XIV. Spinal Cord Injury and Related Neurological Disorders

A. General



Guy A. Howard, PhD; Bernard A. Roos, MD
Research Service, VA Medical Center Miami, FL 33125; Department of Medicine, University of Miami School of Medicine, Miami, FL 33101; email: howard.guy_a@miami.va.gov

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B684-2RA)

PURPOSE--We hypothesize that changes in neuropeptides and neurotransmitters in nerves supplying bone and/or bone marrow osteoprogenitor stem cells are involved in the osteopenia which develops as a result of spinal cord injury (SCI). It is important to understand how these changes affect bone metabolism after SCI, since a considerable number of veterans are paralyzed from SCI. The significance of the research lies in the potential for discovering the mechanism(s) involved in the osteopenia following SCI. These results could lead to a therapy to prevent the loss of bone in newly injured veterans, or aid in the recovery of bone in chronic SCI veterans.

METHODOLOGY--The studies utilize a rat model in which the bone loss is both dramatic and progressive over time. Histomorphometry, radioimmunoassays, and molecular biology techniques characterize bone loss following SCI, as well as changes in neuropeptide distribution and levels in bone. We have focused on calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP), both are in nerves in bone and implicated as modulators of bone metabolism. Immunohistochemistry, receptor binding, and autoradiographic methods are used to evaluate receptor changes in bone and in osteoprogenitor cells obtained from bone marrow.

PROGRESS--We have defined the model and histomorphometrically evaluated the effects of SCI on the bone at various times postlesion. We have developed methods to isolate bone cells and osteoprogenitor stem cells from bone marrow for in vitro evaluation from the bones of lesioned animals, as well as to evaluate the neuropeptide content and respective mRNAs. We have established a human bone cell model to evaluate the effect of neuropeptides on proteins involved in cell-cell communication via gap junctions. We have shown gap junctions to be functionally regulated by VIP and CGRP in these cells.

RESULTS--As the animals age with SCI, they lose approximately 60 percent of their trabecular bone (below the lesion) compared to nonlesioned animals. This loss results in loss of femora mechanical strength. Immunohistochemical and retrograde tracing studies showed that sensory nerves containing CGRP and VIP are particularly dense in the periosteum and penetrate the bone. VIP is capable of acutely up-regulating the mRNA for the gap junction protein, connexin 43, in osteoblasts. CGRP is capable of regulating osteoblast function via potassium channels and intracellular calcium, but with moderate increases in cAMP, suggesting other second messengers for CGRP. We have cloned and characterized a human and murine CGRP receptor component protein (RCP) cDNA, developed antibodies to this RCP, and are currently working on the mechanism of how this component of the CGRP receptor functions. We have begun anatomical/developmental studies to evaluate the presence and distribution of CGRP, the CGRP receptor, and the CGRP receptor component protein during development. We have shown that the osteoprogenitor stem cells from bone marrow are affected by CGRP in terms of increasing the number of osteogenic cells obtained from marrow cultures, as well as demonstrating the neuropeptides are capable of increasing the mineralization in vitro of the osteogenic cells.

FUTURE PLANS--We will continue our studies with bone and bone marrow osteoprogenitor cells of lesioned and nonlesioned animals for neuropeptide effects on mRNA levels and functional status of cell-cell communication, as well as on mineralization of collagen matrix formed in vitro. We are beginning studies to identify post-SCI changes in osteogenic precursor cells from bone marrow for these neuropeptides. We will continue our studies on the mechanism of CGRP and CGRP-RCP modulation of osteoblasts and on bone marrow-derived osteoprogenitor cells in animal and human bone and osteoprogenitor cells.




Linda S. Fehr, MS; Morris A. Fisher, MD; W. Edwin Langbein, PhD
Rehabilitation Research and Development Center, VA Hines Hospital, Hines, IL 60141; Department of Neurology, Stritch School of Medicine, Loyola University, Maywood, IL 60153

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B811-2RA)

PURPOSE--The purpose of this research was to demonstrate that supported standing and/or aerobic upper-body exercise significantly alters signs of upper motor neuron syndrome (UMNS), particularly lower limb tone, in persons with spinal cord injury (SCI).

METHODOLOGY--Twenty-nine subjects with SCI (28 males, 1 female, aged 26 to 63 years, mean: 45.4) were recruited for the study. All reported a history of increased tone and/or spasms in the legs. Time since injury: 1-35 years (mean: 9.6). All but three were receiving pharmacologic treatment (Valium, Baclofen, Diazepam) for "spasticity;" all were instructed not to discontinue these or any other medications and were asked not to engage in any physical exercise, stretching, or ranging prior to any of the experimental conditions. Thirteen withdrew from the study at various points for personal and/or medical reasons; four failed to demonstrate sufficiently increased tone to qualify for further participation (relaxation index >0.85). The remaining 12 (8 with paraplegia, 4 with quadriplegia) completed all phases of the experimental protocol, completing three procedures. To test the effect of moderate-intensity aerobic upper-body exercise on signs of UMNS, subjects performed 20 min of submaximal wheelchair ergometry exercise. To examine the effect of low-intensity activity, subjects completed 40 min of supported standing in a commercially available standing frame. A timeout (control condition) was included to isolate effects of physical activity from changes occurring during quiet rest and testing procedures alone. Baseline measures of tone were followed immediately by an experimental condition (upper-body exercise, standing, or timeout). To examine the temporal pattern of changes in tone following the experimental condition, measurements were repeated immediately following activity or timeout and at 90-min intervals for 3 hrs.

  Tone at the knee was assessed by the pendulum drop test. Electrogoniometers were strapped on the lateral side of each knee, and the subject was placed in as near to supine position as contractures permitted. The subject's legs were alternately lifted to a set position near horizontal then released to swing freely about the knee. Subjects capable of voluntary muscle contraction were instructed to remain relaxed, and rectus femoris activity was visually and aurally monitored. Calibrated electrogoniometer voltages were computer-sampled at 200 Hz. The legs were dropped alternately six to eight times, and the average normalized relaxation index (R2n) for the series was computed with outliers omitted. R2n is a normalized ratio of the angular deflections of the limb in each direction from its final dependent resting position. Values of ;sl1.0 are obtained for normotonic limbs and <1.0 for hypertonic (spastic) limbs; hence, increased R2n indicates an improvement in hypertonicity.

RESULTS--Average R2n for the group increased more following physical activity than timeout with relatively greater increases occurring later in the measurement period. Specifically, R2n increased 14.3 and 13 percent immediately after exercise and standing, respectively, compared to a 10.1 percent increase immediately following timeout. In contrast, increases in R2n observed 3 hrs after exercise and standing were 20.8 and 23.1 percent, respectively, while the increase in R2n 3 hrs following timeout was 6.6 percent.

IMPLICATIONS--If the signs of upper motor neuron syndrome such as hypertonicity can be moderated with exercise, many benefits accrue, including significantly reduced cost of treatment, absence of side effects, and increased control at the disposal of the individual. In addition, facilitation of a healthier lifestyle should decrease the incidence of medical complications secondary to spinal cord injury, contributing to further reductions in the cost of providing health care for these persons.



Abba J. Kastin, MD; Weihong Pan, MD; William A. Banks, MD
VA Medical Center, New Orleans, LA 70146; Tulane University School of Medicine, New Orleans, LA 70146

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B2004-RA)

PURPOSE--Cytokines like tumor necrosis factor-a (TNF) can exert many effects on the central nervous system (CNS). There is evidence that TNF can affect glial cell proliferation and stimulate the synthesis of nerve growth factor, thereby contributing to spinal cord regeneration. Although both TNF and interferon-g exert mainly proinflammatory effects, IFN-a exerts mainly immunosuppressive effects. Their entry into the spinal cord was investigated.

METHODOLOGY--Using sensitive techniques, we studied the penetration of TNF from the periphery into the spinal cord in rats with acute spinal cord injury, experimental autoimmune encephalomyelitis (EAE), and in normal mice. Multiple time-regression analysis was used to measure the rate of entry of the cytokines into the CNS. In normal mice, the permeability was compared with that of interferon-a and interferon-g. Additional techniques that were used included reversed phase high performance liquid chromatography (HPLC) and acid precipitation to verify the intact nature of the recovered cytokine and capillary depletion with perfusion to demonstrate that the material was not bound or adherent to the endothelial cells of the capillaries comprising the blood-spinal cord barrier.

PROGRESS--After complete transection of the lumbar spinal cord of mice, there was increased permeability to TNF in the lumbar region proximal to the lesion; the transport was saturable. This increase was significantly greater than that seen with sucrose, a smaller molecule, or with albumin, a molecule similar in size to TNF. For ebiratide, an MSH/ACTH analog of six amino acids, there was no increase in penetration of the spinal cord after lumbar transection, again emphasizing the selective nature of the increased permeability to TNF that cannot be explained by simple disruption of the blood-spinal cord barrier.

  In EAE, saturable transport of TNF into the spinal cord was highest in the lumbar region and was greater than that seen with albumin. In both EAE and the spinal cord transection model, the increased transport of TNF was paradoxically greater than could be explained by the leakiness accompanying these conditions. It appears that the saturable transport of TNF into the spinal cord is activated by EAE and by transection of the lumbar spinal cord.

  Although the interferons entered the spinal cord after peripheral administration to a greater extent than into the brain, for the most part the entry was not saturable. Only in the cervical region of the spinal cord and only for interferon-g was saturation of the radioactively labeled cytokine seen after co-administration of excess unlabeled interferon-g, but the highest dose used was only 1 µg. For each region, the penetration of interferon-a was greater than that for interferon-g. TNF was used for comparison, and again its entry was saturable in all three regions of the spinal cord: cervical, thoracic, and lumbar.

  In each study in normal animals there was a greater penetration of every substance tested into the cervical and lumbar areas of the spinal cord in comparison with the smaller rate of penetration into the thoracic region of the spinal cord.

FUTURE PLANS--The permeability of the spinal cord to neurotrophins will be studied next.




