Warren Grill - US grants

9709488 Grill Neural prostheses are a developing technology that use small electrical currents to activate the nervous system and restore lost function to individuals with neurological impairment. Electrical activation of intact nerve cells, in the form of a neural prosthesis, is presently the only method available to restore function to individuals with spinal cord injury. The long-term goal of the principal investigator's research program is to develop advanced neural prostheses based on electrical stimulation of the spinal cord. The novel approach being pursued is to activate electrically the intact neural control circuits of the spinal cord to generate distributed commands to groups of last-order neurons. There is abundant evidence in animals, and increasing evidence in humans, that the neuronal control circuitry of the isolated spinal cord is capable of generating complex movements with coordinated muscle activity including reaching, locomotion, scratching, and micturition. Exploiting these intact neuronal control circuits would significantly improve the function of and simplify the implementation of neural prostheses. One fundamental requirement to implement a neural prosthesis using microstimulation of the spinal cord is the ability to generate selective and controlled electrical activation of specific groups of neurons. The outcome of the proposed research will be new techniques to effect selective excitation of targeted neurons. Two fundamental questions will be answered using a combination of experimental measurements, computer-based modeling, and engineering optimization. First, what neural elements are activated by stimulation of the spinal cord with penetrating microelectrodes? Second, how can targeted populations of neurons be selectively stimulated? The techniques and knowledge which result from this research will find application in fundamental studies in neurophysiology and in design of advanced neural prostheses utilizing microstimulat ion for restoration of function in individuals with neurological impairment. ***

The objective of this research is to explore the safety and effectiveness of microstimulation of the spinal cord. If successful, such a technique could be part of a prosthesis to restore genito- urinary, bowel, and other motor functions to victims of spinal cord injury. Information from spinal cord microstimulation studies is especially needed by designers of neural prostheses for paraplegic individuals who have sustained injuries to their spinal cords above the lumbosacral region. In particular, evidence from current studies indicate that is possible to selectively excite neurons innervating the bladder detrusor muscle while simultaneously stimulating interneurons which have inhibitory synaptic connections with neurons innervating the external urethral sphincter. Likewise, discrete control of penile erection, ejaculation, bowel evacuation, and control of the somatic musculature of the limbs may be possible by selective spinal cord microstimulation below the level of spinal cord injury. Current contract research has provided information about the locations of afferent and efferent neurons as well as interneurons controlling urinary function in the cat spinal cord using both normal and spinalized animals. Limited mapping has also been performed on the neurons that control erection in the male cat. The current contract research is also studying the possibility of controlling, by spinal cord microstimulation, the somatic musculature of individuals paralyzed as the result of spinal cord injuries. As an initial feasibility study, the locations of the neurons controlling the flexors and extensors of the knee are being mapped. Microstimulation of these mapped areas has demonstrated activation of both knee flexors and extensors. The present research will provide more detailed maps, and will determine quantitatively, the degree of motor control of paralyzed muscles that can be produced by microstimulation of the lumbosacral spinal cord.

DESCRIPTION (Adapted From The Applicant's Abstract): The primary objectives of the proposed work are to determine what neural elements are activated by DBS, to develop methods to activate selectively local neurons and axons of passage, and to determine the motor effects) of stimulation of different neuronal groups. We will use computer-based modeling of thalamic neurons and the fields generated by DBS electrodes to determine the effects of stimulus parameters and electrode geometry variations on neuronal excitation and block. Hypotheses formulated from computer modeling will be tested. First, using paresthesias evoked by thalamic stimulation in awake human as a unique assay allowing Discrimination of activation of local or remote neural elements, and secondly by quantifying the motor effects:)f selective stimulation of local neurons and axons of passage. The outcomes of this research will be a thorough understanding of what neuronal elements (both type and spatial extent) are affected by DBS and methods to activate selectively targeted populations. We expect to design new stimulus waveforms and electrode geometries that will allow element- and location-specific; st1mulation of the human thalamus. These new techniques will enable us to define the populations of neurons that produce desired and undesired motor effects during DBS, and to specify the next generation of implantable electrodes and stimulators. Collectively, these results will improve the efficacy and expand the range of applications for DBS. Chronic high frequency electrical stimulation of the brain, also called deep brain stimulation,(CBD) is effective in treating a number of neurological disorders, but the mechanisms of action of unclear. A number of plausible hypotheses have been proposed, however, these hypotheses are difficult to support or refute because it is not known what neural elements (local cells, axons of passage) respond at similar stimulation thresholds. This lack of selectivity of the neural response complicates our understanding of the mechanisms of action of DBS, and limits our ability to maximally exploit DBS for therapy. However, if the responsive elements could be controlled selectively, then their differential effects may be used to expand the applications of DBS and minimize undesirable side effects.

