical areas of the brain. To explore these hypotheses and to develop rigorous theoretical tools for experimental studies on brain injury, we propose: 1: Theory - a) Derive a time domain entropy measure with a view to monitor the progress of recovery of EEG following global ischemic brain injury. b) Derive an MRWE-based segmentation procedure to identify the characteristics of initial bursting EEG, seen during early phases of post-ischemic recovery. 2: Experiments - Using experimental single and multi-unit recording by the microelectrode method, show that the varying levels of MRWE derived from the cortical field potentials reflect the transitional stages of post-ischemic rhythmic activity of neuronal population in the thalamus and the cortex. The significance of this project primarily lies in developing a novel quantitative tool that can benefit basic and clinical scientists studying brain injury.

[unreadable] DESCRIPTION (provided by applicant): Brain slices provide a direct access to electrically, chemically or optically probe brain function in vitro. This proposal presents a novel technology to allow multifunction, electrical and optical, assay of brain slices. The key proposed technology involves novel microfluidics system for brain slice perfusion along with the capability of simultaneously recording electrical and optical activity from brain slices. Specifically, we propose to: 1) design novel microfabricated perfusion chambers for brain slices with embedded electrodes and optical imaging capabilities, 2) carry out computational fluid dynamics, oxygen transport analysis and experimental measurements to test perfusion adequacy of the chambers, and 3) demonstrate electrical and optical transmission imaging of spreading depression in hippocampal brain slices. The proposal has been significantly revised by proposing two new designs - a) submerged microchannel chamber and b) microcapillary interface chamber - and further strengthened by improved fluidics designs and critical theoretical analysis of fluid and oxygen transport. The technology will be experimentally tested, and proof of the concept will be obtained with the help of in vitro models of spreading depression and epilepsy in hippocampal slice preparations. This project will result in a novel measurement platform for brain slice research which will facilitate basic research inquires into the study of brain's pathophysiological response in problem areas such as spreading depression, epilepsy and stroke.

DESCRIPTION (provided by applicant): Resuscitation after cardiac arrest (CA) entails significant risk of coma or disorders of consciousness resulting in poor neurological outcome. There is an acute need to monitor the brain function during and after resuscitation to optimize intervention and improve outcome. Our previous studies developed electrophysiological markers of post-CA brain injury, including quantitative EEG (qEEG) and quantitative evoked potentials (qEP), and their relationship to outcome and neurological deficits. Further, we demonstrated benefits of therapeutic hypothermia using these objective means. We discovered quantitative methods to track neurological injury from CA and patterns of electrical rhythms associated following resuscitation, such as burst suppression, and utilized these novel tools to demonstrate electrophysiological recovery and enhanced neurological outcome assisted by therapeutic hypothermia. The central hypothesis for this renewal is that recovery of cortical function has both cortical and subcortical origins and arousal from coma and recovery can be facilitated through hypothermic protection and pharmacological stimulation of both cortical and subcortical structures, and guided using quantitative electrophysiological markers. The specific aims are: 1) To discover clinically relevant, quantitative cortical electrophysiological markers o arousal from coma. 2) To discover changes in cortical-subcortical neurological signals and their coupling after resuscitation. 3) To establish the neuroprotective effects of therapeutic hypothermia assessed through restoration of cortical electrophysiological function and cortical-subcortical network connectivity. 4) To promote arousal from coma through pharmacologic intervention by Orexin-A infusion and resulting stimulation of cortical-subcortical network connectivity. 5) To translate this research into an objective feedback system and optimization of delivery of titrated therapeutic hypothermia for neuroprotection and pharmacological arousal by Orexin-A infusion. CA results in hundreds of thousands of deaths each year and, even for survivors, the outcome remains dismal. Our multi-faceted approach will result in mechanistic understanding of arousal, means of monitoring cortical function, and treatments to accelerate recovery of cortical function. Starting with direct multi-unit recordings of cortical and subcorticl components of the arousal system, we will provide mechanistic understanding of arousal and successful restoration after resuscitation. Further, our qEEG and qEP based monitoring approaches will result in clinically relevant, translatable monitoring of interventions, both hypothermia and pharmacological. Our research will thus result in a comprehensive development of real-time neurophysiologic monitoring technology to optimize treatment options. Upon validation, the proposed quantitative, neuroelectrophysiology-guided optimization of TH/Orexin-A delivery should be applicable to monitoring patients and guiding clinical management.