Hosea Fu-Shih Huang, PhD; Shih-hon Chao, MD; John E. Ottenweller; PhD; Leonard M. Pogach, MD
East Orange VA Medical Center, East Orange, N. J. 07019; Department of Surgery Section of Urology, UMD-New Jersey Medical School, Newark, NJ 07103 email: huanghf@umdnj.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B885-RA)

PURPOSE--The purpose of current experiments was to investigate the efficacy of hormone replacement in the prevention of regression of spermatogenesis after spinal cord injury (SCI) and to determine whether disruption of neural supplies to the testes might contribute to the chronic effects of SCI on spermatogenesis.

METHODOLOGY--SCI was induced in adult Sprague-Dawlay rats by surgical transection of the spinal cord at the level of the 9th thoracic vertebrate. Immediately following the surgery, the rats were given daily injection of FSH, implantation of 2×5 cm testosterone capsules (TC) or combination of both. Animals were hemicastrated 1 mo later. The hemicastration unexpectedly resulted in heavy loss of the SCI animals. This is due to the loss of voiding capability of the animals and rupture of the bladder is the major cause of death in the hemicastrated animals. The surviving animals were killed 2 months later (3 mo after the SCI).

  For testicular denervation, the testes of adult rats were exposed through a mid-scrotal incision. The superior nerve (SSN) and inferior spermatic nerves (ISN) were isolated from the surrounding fat tissues and dissected. Testicular tissues were fixed in Bouin's solution and processed for histology or preparation for whole mounts of seminiferous tubules. Quantitative analysis of spermatogonial proliferation was performed on whole mounts of seminiferous tubules. The status of spermatogenesis was evaluated in testicular histology.

RESULTS--Four weeks after SCI, abnormal spermatogenesis was evidenced by the presence of lesions such delayed spermiation, vacuolization of germ cell nuclei, phagocytosis of mature spermatids, and incomplete cellular association. In addition, the numbers of A1 and B spermatogonia and preleptotene spermatocytes were reduced by 20-30 percent. Administration of FSH, testosterone, or a combination of both did not prevent the decrease in spermatogonial proliferation. Testicular histology revealed that spermatogenic lesions in SCI rats receiving FSH were far more extensive than that in the untreated SCI rats. Testosterone alone, however, attenuated the severity of spermatogenic lesions in SCI rats. These results suggest that deprivation of FSH and testosterone during acute phase of SCI is not the sole reason for the decrease in spermatogonial proliferation and spermatogenic lesions in SCI rats.

  Three months after the surgery, regression of spermatogenesis in SCI rats without hormone replacement had attained its maximum. In two SCI rats receiving FSH and testosterone, active spermatogenesis was observed in 21 and 100 percent of the seminiferous tubules and qualitatively complete spermatogenesis was observed. These results demonstrated that combination of FSH and testosterone replacement is beneficial for the recovery of spermatogenesis in SCI rats.

  Four weeks after denervation of the SSN, alteration of spermatogenesis was evidenced by the presence of lesions including phagocytosis of mature spermatids, incomplete cellular associations and incomplete spermatogenesis. However, delay or failure in spermiation did not occur in the denervated testes. Denervation of the ISN did not affect spermatogenesis. Quantitative analysis of spermatogonial proliferation in whole mounts of the seminiferous tubules revealed that normal numbers of Aal, A1, and B spermatogonia and preleptotene spermatocytes were maintained. These findings indicate that while testicular denervation will result in abnormal spermatogenesis, the mechanisms leading to these changes are different from that occur after SCI. In addition, testicular denervation does not contribute to the decrease in spermatogonia proliferation during acute phase of SCI.

  By 3 months, spermatogenesis in SSN denervated testes was totally regressed as that occurs in chronic SCI rats. These results suggest that denervation of SSN as a result of SCI may contribute to the final regression of spermatogenesis in SCI rats.

IMPLICATIONS--Results of these experiments demonstrate that both endocrine deprivation and testicular denervation could contribute to the SCI-induced regression of spermatogenesis, perhaps through different mechanisms. Thus, multiple modalities could be considered to preserve spermatogenic function in SCI men. Enhancement of spermatogenic recovery in SCI rats by combinations of FSH and testosterone replacement indicates that hormone replacement during acute phase of SCI may be effective for the maintenance/recovery of spermatogenesis in SCI men. However, further experiments are required to provide better understanding of cellular or biochemical mechanisms responsible for the SCI-induced spermatogenic lesions. In addition, the effective dose of each hormone and duration of replacement must be optimized in animal model so that such approaches can be applied in SCI men to achieve a maximal recovery of spermatogenesis.




Rory A. Cooper, PhD, Michael L. Boninger, MD, Sean D. Shimada, MS
Human Engineering Research Laboratories, VA Pittsburgh Health Care System, Pittsburgh, PA 15206; email: rcooper+@pitt.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B869-2RA)

PURPOSE--This project has two primary objectives: 1) to perform a detailed biomechanical analysis of the upper extremity during wheelchair propulsion, and 2) to identify specific biomechanical factors that differentiate manual wheelchair users with and without pathologic findings such as carpal tunnel syndrome and rotator cuff tears.

METHODOLOGY--Before the experimental trials, each subject was familiarized with the testing protocol, then gave informed consent. A bilateral kinematic analysis system, OPTOTRAK (Northern Digital Inc.), was utilized for this study. Two carbon fiber composite rigid bodies, composed of three markers each, were used to identify head and trunk motions. Each rigid body had three LED markers, creating an isosceles triangle. Fourteen additional markers were used to identify anatomical landmarks on the upper extremity. Markers were placed on the subject's right and left: acromion process, lateral epicondyle, olecranon process, ulnar and radial styloid, and second and fifth metacarpophalangeal joint.

  The subjects propelled in their personal wheelchair during the entire testing session. Each subject's wheelchair was fitted with a force and torque sensing pushrim, the SMARTWheel to measure three-dimensional forces (Fx, Fy, Fz) and moments (Mx, My, Mz) applied to the pushrim during wheelchair propulsion. There were no other adjustments made to the wheelchair, and the implementation of the SMARTWheel did not change the camber or diameter of the normal pushrim or tire size.

  The subjects pushed on a wheelchair dynamometer prior to the testing period in order to acclimate themselves to the experimental set-up. Then they were instructed to propel their chairs at a self-selected speed, 0.9 m/s, 1.8 m/s, and for a ramp up to maximum speed. Kinematic and kinetic data were collected for 20 s during each trial. The subjects were allowed to rest approximately 1 min between each condition.

PRELIMINARY RESULTS--To date we have tested over 30 manual wheelchair users. The analysis of the data encompassed the motion, forces, and moments occurring at the shoulder and wrist joint. Shoulder abduction, sagittal extension, sagittal flexion, external rotation, internal rotation, and horizontal flexion angles have been calculated using an anatomically based coordinate system. The associative moments have also been calculated. The glenohumeral joint (GHJ) to acromion, acromion to GHJ, anterior to posterior (AP), PA, compressive, and distractive forces were also calculated.

  At the wrist maximal flexion, extension, radial deviation, ulnar deviation, supination, and pronation angles have been described, along with compressive, distractive, radial-ulnar (R-U), U-R, palmar-dorsal (PD), and DP. The maximal moments that tend to flex, extend, radial deviate, ulnar deviate, supinate, and pronate the wrist have also been calculated in an anatomically based system.

FUTURE PLANS--The next stage of our study is to identify the subjects with and without pathological findings, such as carpal tunnel syndrome and rotator cuff tears. Coupled with the biomechanical measures, we are anticipating that we will find biomechanical characteristics that contribute to injury. Future research directed toward prevention of secondary injuries in manual wheelchair users by optimizing wheelchair fit and configuration.



Lucas H.V. van der Woude, PhD; A. Dallmeijer; R.H. Rozendal; A.P. Hollander; H. van As; E. Angenot; M.T. Hopman
Institute for Fundamental and Clinical Human Movement Sciences, Vrije Universiteit, Faculty of Human Movement Sciences 1081BT Amsterdam, the Netherlands; Rehabilitation Center Amsterdam, Amsterdam, The Netherlands; Department of Physiology, Catholic University Nijmegen, The Netherlands; email: L_H_V_van_der_Woude@FBW.VU.NL

Sponsor: Dutch Prevention Fund

PURPOSE--We study the evolution in physical capacity, physical strain, and risk factors for cardio-vascular and musculo-skeletal disease over time in wheelchair-dependent individuals with spinal cord injury (SCI). Parameters of performance capacity and physical strain in ADL are evaluated with repeated standardized wheelchair exercise tests as well as ADL tests in different groups of subjects with SCI, both subjects with a long-standing SCI--sedentary as well as physically active subjects--and those in the course of rehabilitation. Thus the effects of wheelchair use and a wheelchair-confined lifestyle on performance capacity, wheelchair propulsion technique, and cardio-respiratory (and musculo-skeletal) parameters, as well as the risk factors for cardio-vascular disease are evaluated.

METHODOLOGY--Both cross-sectional and longitudinal study experimental designs are used, involving male as well as female subject groups and sedentary as well as physically active individuals. Different subject groups were studied in both cross-sectional as well as longitudinal research designs in the course of the rehabilitation process. Maximum aerobic capacity, anaerobic wheelchair sprint performance, and isometric strength are individually determined in standardized testing procedures at fixed times during and/or after rehabilitation. The physical strain of daily life, and more specifically the therapy sports activities, are simply evaluated with the Percentage Heart Rate Reserve (%HRR) with a SportTester PE4000. Risk factors for cardio-vascular disease (blood pressure, cholesterol, and so forth) and musculo-skeletal problems are repeatedly determined with questionnaires that are also used to study different physical and personal characteristics.

RESULTS--The results on both recently injured, intramurally treated, persons with SCI and those with long-standing SCI indicate an inverse association between physical strain in standardized ADL wheelchair tasks and indicators of maximum performance capacity. Physical strain during rehabilitation does not meet criteria for training as formulated by the American College of Sports Medicine. Intensity, duration, and frequency of physical activity should be increased and tuned more carefully to the individual. Findings on risk indicators for cardio-vascular disease do not show an increased risk among the subjects with SCI at study. Physical or sports activities have a significant reducing effect on such risk factors among subjects with longstanding SCI and those involved in rehabilitation, both high- and low-level lesions.

FUTURE PLANS--A further analysis of the effects of the physical activity components within the rehabilitation process upon performance capacity in subjects with SCI is planned to be conducted in a randomized clinical trial. Additionally, the evolution of wheelchair propulsion technique will be studied over time as a mediating component of performance capacity. Thus, we hope to grasp the process of learning in this complex motor task.




