Edelle C. Field-Fote - US grants

DESCRIPTION (Adapted from Applicant's Description: In the presence of spastic paresis due to incomplete spinal cord injury (SCI), inadequate supraspinal contributions to motor output of the lower extremities result in a number of abnormalities of movement. Among these are unregulated spinal reflexes, inadequate and delayed motor recruitment, and balance deficits. If the individual is ambulatory, these abnormalities are manifest in the resulting gait pattern as aberrant temporal relationships between muscle groups, deficits in weight bearing capacity and inappropriate muscle activity such as prolonged stance phase, clonus and "scissoring." Sensory information from multiple sources contributes to the production of vertebrate locomotion, therefore, by manipulating sensory input it is possible to modify motor output. Two innovative technologies that appear to be effective for achieving this end are body weight support (BWS) and functional electrical stimulation (FES). The capacity of the human spinal cord to respond to and benefit from an innovative treadmill training regimen will be assessed. FES will be used in conjunction with BWS to facilitate locomotor performance on a treadmill in individuals with incomplete SCI. Preliminary studies indicate that, by combining these interventions, gait performance is improved such that more efficient and functional movement is allowed to emerge. The influence of the body weight support and of appropriately timed stimulation on the resulting ipsilateral and contralateral motor outputs will be characterized. The training effects of BWS locomotion augmented by FES over the course of a multi-session training program will be examined. Gait parameters modified by training will be identified and the nature of these changes will be characterized. To further study how BWS may affect spinal neural elements, a second set of experiments will investigate the effects on alpha motoneuron excitability of unloading the lower extremities, in individuals with incomplete SCI and able-bodied (AB) controls. The proposed experiments are to test the hypothesis that (1) locomotor capacity in individuals with incomplete SCI can be positively influenced by a training regimen consisting of BWS in conjunction with FES, and (2) unloading of the lower extremities influences motoneuron excitability in humans. Results from this work are envisioned to provide the foundation on which to develop rehabilitation protocols for SCI individuals with residual locomotor capacity.

In recent years there has been an increased understanding of the role of activity-dependent plasticity in promoting functional recovery following neurologic injury. There is also an emerging appreciation for the role of spinal mechanisms in control of behaviors such as walking. Research indicates that activity-dependent adaptive changes in spinal cord circuitry may play an important part in the recovery of walking function in individuals with spinal cord injury (SCI), perhaps long after the stage of spontaneous recovery. Two technologies that appear effective in promoting functional recovery are body weight support (BWS) and functional electrical stimulation (FES). In preliminary studies, improved overground walking speed, leg strength and endurance was observed in subjects with SCI who trained using an approach combining these interventions. This proposal will assess, in individuals with chronic incomplete SCI, responses to a BWS-assisted treadmill training regimen under one of three training conditions: 1) passive (manual)-assisted stepping, 2) active (FES)-assisted stepping, or 3) non-assisted (voluntary) stepping. Each condition has distinct advantages. Manually-assisted stepping allows assistance to be graded to individual needs; FES-assisted stepping takes advantage of spinal reflex circuitry and may contribute to beneficial changes in spinal cord neurophysiology; and voluntary stepping may encourage the greatest voluntary effort. These investigations will determine which condition best promotes efficient overground walking, and will examine changes in spinal cord neurophysiology, strength and cardiorespiratory capacity associated with the three forms of training. Performance-based measures will include: computerized kinematic analysis to assess lower limb coordination and key parameters of gait (speed, stride length and step rhythm), electromyographic assessment of muscle recruitment and work capacity evaluation to assess changes in strength and gait efficiency. Neurophysiologic techniques (e.g., reflex testing and transcranial magnetic stimulation) will be used to assess supraspinal, spinal and peripheral control of mechanisms that contribute to walking, to voluntary movement and to reflex activation. The proposed experiments will test the hypotheses that: 1) walking performance in subjects with SCI improve to a greater extent when active, as opposed to passive or no assistance is given to advance the limb, 2) post-training spinal cord reflex activity will be more similar to normal values in those subjects who participate in the FES-assisted group, and 3) electromyographic (EMG) activity observed during walking will be more robust than EMG observed during voluntary movement. These studies will allow us to compare the efficacy of rehabilitation strategies aimed at improving functional mobility in individuals with SCI. In addition, they will provide information about neural and cardiorespiratory bases of these functional changes.