DESCRIPTION (provided by applicant): Continuous measurement of neurotransmitters in brain tissue is now possible using electrochemical sensor technology. More recent development by our group, under sponsorship of an NIMH funded grant, has led to the development of an integrated carbon microsensor array capable of mapping the spatial and temporal distribution of neuronal messengers such as nitric oxide (NO) and dopamine. This proposal builds on our previous grant, and addresses the design of an intimate integrated electrochemical sensor and electronic interface in the form of a very large scale integrated (VLSI) chip to make multi-sensor measurement of neurotransmitter activity feasible. The rationale behind this technology development is to a) facilitate measurement of neurotransmitters in pathology in ischemic injury, and b) extreme miniaturization and high integration for in vitro and in vivo studies. The present proposal brings together several innovative design solutions: 1) Cooperative design of the novel microsensor array with an integrated VLSI circuitry presented here. 2) Integrated circuit with several unique features: a) Silicon-on-sapphire substrate technology for very low leakage currents and implementing mixed sensor and analog electronic circuitry, b) Current mode design for very low current, low-noise circuit, and c) Sigma-delta analog-to-digital conversion for high resolution serial digitization and signal transmission (which would eventually facilitate telemetry). This integrated microsensor array/VLSI system will be tested a) in vitro: in a hippocampal brain slice preparation to obtain high-resolution measurements of the neurotransmitter release and distribution, and b) in vivo: in acute rodent model of ischemic brain injury. In our research, this technology will help elucidate the role of neurochemicals in brain slice and in vivo ischemic models. A proof of concept demonstration in brain slice and acute rodent models will set the stage for chronically implanted in vivo animal chronic studies where the fully integrated solution will find the most exciting eventual use.

[unreadable] DESCRIPTION (provided by applicant): We propose a pre-doctoral training program providing an educational and research environment for graduate students at the interface of neurosciences and engineering. The training program will emphasize rigorous education in biological sciences in general and neurosciences in particular. The course work will range from molecular and cellular neurosciences to systems and clinical neurosciences. In addition, the student training will include rigorous coursework in mathematical, computational and engineering systems. The students in the program will have a wealth of research opportunities at our institution, both in basic research on the nervous system, and in clinical aspects of disease diagnosis and therapy. The engineering research opportunities include problems in instrumentation development, signal and information processing, imaging and computational neurosciences. The program is strengthened by the availability of a highly qualified applicant pool, very selective admission processes, and a very strong interest in the field among the applicants. Our institution provides a commensurately high quality training environment through a demanding curriculum and a large number of laboratories that have high levels of peer reviewed funding and outstanding laboratory resources. A unique element of this program is the participation of research faculty from both the basic sciences and the clinical sciences. Finally, the training program will emphasize the freedom to pursue interdisciplinary and collaborative research and encourage participation by students from diverse disciplines. Although our program so far has a good track record of recruiting, retaining and training these candidates there are a number of institutional efforts underway to further stimulate participation from minority candidates. Overall, this training program focuses on recruiting and selecting high quality candidates and providing them rigorous and comprehensive academic and research training. Our long-term goal is to foster an educational, training and research environment that will produce future scientists and educators who will make strong impact on basic and clinical neurosciences. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This is an interdisciplinary, innovative technology research and demonstration project to develop the next generation of neural probes for implanted recording. Current neural probes record electrical signals with the use of multiple silicon micromachined electrodes. In an advancement in this field, supported by previous NIH funding, we have demonstrated miniature neurochemical sensors and developed the specialized VLSI integrated circuitry needed to enable chemical measurements from multiple electrodes in a microprobe assembly. The next challenge is to research methods to harvest power to energize the implanted sensor and circuitry. Towards this goal, we propose two innovative technologies 1) the development of a rechargeable, microbattery system capable of sustaining power to the sensor and circuitry, 2) development of a novel VLSI wireless power harvesting circuit to energize the battery. Our other aims are to 3) develop an integrated probe with neurochemical sensor, VLSI wireless interface, power harvesting circuit and microbattery, and 4) evaluate the probe in a model of global ischemic brain injury. This research contributes to our long term goal to build fully implantable, autonomous microprobes, without any tethering, for neurochemical recording in chronically instrumented and tether less animals. A fully self-powered implanted neural microprobe system will be an enabling tool in the hands of neuroscientists interested in recording neural activity from animal models of brain function or brain disorders with the use of microelectrode arrays. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Recent clinical studies have shown that temperature perturbation either as hypothermia or hyperthermia has a profound effect on brain injury and recovery after cardiac arrest. While the temperature manipulation, either by hypothermia or fever reduction to prevent hyperthermia is widespread in clinical practice, the precise effect of temperature on brain injury is not fully known. Indeed, no methods to directly titrate the efficacy of hypothermia treatment, such as the time to initiate therapy, more optimal range or duration, are available. Effect of temperature manipulation on cortical function is not known either. In our preliminary studies we have observed that the neuroelectrical response, as reflected in the real time neuronal firing and the cortical neural activity, namely electroencephalogram (EEG), is directly affected by temperature. Together these two measurements can provide a real-time assessment of these brain responses from a limited yet specific area (spikes) to bulk or global areas of the brain (EEG). The two aims of this project are (1) to study the neuro- electrical response by quantitative EEG (QEEG) methods serving as a real time, non-invasive, electrical marker of the brain's response to temperature manipulation, and (2) to evaluate the interaction of the subcortical (spike activity) and cortical QEEG responses of the brain to temperature manipulation. Proof of concept obtained through this project will first of all lead to a clinically relevant tool to noninvasively monitor and titrate hypothermic neuroprotection following cardiac arrest. In addition, this feasibility study will open the door to more fundamental research on effects of hypothermia or hyperthermia at neuronal level as well as clinical investigations designed to optimize the therapy in humans. [unreadable] [unreadable]