Isaac Kurtz, MHSc; John Bishop, EEngT
Electronics Service, Bloorview MacMillan Centre, Toronto, ON Canada M4G 1R8

Sponsor: Industry Canada, Ottawa, ON Canada K2H 8S2

PURPOSE--The purpose of this project is to develop a wireless myoelectric switch for communication and computer access. The switch allows individuals who are paralyzed to operate these devices with the contraction of any muscle in the body. For those with advanced Amyotrophic Lateral Sclerosis (ALS) the myoswitch allows them to use their facial muscles for control since these are often the last muscles to be spared. A wireless version of this switch improves on the reliability and cosmesis of the myoswitch.

PROGRESS--A circuit board that incorporates a precision instrumentation amplifier and a digital 900 MHZ RF transmitter has been designed. The requirement for a low voltage power supply (3 V lithium battery) and low power, favored radio frequency (RF) as the technology of choice. RF has the further advantage that it can be transmitted through clothing and other material that may intervene between the transmitter and receiver. The circuit measures 3.81 by 1.59 cm and is small enough to tape to a user's face above any contracting muscle. The antenna is contained within the circuit board. The transmission range, limited by the small antenna size, is approximately 3 m, which is adequate for the application. Current consumption during transmission is approximately 20 mA while the quiescent current consumption is less than 1 mA.

FUTURE PLANS--Identification of a power source for the transmitter remains a significant challenge. Although battery technologies that meet the power requirements and the size constraints of this application do exist, the packaging shape and size required for this application is not readily available commercially and no rechargeable batteries that meet these requirements have been found. As battery technologies for consumer applications rapidly evolve, however, we expect to overcome these challenges within the next year.



Michael J. DeVivo, DrPH
University of Alabama at Birmingham, Spain Rehabilitation Center, Birmingham, AL 35233; email: devivom@sun.rehabm.uab.edu

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Dept. Education, Washington, DC 20202-2646

PURPOSE--There have been several published studies of rehospitalization rates, risk factors for rehospitalization, and associated costs among persons with spinal cord injuries (SCI). However, only limited baseline data on the long-term incidence of a few secondary medical complications, such as renal and bladder stones, have been published, and the relationship between the occurrence of these secondary complications and subsequent rehospitalizations has not been determined. Moreover, the National Spinal Cord Injury Statistical Center (NSCISC) data set cannot be used for this purpose, because there is no established linkage in that data set between reported occurrences of secondary complications and rehospitalizations. The purpose of this study is to provide baseline data documenting the leading causes of unplanned rehospitalizations among persons with SCI and the average costs associated with each cause, so that frequent and costly complications can be given higher priority for further study and the effectiveness of techniques to reduce the incidence of complications and hospitalizations can be assessed using rigorous cost-benefit analyses.

METHODOLOGY--The basic study design is cross-sectional with a 2-yr prospective data collection period. All persons with traumatic SCI who are currently being followed at the University of Alabama at Birmingham Spinal Cord Injury Care System (UAB-SCICS) are eligible for this study, regardless of how long ago their injury occurred.

  Admission sheets for University Hospital are scanned daily to identify rehospitalizations among person with SCI. Persons returning for clinic visits and outpatient annual evaluations are asked whether they have been rehospitalized at another facility since their last contact with us. When appropriate rehospitalization is identified, medical record and billing information are obtained. ICD9CM codes are used to document the primary cause of rehospitalization. Other complications that may have contributed to the need for rehospitalization are documented as secondary causes.

  The percentage of rehospitalizations, average length of stay, and charges due to each type of secondary complication will be determined. Mean length of stay and charges of each cause of rehospitalization will be compared by using Student's t test. The distribution of causes of rehospitalization will be characterized epidemiologically. The chi-square test will be used to compare the percentages of rehospitalizations due to each cause by time postinjury, age group, gender, race, education level, neurologic level of injury, degree of injury completeness, urban/rural hospital location, marital status, and presence of insurance coverage. When sample sizes for individual causes of rehospitalization permit, multiple linear regression analysis will be conducted to determine the effect of these predictor variables on length of stay and charges for rehospitalizations resulting from that cause.

PROGRESS--Data collection is underway: 446 hospitalizations have been identified and collection is complete for 369 of these hospitalizations; 58 have cost data but medical records are pending; medical records have been received for 14 hospitalizations but cost data are still pending; both medical records and cost data are pending for 5 hospitalizations.



Amie B. Jackson, MD
Department of Physical Medicine and Rehabilitation University of Alabama at Birmingham, Birmingham, AL 35233; email: jackson@sun.rehabm.uab.edu

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Dept. of Education, Washington, DC 20202

PURPOSE--Aside from the immediate and obvious consequences of spinal cord injury (SCI), many physiological systems ultimately are altered for varying periods. It is becoming increasingly evident that the reproductive axis is one such system that often is impacted by SCI. In addition to problems with menorrhea, galactorrhea, fertility, and sexual function in women after SCI, disordered hormone production in such persons could potentially result in systemic changes such as accelerated bone loss, accentuated catabolism and nitrogen imbalance, and possibly hypercholesterolemia and atherosclerosis. To date there is little information concerning these complications. The purpose of this research is to determine the changes in reproductive endocrine function both immediately following SCI and in the remainder of the first year postinjury. This research will also examine how these changes affect menstruation, ovulation, vaginal and cervical pathology, and sexual function. As it is felt that many complications of SCI, such as autonomic dysreflexia, muscle spasticity, and bladder management problems are influenced by fluctuations in the woman's hormonal cycles, these correlations will be examined as well. Possible factors that could be responsible for postinjury endocrine changes will be explored.

  Objectives of this study are to document hormonal changes that influence ovulation and menstrual cycles, as well as cause complications such as hyperprolactinemia, with or without galactorrhea; to document endocrine imbalances that may occur following SCI as a result of cardiovascular instability, chest trauma, nutritional or metabolic changes, or concomitant head injury; to document the relationship between reproductive hormone levels following SCI and fertility, sexual well-being, and sexual activity; and to determine the relationship between reproductive hormone levels following SCI and complications such as autonomic dysreflexia, increased muscle spasticity, and occurrence of bladder spasms.

METHODOLOGY--The basic design of this project will be that of a prospective cohort study to assess the natural history of reproductive hormonal imbalances that cause changes in the menstrual cycle, leading to sexual dysfunction and infertility in women during the first year after SCI.

  All women who agree to participate will be interviewed initially by a designated nurse/clinician, who will obtain a complete obstetrical and gynecological history. Other information collected during this interview will be first day of the last menstrual period, age, height, weight, etiology of injury, and loss of consciousness, or occurrence of closed heat trauma or chest trauma at the time of injury. Also during the initial evaluation, vaginal wall samples will be obtained by gently scraping the upper third of the lateral vaginal wall.

  To evaluate postinjury reproductive endocrine status, blood sampling for hormone assays will be performed once a week for 6 wks. A single electrolyte profile, including serum sodium, chloride, potassium, blood urea nitrogen, albumin, creatinine, and glucose will be obtained on admission to the study to assess the metabolic status of each woman.

  Throughout the initial inpatient stay, careful documentation of the onset, duration, and amount of flow of any menses will be recorded. Upon discharge, each woman will be given a menstrual calendar and instructed on recording this same information.

  Over the 3.5-yr study, at least 28 women should be enrolled and at least 336 monthly calendars obtained.

PROGRESS--To date, entry into the study has been slow and determined by the low census of women with SCI who meet the study criteria. Four females have been initiated; one has completed the study.



Samuel L. Stover, MD; L. Keith Lloyd, MD
University of Alabama at Birmingham, Spain Rehabilitation Center, Birmingham, AL 35233

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Dept. of Education, Washington, DC 20202

PURPOSE--Analyzing a spectrum of urologic data acquired from a large number of persons with spinal cord injury (SCI) will help clinicians understand the natural history of the urinary tract and its complications following SCI, thus helping them select those prevention and management methods capable of assuring the most positive prognosis.

  In this study, we seek to document the natural history and clinical course of urinary tract complications among persons with SCI who utilize various methods of neurogenic bladder management; answer a series of important clinical research questions that can impact future urologic management and improve the medical care and well-being of persons with SCI; and encourage the utilization of the UAB-SCI Urologic Database by other institutions, which could provide a much larger cohort of persons with SCI for future collaborative studies.

METHODOLOGY--Data are collected prospectively for each patient admitted to the UAB-Spinal Cord Injury Care System (UAB-SCICS) at admission, discharge, and annually thereafter. In addition, data have been collected retrospectively from chart reviews on 596 patients between 1970 and 1979. Since 1979, persons who were enrolled retrospectively have been followed prospectively along with the more recently injured persons. Persons constituting the prospective study group (n=1,594) were injured and admitted between 1979 and 1995. The latter group continues to grow in size; 2,190 persons have been entered into the project database. The total number of study patients with complete data at this time is 1,655, of whom 1,328 are in the prospective study.

PROGRESS--During the past year, we completed the most extensive analysis accomplished to date on the urology database. A consecutive sample of 1,114 persons with SCI, injured between 1969 and 1994, were studied. Total and individual effective renal plasma flow (ERPF) were compared to determine the effect of different bladder management methods on long-term renal function. It was concluded that renal function was adequately preserved in the great majority of persons with SCI and did not appear to be influenced to any great extent by the method of bladder management. Extensive studies were also conducted on urologic complications.

  Another case study was conducted on 29 patients in the database who had died with a diagnosis of some kind of kidney disorders. An effort was made to determine any more specific causes of death, especially secondary renal amyloidosis. Almost all cases of renal involvement were secondary to some other secondary complication and were not the primary cause of death. Only one case of secondary amyloidosis was found in this database, and even the autopsy files in the pathology department were unable to identify the cases. This information supports the investigators clinical opinion that chronic pressure ulcers that cause secondary amyloidosis and renal failure, a frequent cause of death in the past, are now very rare and one of the key reasons for renal causes of death.

  The database is available on computer software with quality controls that cross-check data for out of range entries and internal consistency. It has been distributed to two other SCI centers in the USA and one internationally. There is no information at this time from those facilities.