DESCRIPTION (provided by applicant): The studies proposed are intended to accelerate the pace of discovery related to interventions for individuals with cervical spinal cord injury (SCI) who face significant challenges in the performance of everyday activities that require functional use of the hands. Beyond the physical damage to the spinal cord, secondary neuroplastic reorganization in the brain exacerbates functional loss. In some reports, the changes in corticomotor excitability that occur after SCI are similar to those that occur following stroke. By increasing voluntary drive to the hands, function can be improved after SCI. The studies in the parent grant apply to individuals with SCI interventions similar to those gleaned from recent studies of stroke. Newer evidence indicates that high-frequency repetitive transcranial magnetic stimulation (rTMS) may be effective at improving hand function after stroke. The proposed studies will use rTMS with the goal of increasing corticomotor drive to improve hand function in individuals with SCI. These supplemental studies will assess the safety, neurophysiologic effects, and preliminary efficacy of rTMS using a two-week, single-blind, sham-controlled, crossover design in 20 subjects. The following aims will be accomplished: 1) Assess within-session changes in pinch force to quantify the immediate effects of rTMS on force production of the contralateral hand, compared to ipsilateral hand and to sham-rTMS condition, 2) Assess effects of a 3-day course of rTMS to quantify the short-term effects on force production, functional task performance, and cortimotor neurophysiology related to contralateral hand function, compared to ipsilateral hand function and to sham-rTMS, and 3) Assess endurance of effects by quantifying the persistence of effects of rTMS on hand function and force production. These studies expand the aims of the parent grant, support personnel, and invest in technological equipment. The supplement will maximize the information that can be learned about the relationship between corticospinal drive and hand function in individuals with SCI within the 2-year abbreviated funding period. PUBLIC HEALTH RELEVANCE: In individuals with cervical SCI, impairment of hand function severely restricts independence and quality of life by limiting performance of self care, work, and leisure tasks. These studies aim to advance the field of rehabilitation science and reduce the burden of disability by improving hand function in individuals with SCI. Few goals are more important for function, independence, and participation in these individuals.

Project Summary This is a proposal to build the Intensive Rehabilitation Research Grant Writing Workshops in the United States more commonly known as TIGRR (Training in Grantsmanship in Rehabilitation Research) into a yearlong (12 month) grant writing and career development education program. TIGRR was funded under the T15 mechanism. The T15 mechanism is no longer available to renew the NIH funding for the TIGRR workshop. We view this as an opportunity to build upon and enhance TIGRR by renewing in the format of a yearlong R25 education program allowing us to more completely build the careers of young investigators by helping them prepare and submit proposals, and prepare them for success following receipt of grant awards. Research in Rehabilitation Sciences is critical to health, particularly as relates to aging populations and those with disability but has lagged other areas of biomedical research. This is due to some extent by a shortage of well-trained researchers and because mentorship often focuses on clinical aspects of practice and research, rather than on skills needed to acquire and manage the funding that is required for a successful research career. Ideally, research training begins in the post-baccalaureate and post-doctoral years. However, many of these potential investigators begin their rehabilitation careers in the clinical ?trenches?. We are proposing a yearlong research education experience that includes an intensive grant writing program that uses TIGRR workshops (which have been refined over the course of the past 5 years) as the centerpiece. Unlike passive, entirely didactic grantwriting training experiences, selected mentees will have intensive one-on-one mentorship including extensive critiquing of their proposals and will gain hands-on experience with critiquing their peers' proposals. Building upon the past five years of the successful TIGRR workshops, we will bring together a nationally recognized group of mentors as faculty for this yearlong program. This yearlong education program will provide the expertise and support to be successful at the national level in obtaining research grant support and guidance in management of multiple grants and lab personnel, and to gain experience in critiquing grant proposals. During the centerpiece workshop, mentees will receive guidance in grant writing, clinical trial design, biostatistics, informatics, collaboration, grantsmanship, budgeting, and career development through lectures and individual consultation. One-on-one mentorship is the most important part of the program. We will be vigilant in our follow-up with mentees and their home institution mentorship team after the workshop to maximize the chance for success, and then continue to prepare the mentees for submission and/or resubmission by having grant review panels made up of mentors and mentees. Thus, we will develop a cadre of well-trained, rehabilitation researchers whose expertise will foster better rehabilitation research. Importantly, we will also work to increase the representation of women, persons with disability, and underserved minorities.