The objective of this research is to develop an optimal predictive feedback control framework for neuroprostheses that are enabled by brain machine interfaces (BMIs). BMIs, broadly defined, are systems that interface the brain and a machine (computer) to sense neuronal activity and cognitive processes to restore impaired motor tasks in disabled subjects. The research focuses on: (1) development of a computational modeling framework for BMI-based neuroprostheses that can incorporate large data sets of intracortical neuronal measurements; (2) identification of natural and "surrogate" optimal feedback sensing paths in neuromotor prostheses; (3) development of computationally efficient predictive control algorithms that exploit models and feedback pathways in neuroprostheses; and (4) experimental evaluation through simulated neuroprosthetic multi-finger grasping.

Current neuroprosthetic devices are largely "open-loop" and have limited performance due to their inability to incorporate multivariable feedback, sensory and interactive signals. This research addresses this limitation, striving to advance next-generation feedback-enabled neuroprosthetic devices. The proposed conceptual integration of optimal control theory with principles of neuroengineering and computational neuroscience provides a framework for analyzing the numerous feedback modalities intrinsically embedded in a complex interconnected system of neurons.

For broader impacts, the research seeks to enable the transition of BMI-based neuroprostheses and assistive devices to stable extended use in human subjects suffering from peripheral neuropathies, spinal cord injuries, neuromuscular disorders, and amputations. The project will introduce a computational neuroscience paradigm in feedback control education while training biomedical engineers to directly employ tools from computational feedback control theory. A science outreach effort with Asa Packer Elementary School in Bethlehem and the middle school Summer Robotics Camp in Baltimore will motivate and excite young minds to think about solving technological "grand challenges" through demonstrations of brain functionality.

DESCRIPTION (provided by applicant): As you grasp your coffee cup, thousands of neurons in your motor cortex control the activity of some 40 muscles that move your hand's 22 skeletal degrees of freedom. The complexity of controlling such an everyday action seems daunting. But recent studies have shown that because the movements of many skeletal degrees of freedom in the hand are highly correlated, as much as 90% of the motion of the 22 degrees of freedom can be captured in only 2 to 7 principal components. In other words, the number of dimensions needed to describe most of the motion of the hand can be reduced from 22 down to 7 or fewer. Similarly, other studies in which electromyographic activity has been recorded simultaneously from 19 muscles have shown that up to 80% of the simultaneously recorded electromyographic activity can be expressed as 3 to 5 time-varying muscle synergies. The number of dimensions needed to describe muscle activity thereby can be reduced from 19 down to 5 or fewer. Might such dimensionality reduction simplify the complexity of controlling such everyday movements? Here we propose to test the general hypothesis that cortico-muscular control of the hand and fingers makes use of dimensionality reduction. By reducing dimensions at three different levels of simultaneously recorded data-neuronal, muscular and kinematic-we will take the novel, comprehensive approach of comparing the correspondence between the reduced spaces at all three levels. Through these comparisons, we will explore the previously unexamined hypotheses that: 1) the biomechanical structure of particular finger muscles produces certain principal components of hand and finger kinematics;2) time-varying muscle synergies correspond to principal components of hand and finger kinematics;3) time-varying neuron synergies represent principal components of hand and finger kinematics;and 4) time-varying neuron synergies represent time-varying muscle synergies. To test our hypotheses, we will acquire data simultaneously from 128 single neuron microelectrodes implanted in the primary motor cortex hand representation, from 16 electromyographic electrodes implanted in various muscles, and from 23 markers tracking finger kinematics, during grasping movements of 16 to 48 different objects. Using these data, we will extract time-varying neuron synergies, time-varying muscle synergies, and principle components of hand and finger kinematics. We will determine whether individual muscles, time-varying muscle synergies, and/or neuron synergies correspond to principal components of hand kinematics, and whether time-varying neuron synergies correspond to muscle synergies. Our hypotheses will be rejected if the spaces of reduced dimensionality at different levels-neuronal, muscular and kinematic-fail to correspond. In contrast, strong relationships between elements in the different reduced spaces would support the notion that cortico-muscular control of the hand and fingers actually utilizes dimensionality reduction. In addition to the long term benefit to society of an improved understanding of how the brain controls movement, the proposed project will have ramifications in the growing field of neuroprosthetics. Dimensionality reduction in the cortico-muscular system would provide a means of minimizing the on-line computational load carried by on-board computers that will control neurally driven prosthetic devices. More broadly, our approach may provide a model for computational reduction and interpretation of large, complex, behavioral and cognitive neuroscience datasets. Our proposal builds upon a relatively new collaboration between Schieber at the University of Rochester, who brings expertise in motor systems physiology, and Thakor at Johns Hopkins University, who brings expertise in biomedical engineering approaches to computation. Through frequent videoteleconferencing and 2-3 month exchange visits, these two labs will provide cross-disciplinary training for the co-PIs, graduate students, and undergraduates (including under-represented minorities) at both institutions. Biomedical engineers from Hopkins will learn to record physiological data while at Rochester. Motor physiologists from Rochester will learn advanced mathematical techniques for analysis while at Hopkins. The students from both groups will present their work at both neuroscience and engineering conferences, where the co-PIs will organize hands-on workshops for further dissemination of the findings per se, and of the project as a model for inter-disciplinary research. The co-PIs also will coordinate an innovative inter-institutional graduate level course.