FUTURE PLANS--Because the database is getting so large, entry of new patients is being decreased and more effort given to long-term follow-up. Therefore, all females with new SCIs are entered, but only every second male with complete or sensory incomplete injuries are now entered into the database.

  Another study now underway looks at the long-term outcomes and prognosis of persons with single kidneys, either due to a congenital defect, trauma at the time of injury, or urinary tract complications necessitating surgical removal of one kidney.




Daniel K. Jones, PhD; Rory A. Cooper, PhD; Steve Albright, BS; Michael L. Boninger, MD
Human Engineering Research Laboratories, VA Medical Center, Pittsburgh, PA 15206, Department of Orthopaedic Surgery, Division of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213; email: dkjones@pitt.edu

Sponsor: Paralyzed Veterans of America Spinal Cord Research Foundation

PURPOSE--The most common means of driving an electric powered wheelchair (PWC) is to use a joystick operated by hand or arm motion. Conventional joysticks are position-sensing devices that rely on the ability of the driver to move the stick accurately and quickly. The ability to use a joystick depends on many factors: degree of impairment, tremor, athetoid movements, balance, cognitive ability, spasticity, fatigue, and range of motion. Some people find it difficult or impossible to obtain sufficient control using existing devices.

  We believe that a force-sensing joystick (FSJ) will enable people with severe physical impairments to drive PWCs. Our intent is to test the FSJ, a rigid device that senses the applied forces with a very small range of motion. Like a conventional joystick, the FSJ gives the driver two-dimensional (2-D), proportional control.

METHODOLOGY--A FSJ has been developed in our laboratories to drive a commercial PWC. A pilot study is being conducted to evaluate the feasibility of the FSJ. Subjects include a group of nonimpaired, inexperienced PWC users (controls) and a group of experienced PWC users with impairments. Subjects are asked to perform computerized tracking and real driving tasks using both the FSJ and their usual access device. Deviations from the tracks provide a measure of the tracking performance, which will be used to compare the FSJ to other access devices.

PROGRESS--A prototype FSJ has been constructed using strain gage technology. A Motorola 68HC11 microprocessor and custom electronics translate strain gage voltages into standard PWC joystick signals.

  For computerized tracking, subjects sit in front of a computer with the PWC on a dynamometer that measures the speed of the PWC wheels. Interactive graphics software displays 2-D tracks and a moving icon representing motion of the wheelchair. Subjects watch the graphics while performing tracking tasks. As the subject attempts to follow the tracks, deviations from the track are measured.

  For real driving tasks, subjects drive the PWC over a course marked on the floor of a gymnasium. The motion of the wheelchair on the course is recorded using a camera mounted to it. A motion analysis system processes the recordings to measure the position of the chair with respect to the course.

PRELIMINARY RESULTS--A prototype FSJ has been built to successfully drive a Quickie P300 via hand control. A group of controls has been tested on the computerized and real tracking courses, using the FSJ and a conventional joystick via hand. Preliminary analysis indicates that the FSJ provides acceptable performance for driving PWCs.

IMPLICATIONS/FUTURE PLANS--Our goal is to enable or improve powered mobility for individuals with spinal cord injuries, multiple sclerosis, cerebral palsy, Parkinson's disease, or other conditions. The next tests will include subjects with quadraplegia who are regular PWC users. The objective is enhance chin control for these individuals using force sensors.

  The FSJ will be used as a clinical tool to measure the amplitude, direction, and frequency of forces applied to the FSJ by subjects with various disabilities. The forces will be evaluated in time and frequency domains to characterize the unique capabilities of each subject. The pilot data will be used to test algorithms for processing joystick signals and to develop filtering and signal conditioning algorithms. Dynamic force measurements will also provide specifications for alternative force sensors and PWC control strategies.



Derek B. Smith, MScEE; D.F. Lovely, PhD
Institute of Biomedical Engineering, University of New Brunswick, Fredericton, NB CANADA E3B 5A3; email: biomed@unb.ca

Sponsor: None listed

PURPOSE--Somatosensory evoked potentials (SEPs) contain important physiological information, and have become a widely accepted and employed monitoring technique during back surgery. However, as surface-recorded SEPs have very poor signal-to-noise ratios (SNR), signal processing is required to acquire usable information from the recorded data. Although coherent ensemble averaging is the conventional method of improving the SNR, it consumes a significant amount of time. As a result, alternative techniques, such as matched filters, have been investigated in an attempt to reduce the number of averages needed for detection. A matched filter is the optimum technique for detecting a known signal buried in additive white noise. The effect of the non-white biological interference afflicting SEP measurements is investigated, and various whitening filter schemes are examined in an attempt to improve matched filter performance. Emphasis is placed on determining a satisfactory linear adaptive whitening filter routine.

METHODOLOGY--Three linear adaptive algorithms--sign adaptive, recursive least-squares, and least-mean square--are evaluated, as are a brute force approach and a nonlinear neural-network technique. The LMS algorithm is found to be best suited for the desired implementation.

RESULTS--By applying signal whitening to surface recorded evoked potentials substantial improvement was made over earlier work. This was especially noticeable at high spinal levels where the contributing noise is contaminated with cardiac and respiratory activity. In this work, the ambiguity, in which peak corresponds, to the SEP has been resolved.

  With no whitening, the output from the matched filter shows multiple peaks; with whitening, only a single peak is resolved with zero latency. Consequently, this is ideal for an amplitude detection scheme.

B. Treatment and Rehabilitation



John S. Kirkpatrick, MD; S. Reza Moeini, PhD; Fred J. Molz, MS; Jason Partin
Spine Biomechanics Laboratory, Birmingham VA Medical Center, Birmingham, AL and Division of Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, AL 35294; email: john.kirkpatrick@ortho.uab.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B365-6RA)

PURPOSE--This project seeks to determine the static and dynamic function of multisegmental spines in human and goat cadaveric models. Flexibility properties of the multisegmental spine will be compared to previously reported single segment studies. Changes in flexibility behavior following cutting soft tissue structures and following the application of spinal instrumentation will be studied.

METHODOLOGY--The biomechanical behavior of cadaveric goat and human spine specimens will be analyzed by stereophotogrammetry when loaded under pure moments under various conditions. Unique to this study, the moments will be applied dynamically. Once control data are obtained, partially destructive studies will be performed. These studies will be followed by the application of spinal instrumentation on the multisegmental spine specimen.

PRELIMINARY RESULTS--A biomechanical study of reconstruction following multilevel corpectomy using dynamically applied moments has been completed and is being prepared for publication. An improved method for applying the moments has been developed and validated.

FUTURE PLANS--Testing of the goat and human cadaveric spine models is anticipated to be complete in 1998 with data analysis and presentations to follow.



V. Rodney Hentz, MD; Felix E. Zajac, PhD; Inder Perkash, MD; Charles Burgar, MD; Kevin McGill, PhD; Machiel Van der Loos, PhD; Francisco J. Valero-Cuevas, PhD; Kai-Nan An, PhD
VA Palo Alto Health Care System, Palo Alto, CA 94304-1200; Departments of Functional Restoration and Urology, School of Medicine, and the Mechanical Engineering Department (Biomechanical Engineering Division) Stanford University, Stanford, CA 94305-3030; Biomechanics Laboratory, Department of Orthopaedics, Mayo Clinic, Rochester, MN 55905; email: zajac@roses.stanford.edu; Web:http://guide.stanford.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B898-2RA)

PURPOSE--Our overall objective is to improve functional grasping in persons with quadriplegia by providing them with the biomechanical ability to grasp objects. Reconstructive surgeries, including tendon transfers, are commonly performed in these persons to restore partial grasping function, but uncertainty in the functional outcome of new surgical approaches hinders our ability to achieve improvements in their treatment.

METHODOLOGY--A biomechanical model of the hand musculotendinoskeletal system will be developed to provide surgeons with an in vitro testbed for improving existing techniques, or trying new techniques, and predicting functional outcomes. A hand model would be, by definition, an encyclopedic knowledge-base relating musculoskeletal anatomy to hand function. Such a model would allow surgeons to determine the precise musculotendinoskeletal parameters to which the functional outcome of a surgical or rehabilitation procedure is most sensitive. Thus, those aspects of the surgical procedure needing close clinical scrutiny could be identified. A model of the index finger and thumb will be the focus because of their importance to grasping (e.g., tip and key pinch) and because of the anatomic similarity between the index finger and the other fingers. The ability of the index finger and the thumb to exert maximum grasping (pinch) forces will be emphasized because they specify the biomechanical limit of grasping performance.

PROGRESS--A computer-implemented musculotendinoskeletal model of the index finger has been developed. Finger tip forces were recorded in five directions as subjects pressed as hard as possible against a low frictional surface with the finger in three different postures. EMGs from all seven index finger muscles were recorded with intramuscular electrodes. Analysis of coordination of force generation in three directions was emphasized.

RESULTS--In the palmar direction, all muscles but palmar interosseus were highly excited. In the distal direction, the interossei were excited the most, the lumbrical and flexor muscles next most, and the extensor muscles the least. In the lateral direction, the palmar interosseus and extensor muscles were excited the most, the dorsal interosseus the next most, and the lumbrical and flexor muscles the least. The 3-D, seven-muscle model of the index-finger was found to reproduce the force and coordination observed during the generation of palmar and distal forces. However, the interossei co-excitation observed in lateral force generation could not be reproduced, perhaps because the subjects used an injury prevention coordination strategy, which was not included in the model.

FUTURE PLANS--We will develop a musculotendinoskeletal model of the thumb and test its validity by recording forces produced by the thumb and intramuscular EMGs consonant with force generation, again with subjects instructed to press as hard as possible against a low frictional surface with the thumb in different postures. With a model of the finger and thumb then developed, the complex biomechanical and neural interactions that make grasping possible can be analyzed.




