Randolph J. Nudo - US grants

DESCRIPTION (provided by applicant): The long-range goal of this research project is to examine the neural mechanisms contributing to functional motor recovery after cortical injury, as might occur in stroke. This application represents years 16-20 of a continuing series of productive and clinically relevant studies that have provided substantial insight into the role of neuroplasticity in post-stroke recovery. Our earlier work showed that functional reorganization occurs in peri-infarct cortex following focal infarct. We also provided the first direct evidence that post-infarct behavioral training (i.e., physical therapy) is a potent modulator of post-infarct plasticity. In the immediately preceding grant period, we extended our neurophysiological findings to demonstrate post-infarct map plasticity in a motor cortical structure remote from the infarct, the ventral premotor cortex. We also demonstrated unprecedented long-distance rewiring of corticocortical pathways between the ventral premotor cortex in the frontal lobe and somatosensory cortex in the parietal lobe that occurs spontaneously after cortical infarct. Because of the potential importance of this latter finding to understanding post-stroke recovery mechanisms and the development of interventional strategies for improving recovery, we will now focus our efforts on determining the functional significance of remote cortical plasticity, its generalizability, and underlying mechanisms. These studies will use behavioral training, neurophysiological, neuroanatomical and molecular biological techniques to examine functional and structural plasticity after an ischemic infarct. The study consists of four separate aims: First, we will establish the functional significance of remote cortical plasticity by making secondary lesions in regions that undergo neuroanatomical and neurophysiology reorganization. Second, we will use neurophysiological and neuroanatomical tract-tracing techniques to determine whether cortical territories that are involved in recovery alter their connectivity after stroke. Third, we will examine gene expression in anatomically identified corticocortical neurons that are either connected with the infarcted zone, or sprout novel axonal connections to determine potential mechanisms underlying adaptive neuroanatomical plasticity. Finally, in the fourth aim, we will use behavioral techniques to determine if post-infarct experience alters cortical connectivity patterns. This project will provide important data that may suggest potential new targets for post-stroke recovery therapy. Project Narrative: This project will determine the brain's capacity for self-repair after injury, as might occur in stroke. It will determine the molecular signals that underlie these self-repair processes, potentially providing new targets for therapy based on the brain's own self-restorative processes.

DESCRIPTION (Adapted from the Applicant's Description) The main goal of this program is to provide interdisciplinary training in the neural bases of motor dysfunction and rehabilitation. The intent is to prepare post-doctoral trainees for independent basic and clinical research careers in rehabilitation sciences. The interdisciplinary nature of this program is unique in that basic science trainees will have the opportunity to participate in clinical aspects of rehabilitative medicine, and clinical trainees will be provided with valuable basic scientific insights and technical experience into the neural bases of motor impairment and recovery from brain injury. The training program will focus on the following three general research themes that form the focal points of a model of motor recovery across the lifespan: (1) characterization of impairments and recovery, (2) rehabilitative interventions, (3) pharmacologic interventions. These three themes will utilize expertise from both basic and clinical research to cross-fertilize research experiences of the individual trainees. The goal of the program is to provide trainees in rehabilitative sciences experience with the complex interdisciplinary models that will be necessary for the next generation of therapeutic approaches in rehabilitative medicine. The core faculty include two clinical researchers and five basic science researchers. Five of the faculty are members of the Mental Retardation Research Center (MRRC), and two have their laboratories in close proximity to one another in the KU-Med Center MRRC. The strength of this group is its focus on motor disabilities and understanding their neural underpinnings. The unifying themes of the faculty and students who participate in the proposed training program is a common interest in the life-long development and function of the brain in both health and disease and the design of approaches to treat abnormal conditions of brain function through the use of behavioral training, through novel drug therapies, or through rehabilitative/pharmacologic interactions. The recruitment and selection of trainees will be coordinated through a program advisory committee, with input from all the participating faculty. Trainees with an M.D. or Ph.D. degree in one of the basic or clinical sciences, or an equivalent degree, and a strong commitment to interdisciplinary research in rehabilitation sciences will be considered for entry into this program. Laboratory research and apprenticeships, courses, seminars, guest lectures, journal clubs, data sessions, and poster presentations will be utilized to ensure frequent interaction of the trainees and faculty from the different research areas.

DESCRIPTION (provided by applicant): Motor recovery after stroke is accompanied by functional and structural plasticity in cerebral cortex. In this Cooperative Program in Translational Research (U54), a new therapeutic approach, intended to enhance motor recovery via modulation of neuroplasticity, will be tested in rat (Projects 1 and 2) and nonhuman primate (Project 3) models of recovery after cortical ischemic infarct. This new approach, Cortical Stimulation (CS), utilizes low-level electrical stimulation over peri-infarct cortex applied during rehabilitative training procedures. In this unique collaboration of basic and clinical researchers in academia and industry, preclinical models will be used to optimize treatment protocols for upcoming clinical trials funded by industry. In Project 1, the electrical stimulation protocol (frequency, amplitude, temporal pattern, electrode configuration and duration) will be optimized and seizure susceptibility will be examined. Efficacy will be assessed with regard to evoked movement thresholds and motor performance. In Project 2, the rehabilitative training protocol will be optimized by combining CS with different rehabilitative training procedures (constraint-induced movement therapy, reach training, acrobatic training). The efficacy of training procedures will be assessed by motor performance during treatment and follow-up. In Project 3, optimal parameters determined in rat models will be tested for generalizability to a nonhuman primate model of cortical ischemia and recovery. Also, treatment parameters that are less feasible in the rodent model will be assessed in primates. An Oversight/Leadership Core will organize meetings, promote scientific exchange, assist in management of U54 cores and projects and provide data management and biostatistical support. The three projects will be performed at four sites, chosen because the investigators have extensive experience in the field of stroke recovery, and because they form an integrated team that has advanced the initial preclinical studies. Preclinical results will be translated into the clinical program by regular meetings of the preclinical group with the medical director for clinical trials and U54 Steering Committee to discuss a) preclinical findings and their impact on the clinical program, and b) findings from the clinical program that may impact the preclinical studies. It is expected that this program will serve as a model for the introduction of new therapeutic approaches to brain repair that are based on underlying neuroscientific principles.