DESCRIPTION (provided by applicant): Survival and neurological outcome after sudden cardiac arrest (CA) remain very poor. Our prior work focused on understanding the return of neuro-electrical activity after CA and led to the discovery of a) quantitative signal processing methods that track brain injury and recovery after CA, b) recovery of thalamocortical networks during restitution of arousal after CA and c) the patterns of electrical rhythms and time course when therapy may impact recovery. Recent clinical reports demonstrate compelling therapeutic benefits of hypothermia following CA and a better understanding of the role of the thalamus in chronic disorders of consciousness after CA. Our proposal harnesses these opportunities to uncover the acute neurophysiologic mechanisms of arousal post-CA to develop clinically applicable diagnostic methods and optimize therapeutic hypothermia delivery. The specific aims of this project are: Aim 1: We will discover the clinically relevant and neurophysiologically validated electrical markers of arousal from coma after CA. We will test the hypotheses that a) coma is marked by abnormal coupling of thalamic and cortical potentials, b) quantitative analysis of cortical somatosensory evoked potentials (SSEP) will track recovery of normal thalamocortical coupling, and c) entropy-based quantitative EEG (qEEG) analysis will capture sequential changes in thalamocortical coupling during recovery from CA injury. Aim 2: We will study the mechanism by which induced hypothermia results in enhanced neurophysiologic recovery. We will test the hypotheses that a) multi-unit (MU) recording from thalamus and cortex will demonstrate accelerated normalization of thalamocortical coupling with induced hypothermia, b) hypothermia accelerates normalization of SSEP indicating restoration of the subcortical pathway, and c) normalization of qEEG signals recovery of cortical function. Aim 3: Most advances in hypothermia are blindly directed toward faster cooling, without objective indicators of the brain's response to temperature. We will test the hypothesis that the depth and duration of hypothermia can be objectively titrated to non-invasive qEEG and SSEP markers of thalamocortical coupling in order to maximize brain recovery. This multifaceted approach - starting with direct multiunit recordings of thalamocortical components of the arousal system followed by non-invasive evoked potential and EEG monitoring - will allow for the comprehensive development of real-time neurophysiologic tools to titrate hypothermia treatment. The first phase of our basic research has already spawned an NIH-sponsored Phase IIB multi-center clinical trial. Our quantitative, neuroelectrophysiology-guided optimization of hypothermia delivery should be similarly applicable to monitoring patients and guiding induced hypothermia clinical trials in the near future. PUBLIC HEALTH RELEVANCE: The focus of the present proposal is on translational research: to study the problem of global ischemic brain injury following cardiac arrest (CA) and develop monitoring technologies for neuro-electrical markers of coma and arousal after CA. The basic research pertains to developing quantitative electrical measures of injury and understanding the cortical and subcortical origins of these signals. The translational research pertains to optimizing the procedure for induced hypothermia after CA using electrical signal measures. The innovation of this project lies in the comprehensive and novel application of quantitative methods, namely cortical (electroencephalography, EEG), subcortical (evoked potentials, EP), and multi-unit (MU) recordings to track injury and recovery. Our work has compelling translational applications: to monitor brain injury after CA in patients and to optimize hypothermia delivery after CA guided by neurological monitoring.