Gary S. Beaupre, PhD; Robert T. Whalen, PhD; B. Jenny Kiratli, PhD; John Drace, MD; Inder Perkash, MD; George Sims, MD; Robert Marcus, MD; Sandy Napel, PhD; Chye Yan, MS; Dennis R. Carter, PhD; Virginia L. Giddings, MS
Rehabilitation Research and Development Center (153), VA Palo Alto Health Care System, Palo Alto, CA 94304; Life Science Division, NASA Ames Research Center, Mt View, CA; Department of Radiology, Stanford University, Stanford, CA 94305; Biomechanical Engineering Division, Stanford University, Stanford, CA 94305; email: beaupre@bones.stanford.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B802-RA); NASA Ames Research Center, Mountain View, CA 94035; National Institutes of Health, Bethesda, MD 20892

PURPOSE--The objective of this study is to use high resolution Quantitative Computed Tomography (QCT) imaging of the calcanues in conjunction with computer modeling to develop a new noninvasive, human model for the study of functional adaptation of bone tissue. By charting the time course of bone loss or gain within small volume elements of bone in subjects with spinal cord injuries or immobilized by fracture casts, we will investigate the nature of bone remodeling and the related issue of reversibility of changes in bone density and structure in cancellous and cortical bone. This study will provide important new insights for better understanding the basic mechanisms of bone adaptation. These insights, in turn, should suggest new and improved clinical treatment strategies.

METHODOLOGY--This study uses a combined experimental and computational approach to investigate skeletal changes with disuse. Our study involves the use of QCT and dual-energy, x-ray absorptiometry (DXA) to measure serial changes in bone mass. Four specific tasks will be accomplished:

  1. registration of serial CT scans of the calcaneus in patients;
  2. accurate and precise determination of bone density in the calcaneus;
  3. determination of the local bone remodeling rate; and
  4. comparison of measured adaptation rates with computer predictions.

PROGRESS--The registration task has been accomplished in collaboration with investigators in the Department of Radiology at Stanford University. The second task necessitates the development of a new technique to eliminate or minimize beam hardening from the CT data sets. The third task will be accomplished by scanning subjects using high speed CT scanner and the above QCT techniques. In the computational component of the study we will use 2- and 3-D finite element models of the calcaneus to simulate skeletal adaptation using a bone remodeling theory previously developed in our laboratory.




Eric E. Sabelman, PhD; Vincent R. Hentz, MD; Feng Zhang, MD; Deborah Kenney, MS OTR; Paula Koran, BS; Min Hu, MD PhD
Rehabilitation R&D Center, VA Palo Alto Health Care System, Palo Alto, CA 94304; Dept. of Functional Restoration, Stanford University Medical School, Stanford CA 94305.

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B588-3RA)

PURPOSE--The recovering damaged nerve normally has a high population of Schwann cells that made up the myelin sheaths of axons prior to injury. These cells secrete growth factors and repair the extracellular matrix in preparation for the extension of regenerating axons into the damaged region. This project is based on replacing the Schwann cells in an otherwise acellular artificial nerve graft (ANG) as a substitute for an autograft taken from elsewhere in the subject's body. The latest ANG formulation is to be tested in lieu of an autograft in persons having trauma to the hand or arm, or to replace sural nerves removed for autografting.

METHODOLOGY--Preparation of the ANG essentially consists of repolymerization of solubilized collagen fibers with added cultured Schwann cells and insertion into a biodegradable conduit. Type I collagen is preferred because it is readily available, relatively inexpensive, and its properties are reasonably well understood. The matrix or conduit walls could include regeneration-promoting agents such as nerve growth factor. The conduit limits penetration of inflammatory cells into the region of axonal regrowth, as well as facilitating microsurgical reanastomosis with the proximal and distal ends of the nerve.

PROGRESS--In a series of animal implantations, a graft formulation has been achieved having the same functional recovery as an autograft. Based on this result, a limited clinical trial (up to 10 persons per year) has been approved. A subject's Schwann cells will be obtained from remnants of the damaged nerve, or from a short (5 mm) donor nerve biopsy that can later be repaired with an ANG. A preclinical phase is underway, in which culture methods for adult human Schwann cells are being optimized. Potentially immunoreactive components are being deleted from the fabrication process, long (30 mm) grafts are being tested for efficacy and durability in a rat model, and clinical sensorimotor measurements for functional recovery are being refined. In the latter activity, former subjects having had nerve repair are being recruited for a comparative database. A collaboration has been established with the Medical Photonics branch of Lawrence Livermore National laboratory to explore laser-assisted measurement of neurally mediated changes in skin blood flow.

FUTURE PLANS--There is potential for tissue-engineered grafts to bridge traumatic defects in the central nervous system. Our laboratory is collaborating with researchers at Hines VA Medical Center by fabricating grafts for testing Schwann cell-seeded implants in spinal cord injuries in rats.



Vernon Wen-Hau Lin, MD; Inder Perkash MD
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; Stanford University, School of Medicine, Stanford, CA 94305

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B803-2RA)

PURPOSE--The purpose of this research was to determine the effects of high-frequency magnetic stimulation (HFMS) of the sacral nerves on bladder and rectal pressures (BP and RP) in persons with spinal cord injury (SCI), and to optimize the magnetic stimulation parameters to obtain functional micturition and defecation.

METHODOLOGY--Eight persons with SCI (C4-T12) were recruited for the 2-day protocol. In day one (Bladder day), each received a screening history and physical examination, bulbocavernosus reflex latency, as well as a full urodynamic study. This was followed by magnetic stimulation of the bladder using a Cadwell stimulator, with a 9-cm magnetic coil placed near the L2-L4 vertebrae while measuring BP and RP. The frequency and intensity stimulation parameters were initially fixed at 20 Hz and 70 percent of maximum while changing the placement of the magnetic coil to optimize the focus of stimulation. Once the optimal placement was determined, the parameters were systematically varied to generate frequency and intensity profiles. Finally, functional micturation was attempted before the end of the bladder protocol. The second day (Bowel day) consisted of a full rectodynamic study, and magnetic stimulation of the bowel. Functional defecation was attempted at the end of the bowel day. Laboratory tests, including a set of Chem 20, CBC with differentials, PT, PTT, UA, and urine cultures, were performed both before and after the experiment.

PROGRESS--We have demonstrated that HFMS of the sacral nerves was effective in elevating bladder and rectal pressures. The optimal stimulation parameters were 20 Hz frequency and 70 percent of maximal power, which provided adequate nerve stimulation in most subjects. We were able to observe functional magnetic micturation in most subjects; defecation was more difficult to achieve but was observed in some cases.

RESULTS--To date, 22 subjects have participated in the bladder HFMS protocol. With sacral nerve root stimulation, the mean increase in bladder pressure of 24.4±4.88 cm of H2O; with suprapubic stimulation, the mean change was 16.5±4.4 cm H2O. The change in bladder pressure was significantly greater with sacral nerve root stimulation (p<0.01). Micturation was observed in 17 of the 22 subjects with either sacral nerve root or suprapubic stimulation. The frequency and intensity profiles showed that a frequency of 20 Hz and 70 percent of maximum generated adequate pressure changes in most subjects, although higher intensities and frequencies could generate higher bladder and rectal pressures. Either suprapubic or lumbosacral stimulation would result in urination. On the second (bowel) day, rectodynamic studies revealed an average rectal capacity of 310±30 ml, and peak defecating pressure of 85±13.3 cm H2O. The mean rise in rectal pressure after HFMS was 22.8±6.05 cm of H2O. Of the 13 subjects who completed the bowel protocol, we observed defecation in two cases.

FUTURE PLANS--We plan to investigate whether the production of micturation by HFMS can be improved by conditioning the bladder muscle; we shall further evaluate the effectiveness of HFMS in producing defecation and whether bowel motility is modified by HFMS by evaluating colonic transit time.




Kathryn J. Jones, PhD; Talat Khan, PhD; Todd Brown, PhD
Rehabilitation Research and Development Center, Hines VA Hospital, Hines, IL 60141; email: KJones1@luc.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B884-RA)

PURPOSE--Gonadal steroids are neurotrophic agents capable of modulating many aspects of neuronal growth and function, and thus have therapeutic potential in the treatment of nerve injuries involving lower motor neurons. The key question that is being addressed is the following: Will systemic administration of the gonadal steroid, testosterone propionate (TP), augment the regenerative properties of spinal motor neurons, analogous to the effects of steroid on cranial motor neurons? The goal of this research is to determine if TP can be used as a therapeutic agent in spinal cord injuries.

METHODOLOGY--The experimental approach that is being used ranges from functional (for the determination of rehabilitation potential) to molecular (for the determination of mechanism). The long-term goal of this research is to determine the therapeutic potential of gonadal steroids in spinal motor neuron regeneration in animal models and subsequently extrapolate this information to human peripheral nerve and spinal cord injury situations. There are four sets of experiments. The experimental model is the rat sciatic motor neuron. The sciatic nerve is crushed at the level of sciatic notch in castrated male rats, with half of the animals receiving subcutaneous implants of TP and the other half sham implanted at the time of injury. Functional assessment of lower limb movement and locomotor behavior has been done. The Sciatic Functional Index (SFI), a quantitative measure of locomotion, was used to analyze footprints from 1-7 weeks postoperative. Molecular analysis of the effects of TP directly on injured sciatic motor neurons has been initiated using in situ hyrbridization with specific probes.

PROGRESS--Currently, details of the behavioral and molecular analyses have been accumulated in pilot studies. The appropriate behavioral tests have been identified and the conditions for use of DNA probes in the in situ hybridization experiments established. This year, behavioral experiments to test the ability of testosterone to accelerate recovery of function were accomplished. In this study, we asked the following question: Will TP treatment accelerate recovery from lower limb paralysis following sciatic nerve crush in the rat? After footprint analysis, we found that at 1-3 wks post-op, the SFI of the TP-treated and control groups were not significantly different. Between 3-4 wks post-op, the TP-treated group had a significantly higher SFI score than controls, indicating a greater degree of functional recovery. At these timepoints, the differences are attributable to the foot print or paw length components of the SFI. These components are associated with calf muscle reinnervation, rather than the toe-spreading component associated with intrinsic foot muscle reinnervation. Beyond 5 wks post-op, there were no differences in the SFI scores. The results indicate that, as with facial nerve regeneration in the hamster, testosterone accelerates functional recovery from lower limb paralysis following sciatic nerve injury in the rat.

FUTURE PLANS--Currently we are preparing for in situ hybridization experiments that will test the hypothesis whether testosterone accelerates the rate of rat sciatic nerve regeneration through differential regulation of cytoskeletal gene expression following injury. Specifically, we wish to address the following questions. Which cytoskeletal genes are differentially regulated by testosterone following crush/axotomy? Does testosterone accelerate the onset of crush/axotomy-induced changes in the expression of these genes? We also plan to use the in situ technique to look at the effects of testosterone on the ribosomal RNA gene after injury.



