Eric J. Perreault - US grants

[unreadable] DESCRIPTION (provided by applicant): The applicant's long-term research objectives are to understand the interdependent relationship between the neural control of multi-joint movements and the mechanical design of the human motor system, and to understand how injury to either of these systems compromises normal motor function. The focus of this particular study is on the stretch reflex contributions to the regulation of human arm mechanics, and how this spinally mediated regulation is altered following stroke. Approximately 400,000 Americans suffer their first stroke each year, and this number is expected to exceed 1,000,000 by the year 2050. Cerebral vascular injuries such as stroke can result in a variety of movement related disorders including muscular weakness, abnormal motor synergies and spasticity. Many of these motor disorders are thought to arise from changes in the behavior of spinal circuits contributing to motor behavior; however, few studies have examined the effect of these changes on the coordination of whole limb function. This study seeks to fill this void by using estimates of limb impedance and the stretch reflex contributions to this impedance to quantify changes in the regulation of multi-joint arm mechanics following stroke. The specific aims are (1) to examine the reflex contributions to whole limb stiffness regulation in able-bodied individuals maintaining arm posture, (2) to quantify the changes in whole limb stiffness regulation and the spinal contributions to this regulation following stroke, and (3) to examine the possible mechanisms by which tizanidine, a promising drug for restoring motor function following stroke, alters multi-joint reflex behavior. For all aims, limb mechanics will be quantified using estimates of arm limb impedance, which describes the dynamic relationship between externally imposed displacements of limb posture and the forces generated in response. Impedance will be quantified in all degrees of freedom (DOFs) relevant to normal motor function using a 6 DOF robotic manipulator to perturb arm posture and a 6DOF load cell to measure the corresponding forces in all DOF relevant to normal function. Measurements will be made in able-bodied individuals and in individuals who have suffered a stroke. A small, complementary animal study will be performed to investigate possible mechanisms underlying the actions of tizanidine. [unreadable] [unreadable]

Recent advances in electric technology make it possible to obtain recordings from multiple cortical neurons. This ability opens a number of possibilities for expanding the understanding of cortical function by allowing the aggregate behavior of neural populations to examine during complex tasks. This project is to develop the computational techniques necessary for efficiently processing data collected from multichannel electrode arrays and to use these techniques for studying the role primary motor cortex in the control animal movement. Systems identification techniques will be used to examine neural information processing. Algorithm development will focus on efficient linear nonparametric multiple-input, single-output techniques for quantifying the transfer of information between neural activity and physiological processes. The algorithm process will then be extended to incorporate nonlinear phenomena such as threshold nonlinearities inherent to neural integration. These techniques will be used to examine it sensory information linked volitional movements influences the plasticity of primary more cortex during performance of skilled motor tasks. If a link is demonstrated this may provide a path for enhancing acquisition of motor skills for a range of tasks.

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how long-latency stretch reflexes (LLSRs) contribute to the control of multijoint posture and movement in the human arm. This is an important problem because many neurological disorders impair stretch reflexes, resulting in well-documented motor dysfunction. Attempts to enhance motor function through a modification of reflex behavior have been largely equivocal, however, due at least in part to the unknown relationships between specific reflex subtypes and motor abilities. Our central theme is that much of the gap can be filled by considering the pathways that contribute to LLSRs and their specific, context-dependent contributions to motor function. LLSRs contain at least two key behavioral compo- nents: stabilizing reflexes, contributing to posture regulation, and triggered reactions for the rapid release of planned actions. We have shown that these behaviors are mediated by separate pathways and that their relative importance depends on the task performed. Our recent work focused on the stabilizing component of the LLSR. Here we propose to investigate triggered reactions. Our central hypothesis is that triggered reactions can act independently from stabilizing reflexes, based on our preliminary data demonstrating that stabilizing LLSRs are lost following stroke but that triggered reactions are spared. Importantly, our data also suggest that appropriately triggered reactions increase speed and coordination in stroke subjects, potentially forming the basis for effective rehabilitation. First, however, we must clarify the LLSR role in controlling unimpaired posture and movement, and its integrity and function following stroke. Our Specific Aims are: 1) to determine if stabilizing reflexes and triggered reactions are controlled independently; 2) to determine how uncertainty affects the planning, execution and efficacy of triggered reactions; and 3) to determine how brain injury due to stroke im- pairs stabilizing stretch reflexes and triggered reactions. The first two aims focus on the behavioral relevance of triggered reactions, and will be completed in unimpaired subjects using a 3D robotic manipulator to charac- terize LLSRs during the key transition from maintaining arm posture to initiating a reach. Our third aim will be completed in stroke subjects and age-matched controls. It parallels the first two aims, but also will use diffusion tensor imaging (DTI) to quantify lesions in the descending pathways thought to regulate the stabilizing and triggered components of the LLSR. The contributions of this research will be a clear description of the role of triggered reactions in the control of movement, how that role is integrated with posture-stabilizing components of the LLSR, and how the LLSR is impaired following stroke in relation to the neural pathways contributing to it. With this refined understanding, we hope to lay the groundwork for using triggered reactions in rehabilitation training paradigms aimed at enhancing the ability to voluntarily initiate appropriate motor patterns at appropri- ate latencies in stroke survivors.