DESCRIPTION (provided by applicant): Our overall goal is to demonstrate within two years human closed-loop control of the DARPA Revolutionizing Upper Limb Prosthesis, based on real-time decoding of electrocorticographic (ECoG) signals. Under visual feedback, our human subjects will achieve sufficient cortical control of the prosthesis to reach out, grasp, and manipulate real objects. Our collaborative team will build on its substantial experience in developing and testing neural control algorithms for the Modular Prosthetic Limb (MPL, developed by JHU- APL), which arose from participation in the DARPA-sponsored RP2009 program. Based on our unique combination of expertise and experience, we are poised to meet the RFA's Grand Challenge with an innovative approach using parallel experiments in human subjects and in animals. While we develop and test ECoG- based neural control algorithms in patients implanted for the clinical aims of epilepsy surgery, parallel studies in animals will afford more consistent and long-term experimental time to validate the control algorithms, and allow deeper investigation into electrode placement and configuration, including investigating the relationship between intra-cortically recorded spikes and local field potentials (LFPs) and surface-recorded ECoG. We will test the hypothesis that both open- and closed-loop control of the prosthetic limb can be achieved using ECoG spectral features at different time and frequency scales, e.g. low frequencies for slow and/or coarse movements and high frequencies (>70 Hz) for rapid and/or individuated movements. Based on these features, subjects will use the prosthetic limb to perform a center-out reach task in 3D space with coordinated grasping of objects requiring different hand conformations that incorporate both wrist and 5 finger actions. Brain control will be implemented with real-time signal processing of ECoG and actuation of the prosthetic limb under closed-loop visual feedback of object-targeted limb movements. Closed-loop control will be first demonstrated using a virtual reality model of the prosthetic limb and subsequently using the JHU-APL modular prosthetic limb itself. Outcomes will be assessed with measures of success rate, time to trial completion, trajectory/grasp-shape similarity to native limb movements, and overall learning/adaptation rate. PUBLIC HEALTH RELEVANCE: Project Narrative This project will demonstrate the feasibility of using the signals recorded from non-penetrating electrodes on the surface of the brain to allow patients who have lost arm and/or hand function to intuitively control a revolutionary new prosthetic limb with far greater versatility and life-like dexterity than previously available prostheses. This could have a profound long-term impact on the ability of future generations of patients seeking to restore lost upper limb function with a lifelike prosthesis.

DESCRIPTION (provided by applicant): This proposal presents a collaboration between laboratories in two academic institutions (Johns Hopkins University and Kennedy Krieger Institute) with complementary capabilities and resources to deliver a state of the art technology for simultaneous optogenetic control of neuronal activity and functional imaging in awake, behaving animals. We propose to deliver within two years a head-mountable, multifunction, tether-free optical system - a novel microscope - capable of remotely controlling genetically targeted neurons and imaging functional blood flow response in free-moving rats. Highly innovative aspects of this proposal are the miniaturized head-mountable optical microscope for light delivery for optogenetic control and a unique, customized very large scale integrated (VLSI) circuit chip for functional imaging using the method of laser speckle contrast imaging (LSCI). A behavioral study on rat whisker involvement in texture discrimination will be carried out to explore how inactivation of the interested barrel cortex fields affects functional responses of cerebral blood flow and how it is translates into explicit behavior. Preliminary work done for this revised application has resulted in a prototype with size and weight compatible for mounting the microscope on awake and undeterred rodents, as well as optics producing artifact free image quality comparable to bench top systems. Changes in blood flow due to optical stimulation by halorhodopsin activation have also been imaged for the first time. The high impact of this work stems from the potential to do functional neuroscience research in awake and behaving animals and thereby addressing one of the biggest limitations of requiring restraint and anesthesia. This technology will open the door for new fundamental research on manipulating neuronal circuits, neurovascular coupling, functional and structural changes during development, and learning and plasticity during natural behavior as well as in models of stroke, migraine or seizure. PUBLIC HEALTH RELEVANCE: A novel head-mounted microscope for simultaneous optogenetic control of neuronal activity and functional imaging in awake, behaving animals is proposed. This approach is made possible by a miniature head mounted system for light delivery and imaging with a novel integrated circuit imager chip. As a proof of concept, optogenetic control of neuronal activity in freely moving rats involved in behavioral study of texture discrimination will be carried out and images of cerebral blood flow in the barrel cortex fields will be obtained by the head-mounted microscope.