DESCRIPTION (provided by applicant): Loss of bladder control as a result of neurological disease or injury such as spinal cord injury (SCI) has devastating effects. SCI results in loss of voluntary control of bladder evacuation, bladder hyper-reflexia, and bladder sphincter dysynergia. These factors often lead to ureteric reflux and obstruction, infection of the kidneys, long-term renal damage, episodes of autonomic dysreflexia with dangerous rises in blood pressure, incontinence which contributes to skin breakdown, as well as frequent urinary tract infections. Loss of bladder control also has profound social impact and leads to decreased quality of life, as well as large direct medical costs from procedures, supplies, and medication. The long-term goal of this research is to develop a neural prosthesis to restore bladder function (continence and micturition) in persons with neurological disorders, particularly spinal cord injury. Restoration of bladder evacuation and continence in individuals with SCI by electrical stimulation of the sacral nerve roots and surgical transection of sacral sensory nerve roots (dorsal rhizotomy) has resulted in documented medical, quality of life, and financial benefits. However, the widespread application of existing technology is limited by the objection of potential candidates to the irreversible dorsal rhizotomy and the complex surgical implant procedure. The PIs propose an innovative approach to restoration of bladder function using a single multi-electrode nerve cuff implanted on the pudendal nerve to detect the onset of hyper-reflexive bladder contractions by electrical recording, to arrest nascent hyper-reflexive bladder contractions by electrical stimulation of pudendal genital afferent nerve fibers, and to produce on-demand bladder evacuation by electrical stimulation of pudendal urethral afferent nerve fibers. This innovative approach differs substantially from existing approaches using electrical stimulation of the spinal roots in that it does not require a spinal laminectomy, does not require irreversible surgical transection of the sacral sensory nerve roots, and stimulates the afferent rather than the efferent side of the system. This is expected to increase the population of individuals who can benefit from neural prosthetic technology, while mantaining the documented benefits. The objective of the proposed work is to demonstrate the feasibility of this approach using complementary experiments in an animal model and in persons with spinal cord injury. Successful completion of this project will lead to the development of an effective neural prosthetic system for restoration of bladder function.