Kathryn J. Jones, PhD; Talat Khan, PhD
Rehabilitation Research and Development Center, Hines VA Hospital, Hines, IL 60141; email: KJones1@luc.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B2081-RA)

PURPOSE--Gonadal steroids have been shown to have profound neurotrophic effects on injured peripheral motoneurons containing the androgen receptor, resulting in an acceleration of the rate of regeneration. Many of these effects are found on a molecular level, with steroids being able to directly alter the expression of many genes. Many populations of central neurons, including upper motoneurons, express the androgen receptor. Could gonadal steroids influence the expression of important repair-associated genes in these upper motoneurons after an injury as they are capable of doing in peripheral motoneurons? The objective of the proposed study is to test the hypothesis that treatment of central motoneurons having a limited capacity to regenerate with testosterone propionate (TP) will produce a reparative response to injury analogous to that observed in peripheral motoneurons capable of successful regeneration. The success of these studies may lead to potential therapeutic uses of gonadal steroids in treatment of head trauma and spinal cord injury.

METHODOLOGY--The experimental model that will be used involves a C7-T1 spinal cord hemisection of gonadectomized adult male hamsters. The hemisection model affords a method of directly observing the effects of injury and TP administration on one tract of an upper motor neuron population, namely the rubrospinal tract, while leaving the contralateral tract intact for a direct nuclear comparison. Using an in situ hybridization technique, relative levels of both product 28S rRNA and precursor 45S rRNA, important components of a cell's protein manufacturing capability, will be examined in the cell bodies of the red nucleus as early as 6 hrs postinjury. Additionally, relative levels of mRNA coding for important regeneration-relevant proteins, including cytoskeletal proteins, GAP-43, and GFAP, will also be examined in the red nucleus using in situ hybridization from 2 days postinjury (dpo) to 21 dpo.

PROGRESS--In situ hybridization studies examining rRNA levels in injured rubrospinal neurons have just recently been initiated. Initial pilot studies have been completed for in situ hybridization examination of rRNA, confirming appropriate probes and conditions for the technique. Additionally, characterization of the red nucleus in hamster, including mapping studies and cell quantification, has been completed prior to the initiation of any molecular-based studies. These anatomical studies have helped in isolating those spinal projecting neurons in the red nucleus which will exclusively be used for studying the effect of a spinal cord injury, and have also proven the comparability of red nuclei between different animals for the purpose of determining effects in an accurate manner.

FUTURE PLANS--In situ hybridization experiments for regeneration-relevant mRNAs will immediately follow the conclusion of the rRNA studies. Additionally, Western blotting and immunohistochemistry will be used to examine the relative levels of cytoskeletal, GAP-43, and GFAP proteins that are altered following an injury and TP treatment. This will determine whether changes in mRNA levels in injured rubrospinal neurons can indeed be equated into changes in functional protein levels, which would be necessary for an enhanced repair response.



Lisa Riedy, PhD; Rani Chintam, MD; James S. Walter, PhD
VA Hines Rehabilitation Research and Development Center, Hines, IL 60141; email: lriedy@orion.it.luc.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Pilot Project #B1840-PA)

PURPOSE--The objectives of this study are to determine the optimum stimulation parameters to manage fecal incontinence in subjects with SCI; to evaluate anorectal function using manometry in these subjects; and to determine whether there are any other benefits associated with external anal sphincter stimulation.

METHODS--Eight nonimpaired male controls were recruited through physician recommendations. Informed consent was obtained from all participants prior to the study. The protocol was approved by the Hines VA Human Studies Subcommittee. Anorectal manometry was carried out at the bedside before, during, and after perianal stimulation. A medically approved sterile, water filled, balloon catheter was attached to a battery operated strip chart recorder via a pressure transducer. The balloon was placed into the rectum for baseline rectal pressures and then pulled into the anal canal for baseline anal pressures. For perianal stimulation, two surface electrodes were placed externally adjacent to the anal opening either laterally or along the midline. Changes in either rectal or anal pressures were recorded as the stimulating current was slowly increased.

PROGRESS--Perianal surface stimulation was effective at increasing anal pressures. This stimulation increased anal pressures up to ten times those recorded with coughing, bearing down, or manually pushing on the perineum.

RESULTS--Of the eight subjects enrolled, five underwent perianal stimulation. Stimulation parameters consisted of a pulse duration of 300 µs, stimulating frequency of 35 pps, and a current sweep of 0-100 mA. Four of these five had increases in anal pressures with electrical stimulation. The average increase in anal pressure was 71.38±44.04 at an average current of 81.25±14.36. There was no effect on rectal pressures with electrical stimulation. Lateral electrode placement was evaluated in one subject and found to be more effective than the midline orientation. One subject indicated that the device was effective at reducing his rectal pain.

FUTURE PLANS--We shall modify our approach to include a combination intra-anal electrode and balloon catheter assembly.




James S. Walter, PhD; John S Wheeler, Jr., MD; Rani Chintam, MD; Margot Damaser, PhD; Paul Zaszczurynski; Kimberly Kaczowka
Rehabilitation Research and Development Center, VA Hines Hospital, Hines, IL 60141; Loyola Medical Center, Department of Urology and Physiology, Maywood, IL 60153

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B883-RA)

PURPOSE--Individuals with spinal cord injury (SCI) and multiple sclerosis (MS) have a high incidence of urinary incontinence, kidney dysfunction, and other urological pathologies. To aid in the early detection and possibly the prevention of these pathologies, we evaluated a simple home-use pressure gauge with tubes to measure bladder pressure and urine volume as an adjunct to intermittent self-catheterization (IC) in individuals with SCI and MS.

METHODOLOGY--The home-monitoring pressure gauges and clinical urodynamic equipment were calibrated with a standard water column to read the same pressure within 1 cm of water. Two different gauges were used. The first was a digital gauge with a zero adjustment, a highly accurate pressure reading and a small volume displacement for pressure recording. However, subjects found it hard to read. The second home gauge was a mechanical bellows type with pressure indicated in cm H2O on the dial face. We currently use this second gauge. Initial clinical urodynamic evaluation, including bladder filling, or cystometrogram (CMG), was conducted with simultaneous recording of pressure using the clinical equipment and the home gauge.

  For home use, subjects were given instructions on connecting a sterile tube from the pressure gauge to their catheter for IC. They were asked to record their bladder pressure when they initially catheterized, a full bladder pressure, and a nearly empty bladder pressure as a measure of abdominal pressure. They were asked to conduct pressure and volume recording on a weekly basis, more often if they were having a urological problem, and to conduct the recording for 1 yr. An estimate of detrusor pressure, the pressure due to the bladder wall, was obtained by subtracting a nearly empty bladder pressure from the full bladder pressure obtained upon initial catheterization.

RESULTS--Eight subjects have entered this study, seven with SCI and one with MS. The average age was 46.4±9.3 years. All the SCI subjects had upper motor neuron lesions. All subjects were on IC for bladder emptying, and home monitoring of bladder pressure was conducted without adverse effects. In the urodynamic clinic, the home pressure gauge was found to record the same pressures obtained with standard clinical urodynamic equipment within 3 cm H2O.

  Although home monitoring was proposed for 1 yr, all of the subjects withdrew sooner. Five of eight recorded an average of 27±21 home pressure recordings over 3.5±2.9 months. Three did not record any home data. Reasons for withdrawing included too busy, personal problems, or procedures were too bothersome. Two subjects also stated that they did not think the pressure recordings were helping them.

  Subjects on IC were able to conduct home monitoring of bladder pressure and volume. For the majority, the bladder capacities between CMG and home records could not be compared because the CMG was stopped at a volume of 500 ml. At each volume of overlap, CMG vesical pressures were compared to home full bladder pressures; CMG rectal pressures were compared to home empty bladder pressures; and CMG detrusor pressures were compared to home detrusor pressures. When the results from five subjects were combined and mormalized to the percent pressure at maximal CMG capacity, the home full- and nearly empty bladder pressures were significantly lower than the CMG bladder and rectal pressures, respectively. In contrast, there was no significant difference between the home estimate of detrusor pressure and CMG detrusor pressures.

FUTURE PLANS--A CMG recording is the gold standard for determination of bladder function in subjects with SCI. Home monitoring of bladder pressure cannot substitute for clinical CMG measurement. However, CMGs are time-consuming and expensive and may not be performed as often as are needed. We suggest that, in subjects performing intermittent catheterization to empty the bladder, frequent home monitoring of bladder pressure could supplement CMG recordings and would enable early identification of high detrusor pressures. Home monitoring could be an effective adjunct to clinical CMG studies.




Robert J. Jaeger, PhD; W. Edwin Langbein, PhD; Cindy Orebaugh; Chris Maloney; Katherine Blossfield; Desi Avila
Rehabilitation Research and Development Center, VA Hines Hospital, Hines, IL 60141; email: langbein@research.hines.med.va.gov

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B2027-RA)

PURPOSE--Pulmonary complications are one of the major contributors to morbidity and mortality of persons with spinal cord injuries (SCI). The purpose of this study is to improve electrically stimulated cough in individuals with SCI; to establish a quantitative measure of the quality of cough in individuals with SCI as a function of the characteristics of injury, anthropometric measurements, and standard measures of pulmonary function; and to classify individuals at risk of pulmonary complications based on cough ability, suggesting those who might benefit from electrically stimulated cough.

METHODOLOGY--Three hypotheses will be tested. I: whether the existing scheme of electrically stimulated cough production can be improved to obtain cough peak flow rates (CPFR) of at least 350 L·min-1, by triggering the cough on sensing an event related to glottis closure. In a random order, CPFR will be measured in 25 individuals during electrically stimulated cough with and without the new triggering method. A paired t-test will be used to evaluate differences in CPFR between the original and new triggering methods.

  II: whether efficacy of volitional cough in a given individual (as measured by CPFR) is related primarily to level of injury, sex, and the volume of air exhaled in the first second of a forced exhalation (FEV1). Unassisted CPFR will be measured in 250 to 300 individuals with SCI. Participants will complete a pulmonary function test and anthropometric measurements. Multiple linear regression analysis with CPFR as the dependent variable will be performed. The hypothesis will be accepted if level of injury, sex, and FEV1 are the only variables retained.