Objective: Brain-machine interactive control (BMIC) of prosthetic limbs for high speed and natural movements is a major challenge. The current BMIC paradigm employs a feedforward interface between the brain and prosthetic, referred to as the "decoder", whose success relies heavily on the ability of the brain to adapt appropriately utilizing visual feedback information in a "certain" environment. Such decoders are trained using data from healthy subjects but are implemented as interfaces for spinal cord patients. The motor cortical output of the healthy subject is substantially different from that of an injured patient, and decoders do not account for spurious signals generated in the cerebellum due to the loss of proprioceptive data. Thus, the key challenge is to design robust decoders for BMIC of the future that take into account both cerebellar and cortical contributions.

Intellectual Merit: We propose a novel Robust Decoder-Compensator (RDC) architecture for interactive control of fast movements in the presence of uncertainty. The RDC is a feedback interconnection that 1) decodes cortical signals to produce actuator commands that reflect motor intent, 2) corrects for spurious cerebellar signals generated in the absence of proprioceptive feedback, and 3) makes robust the interconnection to account for mismatches between models and reality. Multi-site intracranial EEG recordings in motor areas obtained from epilepsy patients executing fast and loaded movements will facilitate system identification of cortical structures in healthy and in spinal cord patients. The cortical models and the RDC architecture will belong to a class of linear parameter varying systems, and the RDC will be synthesized to maintain performance over a wide range of movements and environments. Finally, we will implement the interactive system on patients with implanted electrodes.

Broader Impact: We provide a unified framework aimed at understanding human motor control, which incorporates cerebellar and cortical models and builds a BMIC for fast and natural movements, allowing patients with spinal cord injuries and cerebellar ataxia to execute rapid natural trajectories. Powerful extensions of closed-loop system identification and robust control synthesis techniques for LPV systems will be developed. This program will also give students rare opportunities to address challenges at the interface between systems engineering and neurobiology.

DESCRIPTION (provided by applicant): The overall project goals are to study the cortical network dynamics of human upper limb motor control spanning two distinct spatial scales recorded with electrocorticography (ECoG), and to demonstrate that these dynamics can be estimated in real-time and used to control the JHU Applied Physics Lab Modular Prosthetic Limb (MPL) during execution of functionally useful complex action sequences. Our human subjects will be instructed to perform complete functional movements characteristic of activities of daily living. We will analyze the task-related temporal evolution in the strength and pattern o interactions among large-scale cortical networks known to be recruited in visually-guided reach-to-grasp tasks. Using multi-scale subdural ECoG with combinations of routine clinical macro-electrodes (2.3 mm diameter, 1 cm spacing) recording activity of broadly spread elements/nodes of neural networks, and inset arrays of microelectrodes (75 ?m diameter, 0.9 mm spacing) recording the activity of local sub-networks, we will test our overall hypothesis that there is a functional hierarchy between the two scales (Aim 1). More specifically, we hypothesize that large-scale network dynamics involving premotor/motor cortex reflect the evolution of sensory-motor processing demands during complex action sequences, while micro-scale population activity and network dynamics in motor cortex reflect the low-level kinematics of these tasks. We will utilize methods of estimating dynamic effective connectivity developed by our team to study interactions between these scales and test whether there exists a spatially heterogeneous and hierarchical structure within the macro-micro scale networks. The results of these analyses have wide-ranging clinical implications for both the optimal scale of functional mapping for clinical diagnostic purposes and the extent of implantations for neuroprosthetic control. We will exploit multi-scale ECoG recordings and online estimates of the dynamics of neural activation and large-scale/local network interactions to achieve control of the MPL during functionally useful tasks (Aim 2). This approach will go beyond traditional paradigms that have developed neural control over individual degrees of freedom. We will do this by embedding low-level control within an innovative framework whereby knowledge of task goals supplement direct kinematic decoding. This project will build on our team's previous successes in implementing a system for semi-autonomous ECoG control of the MPL, employing machine vision and route-planning algorithms, during complex interactions with objects requiring the coordination of multiple joints. This system will be able to leverage for the first time the rich complexity of temporally and spatially resolved network dynamics correlated with high-level goals to achieve functionally useful control of an advanced neuroprosthetic limb.

1646085 - Thakor

This IEEE BIOROB 2016 conference covers many topics pertaining to the application of robotics and mechatronics in medicine and biology. The conference technical program of IEEE BioRob2016 will consist of invited talks, special sessions, posters, and paper presentations. The topics covered by the conference include a) health related topics pertaining to body mechanics, rehabilitation and assistance for disabled, b) advanced robotic and mechanical devices which will lead to automation and augmentation in care of aged and disabled, and in surgery, c) take inspiration from biology or nature to develop new generation of machines that carry unique properties of the living systems, and d) use of brain interface, neural control of machines and prostheses. These are leading edge topics that involve advanced technological fields such as robotics that are greatly in the national interest (e.g. the National Robotics Initiative proposed by the President). Medical and surgical robotics and Neuroroprosthesis will contribute to improvements in human health. More advanced topics of biological inspired robotics may have implications in the development of technologies of interest to the defense. The conference will also provide numerous opportunities and awards for students and other young investigators. The invited students will be eligible to compete for student paper and poster awards and will be given featured opportunities to present. Preference will be given to under-represented minority and women.