[unreadable] DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) has emerged rapidly as a treatment for movement disorders and is under investigation for treatment of epilepsy and psychiatric disorders. However, the mechanism(s) of action of DBS are still unclear, and this lack of understanding limits full development and optimization of this promising treatment. Presently, DBS uses regular (constant interpulse interval) high frequency stimulus trains, and the beneficial (lesion-like) effects of DBS are only observed at high (>100 Hz) stimulation frequencies. Although effective, high frequency stimulation generates stronger side-effects than low frequency stimulation, the therapeutic window between the voltage that generates the desired clinical effect(s) and the voltage that generates side effects decreases with increasing frequency, and high stimulation frequencies increase power consumption and shorten implant lifetime, as compared to lower frequencies. We propose to determine the effect of non-regular (variable interpulse interval) stimulation trains on motor function and side effects in persons with Parkinson's disease and on neuronal activity in a computational model of the basal ganglia. We will apply stimulation patterns with variable interpulse intervals expected to create a range of motor effects from exacerbation of symptoms to relief of symptoms, and these data will be used to test the hypothesis that regularization of the output of the stimulated nucleus is required for efficacy of DBS. The results will provide further insight into the mechanisms of action of DBS and guide design of novel stimulation patterns. Subsequently, we will design and test novel, non-regular stimulation patterns that are expected to produce relief of motor symptoms at lower average frequencies than continuous, high rate stimulation. These stimulus trains are expected to increase the efficacy of DBS by reducing the intensity of side effects, increasing the dynamic range between the onset of the desired clinical effect(s) and side effects (and thereby reducing sensitivity to the position of the electrode), and decreasing power consumption. The outcome of this project will be an increased understanding of the mechanisms of action of DBS, and this will facilitate selection of optimal surgical targets as well as treatments for new disorders. The second outcome will be novel pulse patterns that are expected to improve outcomes of DBS by reducing side effects and prolonging battery life. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The objective of this project is to evaluate the technical feasibility of novel low impedance stimulating electrodes. The power consumption of implanted stimulators is dependent on the impedance of the electrode- tissue interface. Power consumption requires larger implanted packages to accommodate appropriate batteries, and finite battery lifetimes require surgical replacement of devices. Reductions in electrode impedance will reduce power consumption leading to prolonged battery life and/or smaller implant packages. We will develop and evaluate novel high-perimeter electrodes designed to exploit the non-uniform distribution of current density on the electrode surface. Electrodes with increased perimeter are intended to enhance the "edge effect"; the current density on the electrode surface is higher toward the perimeter of the electrode, and a more pronounced edge effect is expected to lower the electrode impedance. We will evaluate the performance of electrodes with an increased perimeter in three domains. First, we will make in vitro measurements of the impedance of across a spectrum of geometries designed in increase the electrode perimeter. These data will be used to test the hypothesis that increasing the electrode perimeter decreases electrode impedance and to inform subsequent electrode designs. Second, the electrode geometry can affect the pattern of neural excitation generated in the surrounding tissue, and we will quantify the patterns of neuronal excitation generated by high-perimeter electrode geometries and compare these to patterns generated by conventional electrodes. Third, the electrode geometry can affect the spatial distribution of current density over the electrode surface, an important factor in stimulation induced neural damage and electrode corrosion. We will conduct in vitro pulse testing of electrode corrosion, and quantify the effects of increasing the perimeter on the magnitude and distribution of current density across the electrode surface to assess the propensity to cause tissue damage. The outcome of these studies will be a comprehensive analytical and in vitro assessment of the technical feasibility of a new class of low impedance stimulating electrodes, and will provide the foundation for subsequent chronic in vivo testing of electrode safety and efficacy. The objective of this project is to design and analyze more efficient electrodes for use in electrical stimulation of the nervous system to treat neurological disease or injury. These electrodes will increase the lifetime of battery-powered implantable electrical stimulators. This will reduce the risks and costs associated with surgical replacement of implanted stimulators due to depletion of the batteries. [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Chronic high-frequency electrical stimulation of the brain, called deep brain stimulation (DBS), has emerged as a well-established therapy for the treatment of movement disorders, including essential tremor and Parkinson's disease (PD). Although the clinical benefits of DBS are well documented, fundamental questions remain about the mechanisms of action, and this lack of understanding will limit the full development and optimization of this promising treatment. One of the hallmarks of DBS is the strong dependence of symptom relief on the frequency of stimulation. High frequency DBS (> 100 Hz) relieves the symptoms of movement disorders, while low frequency stimulation (< 50 Hz) is generally not ineffective. During the prior grant period we established that the effects of DBS are also strongly dependent on the temporal pattern of stimulation. Now, we seek to exploit this finding - that the effects of DBS are strongly dependent on the temporal pattern of stimulation - both to understand the relationship between temporal patterns of neural activity and the motor symptoms of PD and to improve the effectiveness and efficiency of DBS through the design of novel optimal temporal patterns of stimulation. We will combine computational modeling, quantitative behavior and single unit neural recording in an animal model of PD, and translational experiments in humans with PD to advance both the understanding and application of DBS. First, we will measure the effects on tremor and bradykinesia of symptogenic temporal patterns of DBS, designed to generate neural typified by either theta-frequency or beta-frequency oscillations, and determine the causality between these temporal patterns of neural activity and the motor symptoms of PD. Second, we will use model-based optimization to design novel temporal patterns of stimulation intended to suppress maximally the abnormal synchronous oscillations in the theta- and beta-frequency bands, and measure the effects of DBS with these patterns on tremor and bradykinesia in a rat model of PD and in persons with PD and STN DBS. Third, we will measure the effects of the frequency and temporal pattern of DBS on neural activity the basal ganglia and cortex. We will use innovative hardware that enables recording of local field potentials during the application of DBS and correlate the changes in neural oscillatory activity with changes in symptoms in persons with PD and STN DBS, as well as in a rat model of PD. The temporal pattern of DBS is a novel and important parameter that we will exploit, both to understand the relationship between the patterns of neural activity and motor symptoms of PD, and as a novel way to improve the efficacy and efficiency of DBS. The outcomes of the proposed research will contribute to understanding the relationship between patterns of neuronal activity and the symptoms of movement disorders, to improving the treatment of Parkinsonian symptoms with DBS, and to uncovering the mechanisms of action of DBS.