DESCRIPTION (provided by applicant): This proposal seeks funding for the fifth cycle of our training program in Pathophysiology and Rehabilitation of Neural Dysfunction (PRND). The program is directed by Dr. Eric Perreault, PhD, and co-Directed by Drs. CJ Heckman, PhD and Todd Kuiken, MD, PhD. Trainees will be guided by a total of 23 highly collaborative mentors spanning the range from cellular neurophysiology, to engineering, to clinical medicine, all with an emphasis on rehabilitation from neural dysfunction. The specific objectives of our program are to train rehabilitation scientists who understand the broad spectrum of problems confronting people with neurologic disabilities, and who possess the clinical, scientific and quantitative skils to alleviate the burden on this growing population. The program is based at Northwestern University, in close collaboration with the Rehabilitation Institute of Chicago. These two institutions have a long, collaborative history of cutting-edge rehabilitation research, to which or program has contributed. During our first 4 cycles of funding, the program has directly supported 34 pre- doctoral fellows, 24 postdoctoral fellows, and 5 summer interns. Many of these trainees are now established leaders in the field of rehabilitation medicine. In this renewal application, w seek to build on our past achievements and increase our impact through innovations designed to formalize the clinical component of our training program, increase the communication and collaboration between basic scientists and clinicians, and strengthen the career development opportunities that facilitate the transition from trainee to independent scientist. We propose to train three predoctoral fellows, three postdoctoral fellows and two summer interns. This is an in- crease of one postdoctoral fellow and one intern over our current levels. The postdoctoral increase is dedicated to expanding our training pool to MDs. This expansion is aimed at facilitating the translational component of our research program, and increasing the clinical exposure of all trainees. The increase in one summer intern is in acknowledgment of the highly successful summer program we have developed since our last renewal. All predoctoral trainees will be selected from applicants in the departments of Biomedical and Mechanical Engineering, from which there is an abundant and growing applicant pool. Postdoctoral fellows may also joint our program through the departments of Physiology, Physical Therapy and Human Movement Sciences, and Physical Medicine and Rehabilitation. This latter department also will provide a source of research physiatrists through the existing clinical fellowship program. All trainees, regardless of level, will complete 2 year of training in our program. By integrating the proposed innovations with the successful practices we already have in place, we expect to continue advancing the science and practice of rehabilitation medicine by training the next generation of interdisciplinary leaders.

This project will study the adaptation, implementation, and dissemination of best practices in experiential learning in the core middle years of the engineering curriculum where students take the bulk of technical fundamentals. The study will involve two series of junior-year fundamental core engineering courses; one taught at Northwestern University's Department of Biomedical Engineering and the other taught at the University of Florida's Department of Electrical and Computer Engineering. The course sequences use similar tools and teach similar topics geared towards building skills needed for success in the engineering workplace or graduate school. The differences are in methods of delivery and the types of experiential learning modules employed.

Using a mixed method approach, the main goals of this proposal are to 1) assess each course sequence in terms of How People Learn and assess how student experiences and outcomes are linked to those attributes of each course and 2) enhance and expand effective experiential learning modules for broader adoption and implementation. The project will evaluate student learning preferences, student engagement, retention of material in subsequent courses in their respective sequences, transferrable skills between courses and learning of course concepts. Both schools have highly selective engineering programs, but the student demographics differ. These differences give the opportunity to consider more demographic factors in assessing the courses and in designing materials to take advantage of diversity. The knowledge gained will guide future design or development of new interventions and their dissemination strategies.