  III: whether CPFR can be used to classify subjects as having or not having had pulmonary complications in the past 2 yrs. Using the data obtained in II, and evidence from medical records, subjects will be divided into two groups: pulmonary complications and no pulmonary complications. The expectation that CPFR is normally distributed in each group (as suggested by preliminary data) will be verified. Employing receiver-operator characteristic curves and using CPFR as a predictor, the sensitivity and specificity for prediction of pulmonary complications will be calculated.

PROGRESS--Over the first 8 mo of the study, CPFRs were collected from 64 individuals with SCI between C5-L5. Based on subjective report of complications, individuals without complications had a mean CPFR of 334 L·min-1 (sd=141); individuals with complications had CPFR of 220 L·min-1 (sd=128). Medical records are now being reviewed to precisely determine presence or absence of pulmonary complications. Engineering of the electrical stimulation system for augmentation of cough is in progress. A computer monitors airflow from a pneumotachograph, continuously analyzing the breathing pattern. When a cough is desired, as indicated by a push button, the computer begins searching for a deep inspiration, followed by the zero air flow that indicates glottis closure. Abdominal stimulation then can be precisely triggered relative to glottis closure. An attempt will be made to determine if CPFR can be increased based on timing of delivery of stimulation.

IMPLICATIONS--Independence from care givers is nearly always a hallmark of effective rehabilitation in SCI. The longer-term goals are to confer this independence upon individuals with SCI with respect to cough, and to lower the incidence of pulmonary complications.



Joseph B. Green, MD; Elena Sora; Yolanda Bialy; Anthony Ricamato, MSBE; Robert W. Thatcher, PhD
Rehabilitation Research and Development Center, Edward Hines, Jr. VA Hospital, Hines, IL 60141; Bay Pines VA Medical Center, Bay Pines, FL 33504

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #2065-PA)

PURPOSE--We have determined it is feasible to detect reorganization of motor control in the cerebral cortex following spinal cord injury (SCI) and have now characterized that reorganization.

METHODOLOGY--We are applying a new technology of 128-electrode high resolution electroencephalography (EEG) to determine the topography of motor representation changes by mapping electrical potential distributions (MPs) with actual and attempted movements of the fingers and toes in nonimpaired controls and SCI subjects. Movements are self paced if subjects are able, or visually cued if only attempted. The generators of the potentials are localized by dipole source analysis, utilizing subject-specific magnetic resonance images (MRI) in a realistic head model. The dipoles and current density fields are co-registered with the subjects' MRI images.

PROGRESS--We have studied 12 subjects and 15 controls.

RESULTS--EEG recordings in seven persons with quadriparetia (C2-3 through C7-T1) during finger movement showed MPs displaced posteriorly in all. One of five persons with paraplegia had a posterior location. Dipole Source analyses suggested an origin in the somatosensory cortex.

FUTURE PLANS--We must now initiate our studies as soon as subjects are admitted for rehabilitation and follow them with EEG's and appropriate scales to measure outcome. In this way we should be able to establish a relationship between posterior reorganization and clinical course and prognosis. If detrimental to recovery, it may be desirable to attempt clinical trials at prevention.




David J. Edell, PhD; Amico Bignami, MD; Bruce C. Larson; Lisa P. Devaney; Cynthia M. Vanaria; Terry 0. Herndon
Division of Health Science and Technology, MIT, Lexington, MA 02173; Research and Development Brockton/West Roxbury VA Medical Center, West Roxbury, MA 02132

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B706-2RA)

PURPOSE--The objective of this research is to develop technology capable of transducing neural information from the motor cortex, so that persons with quadriplegia can control of FES systems via chronic implantation. Currently, wiring from the skull to the brain surface causes relative motion of electrodes with respect to the brain. Our specific aim is to develop the integrated circuit telemetry techniques and implant structure that will provide a wireless, mechanically stable neural interface for many years. The key question to be addressed is: what would be a reasonable design for a chronic neural information sensor that could be chronically implanted for the rehabilitation of the person with SCI?

PROGRESS--Atraumatic electrode fabrication techniques were developed and acute trauma due to insertion was evaluated. Long-term studies indicated excellent neuron survival within a few microns of the shafts. An electrically isolated, low-noise recording system was constructed and used to document cortical signal characteristics. A low-noise test system for characterization of integrated circuit transistors was designed, constructed, and used to develop advanced mathematical noise models for use in design of optimized neural encoders. Optical telemetry techniques for data and power were developed. Two integrated circuit chips were fabricated for analysis of basic design issues, low-noise pre-amplifiers, and transmitter modules. The second circuit also included a functional 8-channel neural waveform encoder/transmitter that consumed only 31 µW. With minor modifications, this design will serve as the basis for a free-floating, implantable, 8-channel multiplexed neural waveform transmitter. Instrumentation was developed for detecting the optical data pulses. Efficient data decoders were developed for acquiring the neural information. An animal model using visual evoked potentials (VEPs) suitable for studying chronic neural signal transmitters was developed. Techniques for processing and interpreting VEPs to identify the retinal representation of the implanted microelectrodes were developed. Prototype circuits were developed and implanted subcutaneously in two animals.

RESULTS--An assembly error caused the encapsulation used for the first implant to fail after a few weeks. The second implant has transmitted neural signals from the visual cortex for over 1 yr and has been used extensively to test new instrumentation and software. A technique for generating contour plots of activation as a function of time post-stimulus was developed and used to locate the area of the retina associated with the implanted microelectrodes. The area associated with the implant can then be focally driven to elicit single unit activity that can be followed over time. Thus far, the characteristics of the VEPs have been remarkably similar month to month.

FUTURE PLANS--Immediate plans are to publish results thus far and finish fabrication and testing of the multiplexed neural waveform transmitter. Biocompatibility issues should continue to be studied as the new technology is refined. In particular, quantitative histological studies should be conducted once free-floating implants are available. Free-floating neural signal transmitters should be constructed and tested in a dog model where subdural space and brain movements are larger. Action potential encoders should be developed to allow transmission of many more channels of information than can be accomplished with the current analog encoding approach. Free-floating devices should evaluated for long-term damage and function in dogs. Experiments to determine whether motor control information can be extracted should be carried out in dogs with free-floating multichannel transmitters using behavioral techniques. A limited clinical trial should then be designed to evaluate use of the technology for extraction of motor control commands from the motor cortex for prosthetic control.




Roger D. Madison, PhD; Darion Rapoza, PhD; Lisa Wrage; Alan Smith, PhD
Research Service, Veterans Affairs Medical Center, Durham, NC 27705; Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710; Département de Physiologie, Centre de Recherche en Science Neurologiques, Université de Montréal, Montréal, Québec H3C 3T8, Canada; email: madis001@mc.duke.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B2028-RA)

PURPOSE--The overall goal of this research program is to increase the degree of functional recovery following nerve injury, using the nonhuman primate hand as a model system.

  The balance and coordination between the magnitude of grip force and weight of an object (or load force) is critical for manual manipulation of objects. Too weak a grip force may cause slippage, while excessive grip force may damage an object and/or cause unnecessary muscle fatigue. The use of excessive grip force imposes a greater resistance against which antagonist muscles must work. This may make it more difficult to further manipulate an object, as would normally be accomplished by the application of additional forces superimposed upon the basic grip force. Rapid adjustments to unanticipated or inaccurately predicted changes in load force is critical both to the effective manipulation of objects in the environment (such as a screwdriver or wrench), and to the safety of the individual (as in the manipulation of power tools). Paramount to these movements in normal functioning of the hand is the ability to exert voluntary motor control.

  We have compelling evidence that application of nerve growth factors (NGF and aFGF) to a nerve repair site in rodents significantly increases the proportion of motor axons that correctly regenerate into a distal motor nerve branch rather than an inappropriate sensory nerve branch. Data from related primate studies consist of electrophysiological and histological assessments of regeneration, and also show a tendency for motor axons to reinnervate a terminal motor nerve pathway. However, this type of data can only provide correlates of functional recovery: we have no data on the actual recovery of hand function in the awake, behaving animal. This study will attempt to answer the very complex yet seemingly simple question, "But, how well can the animal use its hand?"

METHODOLOGY--We will compare the rate and extent of recovery of normal hand function following surgical repair of the median nerve with and without the addition of growth factors. Monkeys will be trained to grasp a manipulandum using the "key grip" (the grip one would employ when using a key), lift it 1 to 2 cm, and briefly hold it suspended in order to obtain a reward. The device will monitor the applied grip force, load force, and elevation throughout each trial.

  The ability to scale grip force reflexively in response to sensory input will be assessed by altering the manipulandum's surface texture, varying the load force required to suspend the device, and by simulating slippage by exerting a sudden downward force on the suspended manipulandum during the hold phase of the task (smooth objects, heavy objects, and objects that are slipping are normally grasped more firmly than their counterparts). Since the ability to scale grip force to surface texture, load force, and slippage depends upon sensory feedback mediated in part by the median nerve, it will be of interest to determine whether the addition of growth factors may be of benefit to these abilities.

  In a second task designed to assess voluntary motor control, the monkeys will be required to adjust their grip force in response to visual cues presented on a computer monitor. We predict that the enhanced motor reinnervation induced by the growth factors will significantly enhance the recovery of the ability to voluntarily scale grip force in response to a visual stimulus.

PROGRESS--Four monkeys are currently engaged in behavioral training prior to surgical transection and repair of the median nerve.

FUTURE PLANS--Future work will be directed toward developing the technique as a adjunct to standard clinical nerve repair.



Todd A. Linsenmeyer, MD; John Ottenweller, PhD
Kessler Institute For Rehabilitation, W. Orange, NJ 07006; VA Medical Center, E. Orange, NJ 07018-1095

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B887-RA)

PURPOSE--Infertility is a common problem in men following spinal cord injury (SCI). This is due to ejaculatory dysfunction and poor semen quality. With advances in techniques of electroejaculation, semen may be obtained in approximately 90 percent of men with SCI. Unfortunately, semen parameters, particularly sperm motility, are usually of poor quality following SCI. An acute decline in semen quality has been documented to occur shortly after SCI both in humans and in an SCI animal model. Advances in assisted reproductive technologies such as in vitro fertilization have allowed some men to father children. However, these techniques are extremely expensive and often have limited availability. The purpose of this project is to identify the causes of this decline in sperm quality and to identify treatment strategies that may help to prevent this decline.