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) treats the cardinal symptoms of Parkinson's disease (PD) including bradykinesia, rigidity, and tremor, and the efficacy of DBS is strongly dependent on finding stimulation parameters (frequency, pulse width, voltage) that maximize symptom reduction without causing side effects. However, there are presently few guidelines to inform programmers regarding selection of stimulation parameters. Thus, device programming is an ad-hoc process, with difficulties of time, expense, and patient discomfort, and patients are often deprived of the optimal benefits of stimulation. A major obstacle to developing rational methods of programming deep brain stimulation parameters for PD is the lack of understanding of the temporal evolution of the motor symptom response to changes in stimulation condition. While tremor responds immediately, bradykinesia and rigidity have delayed responses to changes in stimulation. The delayed responses result in carry-over effects during programming and complicate selection of effective stimulation parameters. The long-term goal of this research is to develop automated methods for programming optimal stimulation parameters. The immediate goals of this proposal are to quantify the temporal changes in symptoms when DBS is turned ON or OFF, and develop an appropriate protocol to measure the effects of stimulation parameter variations on motor symptoms. In aim 1, motor symptoms will be quantified at regular intervals after DBS is turned ON and OFF in human subject volunteers. In aim 2, the motor symptom response data will be fit with mathematical models to quantify the time constants of symptom change and to determine whether the temporal changes depend on the stimulation duration and/or parameters. The results of aims 1 and 2 will be used in aim 3 to design a protocol to measure the steady-state response to stimulation at short times after stimulation is turned ON. The outcome will be an understanding of how the symptoms change over time after stimulation is turned ON and OFF. This will enable the design of programming methods which minimize carry-over effects and the selection of optimal DBS parameters. Optimal stimulation parameters will maximize symptom relief, allow patients to reduce their dopaminergic medications, maximize battery life, and minimize both electrical and drug- related side effects. PUBLIC HEALTH RELEVANCE: Successful treatment of the disabling motor symptoms of Parkinson's disease with deep brain stimulation depends on the proper selection of stimulation parameters. The outcome of this research will be an understanding of how the motor symptoms of Parkinson's disease respond over time to deep brain stimulation. Understanding how the symptoms change over time is required to develop methods to select optimal deep brain stimulation parameters.

DESCRIPTION (provided by applicant): Deep brain stimulation is a clinically effective treatment, but the selection of the parameters of stimulation remains a significant clinical challenge and many recipients are deprived of benefit due to non-optimal parameter selection. This project will advance an innovative approach to automatic selection of stimulation parameters based on monitoring of neural signals in the brain during stimulation. We propose to conduct first in human recordings of brain signals and evaluate them as a possible biomarker for the effectiveness of deep brain stimulation (DBS). DBS - an implanted brain pacemaker - is an effective therapy for essential tremor and Parkinson's disease. Present DBS systems operate in an open-loop fashion; a clinician sets the stimulation parameters, and patients receive invariant stimulation 24 h/day indefinitely. Selection of stimulation parameters is a non- systematic process that requires substantial time and clinical expertise and often results in sub-optimal outcomes. Further, in applications like treatment of epilepsy or depression, there may be no overt or immediate changes to guide selection of stimulation parameters. Closed-loop DBS, where the system adjusts parameters automatically and in a manner responsive to the needs of the patient, has the potential to improve outcomes by maintaining treatment during fluctuations in medication status, as the disease progresses, or as the response to DBS changes over time. The objective of the proposed project is to determine the feasibility of using recordings of neural activity, obtained using the same electrodes implanted to deliver stimulation, as a feedback signal for closed-loop control of DBS. We will conduct recordings of EEG-like brain activity during DBS and correlate changes in the amplitude and character of these signals with changes in symptoms. These experiments use innovative hardware that we developed and validated in animal studies and a novel intraoperative setting that allows direct connection to the DBS brain lead. The outcome will provide clinical validation of the suitability of brain electrical activity s a biomarker for the effectiveness of DBS. We will also conduct complementary animal studies and computational modeling to determine the source(s) of the neural signals constituting the biomarker. The outcome will provide insight into the mechanisms of action of DBS relevant to the design of future DBS systems.