Pathological changes in muscle stiffness can result from disease, blunt trauma, overuse, or as secondary complications from other injuries and treatments. Changes in muscle stiffness can lead to reduced mobility, chronic pain, discoordination, and increased rate of injury. Consequently, many therapeutic interventions target muscle or joint stiffness. While there is a long history of measuring joint stiffness, there are no validated methods to directly quantify the intrinsic stiffness of individual muscles independently from the other factors influencing the mechanics of a joint. This is a major obstacle to identifying, treating, and monitoring muscle contributions to stiffness-related impairments. Our long-term goal is to improve treatments for musculoskeletal disorders associated with changes to the intrinsic properties of muscle. The central hypothesis of this proposal is that ultrasound elastography (USE), a relatively new imaging tool for the clinic, can be used to measure the intrinsic stiffness of living muscles. Variants of this hypothesis have been widely assumed, but not directly tested aside from the preliminary data provided in this proposal. Our rationale is that providing an objective measure of intrinsic muscle stiffness will clarify the role of muscle in stiffness-related impairments, and lead to a personalized approach to treatment design and evaluation. Our central hypothesis will be evaluated using three aims. Aim 1 will determine the extent to which elastography can measure the intrinsic stiffness of muscles during active contractions. This will be completed in architecturally different muscles of the cat hind limb, where activation can be controlled precisely and direct mechanical measures obtained for comparison. Parallel human experiments will assess feasibility in clinically relevant settings, when muscle is activated by normal patterns of recruitment and rate modulation. Aim 2 will determine if substantial passive forces alter the stiffness estimates obtained by USE. For clinical utility, USE must provide accurate measures during the many conditions in which passive and active structures are relevant. These experiments will be conducted only in cats, as direct measures of passive muscle force are difficult to obtain in humans. Aim 3 will determine if USE can detect microstructural changes in muscle, which are typically only accessible by invasive techniques such as biopsies. Our prior work demonstrated that magnetic resonance elastography (MRE) is sensitive to changes in tissue structure at scales well below image resolution. This project will determine if USE, a more clinically viable technique, can have a similar sensitivity. This will be evaluated by applying MRE and USE to imaging phantoms created using our ability to print biomaterials with known properties in 3D, and to living muscles from cats and humans. This third aim will extend current technologies to characterize muscle and its underlying microstructure more completely. Together, our results could profoundly impact the way disease-related changes in muscle stiffness are quantified and lead to more targeted interventions that alleviate impairments associated with changes to intrinsic muscle stiffness.

Project Summary In the space of barely over ten years, Brain Computer Interfaces (BCIs) used to restore movement have developed from the stuff of science fiction to clinically relevant devices. However, most existing BCIs, while technically remarkable, require the user to be wired to stationary equipment, and allow only intermittent control of a computer cursor or disembodied robotic limb. They require that the algorithm linking brain activity to the restored movement be frequently recalibrated. We have developed a wireless BCI that will operate 24 hours a day, restoring voluntarily movement to monkeys despite paralysis of their hand, for a broad range of their normal motor behaviors, such as foraging, feeding, or playing with enrichment toys. By using ?autoencoding neural networks? we will be able to greatly extend the period over which the BCI will work without recalibration. We have developed a unique model of spinal cord injury (SCI) using a chronically implanted infusion pump that delivers a potent drug (tetrodotoxin) to cuffs placed around two key nerves in the arm. The drug causes a nerve block that produces the acute effects of spinal cord injury for indefinite periods of time, yet with full recovery within a day of stopping the drug. Prior to the nerve block, we will record wirelessly not only neural signals from the brain, but also electromyograms (EMGs) from a large number of muscles in the arm and hand. We will make these recordings not only during typical, constrained motor behaviors in the lab, but also during completely unconstrained behaviors while the monkey is in its home cage. We will use the data to develop algorithms (?decoders?) that transform the neural signals into predicted EMG signals. Following the onset of paralysis, our BCI will use these EMG predictions as control signals for Functional Electrical Stimulation (FES), causing contractions of the paralyzed muscles that the monkey can control voluntarily through the computer interface. We will study the gradually changing brain activity as the monkeys learn to use this FES BMI. In addition, we will attempt to augment the monkey's performance by developing ?adaptive? decoders that improve their performance in parallel with the monkey's own adaptation, as well as ?teacher? decoders that coach the monkeys, pushing them toward desired control strategies and away from counterproductive ones. This technology gives us the ability to study the brain's representation of movement across a range of motor behaviors that has never been possible before. During paralysis, it will allow us to study motor learning and adaption without the limitations imposed by the intermittent availability of current BCIs. Finally, it provides a platform close to that necessary for clinical translation, with which we will be able to study the limits of current decoders and to develop nonlinear and adaptive decoders designed to assist the monkey's own adaptive processes. While this application is focused on restoration of grasp, its general principles will extend to the control of reaching, lower limb function, and even prosthetic limbs. Ultimately, this work will develop the interface, decoder, and control technology that will be necessary to move BCIs from the lab to the clinic.