The IEEE Robotics and Automation Society and the Engineering in Medicine and Biology Society have teamed up to run the International Conference on Biomedical Robotics and Biomechatronics - BioRob 2016. Previously this international meeting took place in Rome and Brazil. This year the meeting will take place in Singapore. This conference proposes exciting topics at the frontiers of important fields that have impact on human health and disabilities, as well as advancing the technology with implication for industrial advances and defense. The BIOROB conference covers both theoretical and experimental challenges posed by the application of robotics and mechatronics in medicine and biology. Biorobotics field represents a multi-disciplinary science and technology approach marrying many disciplines. These include the interplay of biology and medicine, human disease and health, with the help of technology spanning many disciplines and fields. The primary technology focus of BIOROB is robotic, mechatronic, and biomechanical/biomimetic systems. The application areas would include the fields of prosthesis, exoskeletons, and assistive devices. Application areas include treatment of neurological, muscular, and neuromuscular disorders. Technology and applications would include surgical systems, rehabilitation systems, neuroprosthesis and brain machine interfaces. The research presented will greatly add to our understanding of how biological systems work, behave and interact and will guide us in the design and fabrication of novel, high performance bio-inspired machines and systems for many different applications. Research presented will demonstrate novel mechatronic and robotic devices, as well as computational methods and technologies assist human beings in prevention, diagnosis, surgery, prosthetics, rehabilitation and personal assistance.

Project Summary The steadily growing aging population, worldwide prevalence of chronic diseases, and outbreaks of infectious diseases are some of the urgent global health challenges of our present-day society. To address these unmet healthcare needs, health informatics which deals with the acquisition, transmission, processing, storage, retrieval and use of information has emerged as an active area of interdisciplinary research to enhance the quality and efficiency of health care, to realize the early diagnosis and treatment of major diseases as well as to respond to public health emergencies. This GRC-AHI will focus on the new frontiers of health information acquisition, information transmissions via wireless/mobile internets, and big data processing/mining for health. Five major themes are proposed: 1) Human Health Informatics, 2) Precision Medicine and Medical Informatics, 3) Imaging Informatics, 4) Neuro Informatics, 5) Wearable and Mobile Health Informatics. The GRC-AHI will emphasize participation by experts and emerging young investigators, and particularly promote diversity through invitation and support for women, both leaders and emerging researchers. The conference will be promoted through a website, international messaging, advertising in Science Magazine, and major international conferences.

This project aims to enhance the sense of touch for robotic hands. The main goal is to develop prosthetic hands with a sense of touch. The touch sensor's primary application is for upper limb amputees. The research team plans both fundamental research and its application. The types of applications of this kind of sensor include: humanoid robots for assistive work and elder-care, surgical robotics, underwater robotic manipulators and spacesuits. Additionally, educational initiatives including internships, training of under-represented minority, and research experiences and summer modules for high school students are planned through the Johns Hopkins Center for Talented Youth.

The technical goal of the project is to build a highly scalable sensor design mimicking different tactile receptors in human skins and encode information from the sensors in a manner analogous to the neural activity of the tactile receptors. The sensor will encode the tactile information at multiple scales, firstly based on different receptor properties, and secondly based on neuron-like encoding of the sensor signals. This technique of encoding the neural activity, known as neuromorphic encoding, converts the sensor activity as an event stream, and from that data obtains finer features. The receptor based sensing along with the various neural network algorithms, for the first time, will provide an approach to texture and shape recognition and, as such, can also be useful for intelligent palpation and tactile perception by dexterous robotic 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.