Spinal cord injury causes both paralysis and loss of sensation from the limbs. The past 15 years have seen remarkable advances in ?Brain Machine Interfaces? (BMIs) that allow paralyzed persons to move anthropomorphic limbs using signals recorded directly from their brains. However, these movements remain slow, clumsy, and effortful, looking remarkably like those of individuals who have lost sensation from their arms due to peripheral neuropathy. Brain-controlled prosthetic limbs are unlikely to achieve high levels of performance in the absence of artificial sensory feedback. Early attempts at restoring somatosensation used intracortical microstimulation (ICMS) to activate somatosensory cortex (s1), requiring animals to learn largely arbitrary patterns of stimulation to represent two or three virtual objects or to navigate in two-dimensional space. While an important beginning, this approach seems unlikely to scale to the broad range of limb movements and interactions with objects that we experience in daily life. To move the field past this hurdle, we propose to replace both touch and proprioception by using multi- electrode ICMS to produce naturalistic patterns of neuronal activity in S1 of monkeys. In Aim 1, we will develop model-optimized mappings between limb state (pressure on the fingertip, or motion of the limb) and the patterns of ICMS required to evoke S1 activation that mimics that of natural inputs. These maps will account for both the dynamics of neural responses and the biophysics of ICMS. We anticipate that this biomimetic approach will evoke intuitive sensations that require little or no training to interpret. We will validate the maps by comparing natural and ICMS-evoked S1 activity using novel hardware that allows for concurrent ICMS and neural recording. In Aim 2, we will test the ability of monkeys to recognize objects using artificial touch. Having learned to identify real objects by touch, animals will explore virtual objects with an avatar that shadows their own hand movements, receiving artificial touch sensations when the avatar contacts objects. We will test their initial performance on the virtual stereognosis task without learning, as well as their improvements in performance over time. Aim 3 will be similar, but will focus on proprioception. We will train monkeys to report the direction of brief force bumps applied to their hand. After training, we will replace the actual bumps with virtual bumps created by patterned ICMS, again asking the monkeys to report their perceived sense of the direction and magnitude of the perturbation. Finally, in Aim 4, we will temporarily paralyze the monkey's arm, thereby removing both touch and proprioception, mimicking the essential characteristics of a paralyzed patient. The avatar will be controlled based on recordings from motor cortex and guided by artificial somatosensation. The monkey will reach to a set of virtual objects, find one with a particular shape, grasp it, and move it to a new location. If we can demonstrate that this model-optimized, biomimetic feedback is informative and easy to learn, it should form the basis for robust, scalable, somatosensory feedback for BMIs.

Experiments to map physiological functions of autonomic nerves and the continued advance of bioelectronic therapies are limited by inadequate activation or block of targeted nerve fibers and unwanted co-activation or block of non-targeted nerve fibers. More fundamentally, the relationship between applied stimuli and the nerve fibers that are activated or blocked, how this relationship varies across individuals and species, and how these relationships can be controlled remain largely unknown. We will develop, implement and validate an efficient computational pipeline for simulation of electrical activation and block of different nerve fiber types within autonomic nerves. The pipeline will include segmentation of microanatomy from fixed nerve samples, three- dimensional finite-element models of electrodes positioned on nerves, and non-linear cable models of different nerve fiber types, enabling calculation of quantitative input-output maps of activation and block of specific nerve fibers. As key benchmarks of pipeline development and for the proposed analysis and design efforts, we will implement models of the cervical (VNc) and abdominal (VNa) vagus nerves in rat, in a SPARC-identified animal model, and in human. The VNc is an excellent test bed as it contains a broad spectrum of nerve fiber types, there are experimental data to facilitate model validation, and there are multiple applications of VNc stimulation where a lack of fiber selectivity limits the therapeutic window. The VNa is an excellent complement to the cervical VNc, as a prototypical autonomic nerve of a size comparable to many of the small autonomic nerves targeted by SPARC projects. We will use the models that emerge from the pipeline to achieve analysis and design goals to address critical gaps identified as SPARC priorities. Specifically, we will quantify of the effects of intra-species differences in nerve morphology on activation and block by building individual sample-specific models for each nerve and specie. These models will also be used to quantify inter-species differences in nerve fiber activation and block and to identify electrode designs and stimulation parameters that produce equivalent degrees of activation and block across species. We will combine the resulting models with engineering optimization to design approaches to increase the selectivity and efficiency of activation and block of different nerve fiber types. The outcomes will be a pipeline for modeling autonomic nerves, electrode geometries, and stimulation parameters, as well as tools that address the limitations of nerve stimulation selectivity and efficiency that hinder the continued advance of physiological mapping studies and the development of bioelectronic therapies.