DESCRIPTION (provided by applicant): Project Summary Funds are requested for the second cycle of the Kansas Training Program in Neurological and Rehabilitation Sciences. The aim of the program is to provide interdisciplinary practical training and theoretical instruction in translational research in basic and clinical aspects of neuroscience, especially as it applies to neurological conditions amenable to rehabilitative treatments. The interdisciplinary nature of this offering is unique in that basic science trainees participate in clinical aspects of neurological disorders and clinical trainees are exposed to laboratory research and basic neurobiological mechanisms. During the first round of funding, the program directly supported 12 full-time, predoctoral trainees and 40 short-term, summer trainees. While the program is only four years old, some of the full-time trainees are now beginning their postdoctoral training and academic careers. The training program utilizes basic science and clinical research expertise of the faculty to cross- fertilize the training experience. Didactic training includes core curricula for predoctoal students in the Integrated Graduate Program in Biomedical Science, the Graduate Program in Neuroscience, the MD/PhD program or the Graduate Program in Rehabilitation Science, providing a firm groundwork for understanding basic genetic, molecular and cellular mechanisms. Besides the two to three years of support offered to full-time trainees, short-term, summer training experiences are offered to medical and health professions (Doctorate in Physical Therapy) students. The summer training program is designed to expose clinical students to the complex interdisciplinary approaches needed to maximize neurorehabilitation approaches. The summer research experience has made the short-term trainees more competitive for top flight residencies. Because of their research experience in this training program, some of the summer trainees altered their career path to develop into clinician-scientists. The faculty is composed of 26 basic science and clinical mentors, along with 16 teaching faculty. The primary faculty are located within eight Departments in two Schools at the University of Kansas Medical Center. The strength of this group is evidenced by the expertise and caliber of the research faculty, the outstanding research infrastructure, the focus on translating basic neuroscience discoveries into treatments for neurological disorders, and the collaborative interactions between the basic and clinical faculty that are needed for an effective interdisciplinary training program. Laboratory research and apprenticeships, courses, seminars, guest lectures, journal clubs, data sessions, and poster presentations are included in the program to ensure frequent interactions between the trainees and faculty. A unique aspect of the offering is a multidisciplinary clinical rotation with faculty in Neurology, Physical Therapy ad Rehabilitation Medicine. The recruitment and selection of trainees is overseen by an Internal Advisory Committee, with input from the participating faculty. In addition, the program is monitored by an External Advisory Committee composed of national leaders in graduate training in neuroscience and rehabilitation science.

PROJECT SUMMARY [Parent R01 NS030853] The capacity for individuals to recover motor function after stroke or traumatic brain injury is thought to be largely dependent upon adaptive plasticity mechanisms in uninjured regions of the brain. Over the past 20+ years, investigators have demonstrated a remarkable array of neurophysiological and neuroanatomical changes after focal cortical injury in animal models, especially in spared cortical areas. Many of these changes have been correlated with functional motor recovery. Also, neuroimaging and noninvasive stimulation studies in human stroke survivors have shown changes in both the injured and the intact (or contralesional) hemisphere. However, a focus of continuing debate is whether contralesional plasticity is adaptive, maladaptive, or epiphenomenal. From a clinical perspective, this is a critical topic, since many investigators are now employing non-invasive stimulation techniques to modulate activity in the intact hemisphere after stroke to improve motor function. Our long-term goal is to provide a comprehensive understanding of the neural mechanisms underlying recovery of function after brain injury. The objective of this application is to assess the behavioral significance of post-injury neuronal plasticity, especially within the intact hemisphere. To this end, we will utilize our extensive experience in neurophysiological recording, neuroanatomical tract-tracing and behavioral approaches in mammalian models of injury and recovery to describe in detail the role of neuronal plasticity in recovery of motor skills. Our central hypothesis is that spared cortical motor areas in the injured and uninjured hemispheres play evolving and interdependent roles in the execution of motor tasks during functional recovery (Aim 1), and that the participation of the intact hemisphere is dependent upon task complexity (Aim 2), lesion anatomy (Aim 3), and post-injury behavioral experience (Aim 4). We also propose that post-injury plasticity is associated with altered interhemispheric neuroanatomical connections (Aim 5). With this new and unique information, investigators will be better able to design evidence-based interventions to help restore function after cortical injuries. The application of chronic microelectrode recording techniques to the question of neural network plasticity after cortical injury is quite novel. While motor output maps in anesthetized animals have revealed behaviorally- relevant changes after injury, neuronal activity patterns (task-related spike activity, local field potentials, interhemispheric communication) after injury in ambulatory animals is largely unknown. At the conclusion of the proposed five-year project, we expect to have contributed in a unique and substantial way to understanding cortical network dynamics after injury, significantly advancing our ability to design future therapeutic interventions based on a firm mechanistic footing.