DESCRIPTION (provided by applicant): The overall project goals are to study the cortical network dynamics of human upper limb motor control spanning two distinct spatial scales recorded with electrocorticography (ECoG), and to demonstrate that these dynamics can be estimated in real-time and used to control the JHU Applied Physics Lab Modular Prosthetic Limb (MPL) during execution of functionally useful complex action sequences. Our human subjects will be instructed to perform complete functional movements characteristic of activities of daily living. We will analyze the task-related temporal evolution in the strength and pattern of interactions among large-scale cortical networks known to be recruited in visually-guided reach-to-grasp tasks. Using multi-scale subdural ECoG with combinations of routine clinical macro-electrodes (2.3 mm diameter, 1 cm spacing) recording activity of broadly spread elements/nodes of neural networks, and inset arrays of microelectrodes (75 ?m diameter, 0.9 mm spacing) recording the activity of local sub-networks, we will test our overall hypothesis that there is a functional hierarchy between the two scales (Aim 1). More specifically, we hypothesize that large-scale network dynamics involving premotor/motor cortex reflect the evolution of sensory-motor processing demands during complex action sequences, while micro-scale population activity and network dynamics in motor cortex reflect the low-level kinematics of these tasks. We will utilize methods of estimating dynamic effective connectivity developed by our team to study interactions between these scales and test whether there exists a spatially heterogeneous and hierarchical structure within the macro-micro scale networks. The results of these analyses have wide-ranging clinical implications for both the optimal scale of functional mapping for clinical diagnostic purposes and the extent of implantations for neuroprosthetic control. We will exploit multi-scale ECoG recordings and online estimates of the dynamics of neural activation and large-scale/local network interactions to achieve control of the MPL during functionally useful tasks (Aim 2). This approach will go beyond traditional paradigms that have developed neural control over individual degrees of freedom. We will do this by embedding low-level control within an innovative framework whereby knowledge of task goals supplement direct kinematic decoding. This project will build on our team's previous successes in implementing a system for semi-autonomous ECoG control of the MPL, employing machine vision and route-planning algorithms, during complex interactions with objects requiring the coordination of multiple joints. This system will be able to leverage for the first time the rich complexity of temporally and spatially resolved network dynamics correlated with high-level goals to achieve functionally useful control of an advanced neuroprosthetic limb.

Abstract Cardiac arrest (CA) has devastating consequences to survival and, even after successful resuscitation brain injury can be quite severe. The broad goal of our research is to develop translational, therapeutic technologies for mitigating brain injury from global ischemia following CA. One prevailing solution is therapeutic hypothermia (TH). While TH has been shown to improve outcome, it does not promote arousal or reduce neuro- inflammation. We now propose a novel and potentially translational delivery approach to promote arousal by intranasal delivery of ORXA. In addition, we also focus on examining the intrinsic bio-distribution and anti- inflammatory properties of dendrimers in a chronic long-term survival after CA. We propose discovery experiments that, we hope to show, will lead to clinically translatable solutions. This proposal is founded on exciting preliminary results. We have discovered an approach to targeting the orexinergic pathway through the delivery of Orexin-A (ORXA). This idea is supported by our preliminary studies that first showed that intra-cerebral ventricle (ICV) ORXA treatment reduces inflammation, and in addition, rapidly enhances arousal. This idea is further validated by our novel quantitative EEG (qEEG) monitoring technology. We have observed brain injury and poor outcome due to neuro-inflammation post-CA brain injury. In our preliminary studies, we found that uptake of dendrimers, specifically Dendrimer- N-acetyl cysteine (D- NAC), occurs at injured brain regions. We have shown that dendrimers serve as a targeted therapeutic technology for neuro-inflammation by attenuating neuro-inflammation, oxidative stress and excitotoxicity. Further, we extend our work to long term observations and set up gender-specific models. For the proposed investigations, we will utilize extensively researched and validated rodent model of CA and resuscitation, propose both acute and chronic experimentation in male and female subjects and carry out the monitoring of systemic perfusion, electrophysiological (qEEG) monitoring, comprehensive behavioral examination, and histopathological analysis. Our overarching hypothesis is that intranasal ORXA will initiate brain arousal effects and early anti-inflammatory response, while dendrimer nanotherapy, D-NAC, will reduce chronic neuro-inflammation; and together, these therapies will improve long term survival. The specific aims of this project are to: Aim 1: Determine the therapeutic effects of intranasal ORXA treatment on early neurophysiological recovery, cognitive and behavioral outcome following post-CA coma. Aim 2: Determine the window of anti-inflammatory therapeutic effects of intranasal ORXA applied immediately post-resuscitation. Aim 3: Demonstrate that treatment with dendrimer nanotherapy using dendrimer conjugated to N-acetyl-L- cysteine (D-NAC), increases survival, improves neurobehavior and reduces chronic neuro-inflammation, after resuscitation. Aim 4: Achieve early arousal and neuroprotective effect from post-CA neuroinflamation by sequentially using of intranasal ORXA and D-NAC for sustained neuroprotection leading to improved long term neurological outcomes and survival post-CA. There are very limited current therapeutic solutions for improving survival and cognitive outcome after global ischemia resulting from CA. Our dual approaches, intranasal ORXA delivery and dendrimer mediated targeting, serve the unmet needs of promoting arousal, and mitigating post-CA neuro-inflammation for patients. Further, the intranasal delivery approach, once validated, should be amenable to rapid clinical translation. Overall, our research lays the groundwork for future clinical studies directed at improving the patient outcome after resuscitation.