METHODOLOGY--We are studying both an SCI animal model (Sprague Dawley rat) and men with recent SCI. Animal studies involve mature rats with a T9 transection and sham-operated controls. Drug studies investigating the possible impact of medications, specifically verpamil and L arginine on preventing decline in sperm motility have also been evaluated in our animal model. Studies are underway evaluating differences in nitric oxide (NO) in SCI and non-SCI animals. Scrotal temperature studies in men with SCI have just begun. Since electroejaculation has been found to be unreliable in obtaining ejaculates in SCI rats, sperm is obtained by epididymal puncture. Vesicostomy rather than around-the-clock crede of the rat bladders following SCI has also been evaluated. Possible use of a new SCI animal model (guinea pig), which will allow repeated electroejaculation rather than animal sacrifice at specific time intervals, has been evaluated.

PROGRESS--Previous testicular blood-flow studies have revealed a persistent decrease in testicular blood flow in the SCI animals compared to sham controls at 2 and 4 weeks post SCI. A decline in semen quality shortly after SCI may be prevented by maintaining normal testicular blood flow after SCI. Our study has evaluated several medications to maintain testicular blood flow. Pilot studies have shown improvement in semen quality with L arginine but not verpamil when SCI animals were treated and compared to non-treated SCI animals. Since L arginine is a mediator of NO, studies to evaluate testicular NO are underway. While there has been difficulty obtaining ejaculates using electroejaculation in the rat model, there was a high success rate (70 percent) in obtaining ejaculates in the guinea pig SCI animal model. Unfortunately, there was an increased death rate in rats with vesicostomy and guinea pigs with SCI. Therefore, we have made no changes in our SCI animal model.

FUTURE PLANS--Work will continue to focus on medical interventions with a particular emphasis on L-arginine and NO. Studies are also going to begin to evaluate the impact of SCI on testicular temperature regulation after SCI, in both the animal and human model.



Donald R. Bodner, MD; Graham H. Creasey, MD
VA Medical Center, Cleveland, Ohio 44106; Cleveland FES Center, Cleveland OH 44106-3052; Northeastern Ohio Regional Spinal Cord Injury System, Cleveland Ohio 44109; email: ghc@po.cwru.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B804-RA)

PURPOSE--Our research goal is to evaluate an electrical stimulation technique for improving bladder and bowel function after spinal cord injury (SCI).

METHODOLOGY--Finetech-Brindley stimulators were implanted surgically in 20 subjects at least 1 yr after clinically complete SCI. All except two also underwent posterior sacral rhizotomy. Subjects of either gender were selected on the basis of having significant bladder complications, such as chronic or recurrent infection or reflex incontinence and intolerance of anticholinergic medication. Clinical and laboratory investigations were used to assess bladder emptying, infection, urodynamic parameters, vesico-ureteric reflux, and hydronephrosis. Colorectal studies were used to assess defecation and colorectal motility, and new electrical stimulation techniques were tested in an attempt to improve further the restoration of bladder and bowel function. Each subject was used as his or her own control, comparing measurements before and after the procedure.

PROGRESS--All implants are working well and all except one are in daily use at home for bladder emptying. The study, begun at the VA Medical Center in Cleveland, has been extended to the VA Medical Centers in the Bronx and San Diego, as described below.

RESULTS--Fifteen males and 5 females participated in the study; 15 were treated at Cleveland, 4 in the Bronx, and 1 at San Diego. The age at injury (yrs) was 32.2±11.1. The neurological level of injury was C5 through T12. The time from injury to implant (yrs) was 8.5±7.1. The mean length of follow-up was 21 mo. Before implantation, 14 individuals used intermittent catherization and 6 used permanent catheterization for bladder emptying. After implantation, 1 used intermittent catheterization and 19 used the neuroprosthesis for micturition. Post-voiding residual volume (ml) following micturition using the neuroprosthesis was 25.9±31.9 (median) ranging from 3.0 to 136.7 ml. The bladder capacity (ml) prior to implantation was 260±131 and increased to 467±120 following implantation. Prior to implantation, symptomatic bladder infections/year occurred at a rate of 5 (median) and ranged from 0 to 13 occurences.

  After implantation, the rate was reduced to 1 (median) with a range of 0 to 10 occurrences. Changes were seen in gastrointestinal function (n=7) post implantation. Four individuals were feces continent pre-implantation, and 7 were feces continent post-implantation. Prior to implantation, defecation was achieved with suppositories (5 individuals), laxatives (3), digital stimulation (6), and manual evacuation (5). After implantation, defecation was achieved with suppositories (3 individuals), laxatives (2), digital stimulation (2), manual evacuation (5), and stimulator use (6). The duration of defecation pre-implantation was 3.0±1.6 hrs and was reduced to 0.9±0.4 hrs postimplantation at p=0.018. Median (range) bowel FIM scores changed from 3 (1-6) pre-implantation to 6 (1-6) post implantation at p=0.03.

  No implant infections, erosions, or rejections have occurred. In two subjects the posterior rhizotomy performed at the time of implant was later found to be incomplete as evidenced by clinical testing. They underwent a subsequent posterior rhizotomy at the conus medullaris and now show clinical and urodynamic evidence of sacral areflexia, and are continent. They both use the stimulator routinely for micturition.

FUTURE PLANS--We seek to extend this evaluation to other Spinal Units within the VA in order to determine whether these clinical benefits can be replicated in other sites; what resources are required to initiate an implant program at other sites; which subjects among the population of veterans with spinal cord injury are most suited to this technique; and what is the relation of costs to benefits.




J. Thomas Mortimer, PhD
Case Western Reserve University Cleveland, OH 44106-4912; Cleveland FES Center Cleveland OH 44106-3052; email: jtm3@po.cwru.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B634-3RA)

PURPOSE--The purpose of this work is to develop a diaphragm-pacing system that will support the ventilatory needs of persons with compromised respiratory function. The unique aspect of our approach is the use of intramuscular (IM) electrodes implanted through a laparoscopic procedure rather than nerve cuff electrodes implanted through an open cervical or thoracic surgical procedure.

METHODOLOGY--These studies involve both humans and animals. Animals are used to determine safety and estimate efficacy. Humans are necessary to test our complete system.

PROGRESS--The method we have developed to activate the diaphragm reduces the risk of phrenic nerve damage, requires less time to implant and uses a less invasive implant procedure than conventional methods.

  We have developed a vacuum attaching device and computer-controlled stimulation and data acquisition software to identify the preferred implant site. We also added on-line acquisition of a digitized frame from the laparoscopic video image of each test location. The captured images form a visual record to aid in logging the order and relative location of tested sites as a basis for choosing the next site or for predicting a region that indicates the location of the desired implant site. With this methodology, we can accurately locate the ideal placement site with 95 percent confidence level with four test locations (lasting a total of 15 min).

  We have developed an implant instrument to safely and accurately place IM electrodes in the diaphragm muscle using an implant needle only 30 mm in length, as compared with the 300 mm needle used in previous IM electrode studies. The electrode insertion instrument enables the surgeon to approach the abdominal surface of the diaphragm from any angle, ensuring that the track of the implant needle is always parallel to the surface of the diaphragm and controlling the depth of the needle within the muscle. The needle is kept in tension away from the thorax, so as to keep the electrode close to the abdominal surface, permitting the surgeon to "see" the electrode the entire time. This tool has reduced the possibility of accidentally passing the implant needle from the abdominal cavity to the thoracic cavity, even in a diaphragm that is unusually thin due to disuse. This instrument has been used to successfully implant electrodes in both acute and chronic animal experiments.

  We have developed a radio frequency stimulator control unit for the IRS-8 implantable stimulator. This programmable control unit serves as the interface between the computer and the stimulator. We plan to implement a fully implantable diaphragm pacing system in an animal September 1997.

  Over the past 6 months, we have been unable to recruit volunteers from persons undergoing routine laparoscopic surgery at University Hospitals of Cleveland for our human diaphragm mapping study. In response to this, we will perform additional animal tests in preparation for our first human implant. We will continue to pursue the mapping study.

IMPLICATIONS--Cervical spinal cord injuries (above the C5 level) usually result in a loss of respiratory function. At present, treatment of this condition involves primarily mechanical ventilators, and less frequently, phrenic nerve stimulation with cuff electrodes. Both of these techniques have shortcomings.

  The methods and technology we have developed will make diaphragm pacing less risky to the individual and less costly to the health care delivery system. The combined effects are expected to enhance the quality of life and independence of the ventilator-dependent population.




Michael M. Priebe, MD; Arthur M. Sherwood, PE, PhD
Spinal Cord Injury Service, VA Medical Center, Dallas, TX 75216; University of Texas Southwestern, Dallas TX; Baylor College of Medicine, Houston, TX 77030; email: PRIEBE.MICHAEL_M@dallas.va.gov; ams@bcm.tmc.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B705-5RA)

PURPOSE--In a previous study of spasticity and spinal cord injury (SCI), we identified a number of subjects in whom spasticity was not well controlled by current medications, demonstrating that the brain motor control assessment (BMCA) protocol, a multichannel surface EMG recording during a comprehensive, standardized examination, is both valid and useful. This BMCA protocol made it possible to separate out components of spasticity in a reliable and reproducible manner and hence to study the effects of various procedures on those components separately. Furthermore, we demonstrated that it is necessary to provide a comprehensive assessment of spasticity in such individuals to avoid misrepresenting the full magnitude of the clinical problem. We identified five components of particular importance: phasic reflexes, tonic reflexes, cutaneous reflexes, inappropriate coactivation in voluntary control, and "spontaneous" (triggered by identified/unidentified means) spasms.

  The present project evaluates persons with problematic spasticity, using the procedures developed in the previous study. The long-term objective is to develop new methods of treating spasticity after SCI. In this study, specific features of spasticity and how they are altered by current medications are documented using an objective, neurophysiological method of assessment (BMCA). Subjects are evaluated as their antispastic medications are reduced. Aspects of spasticity analyzed are (in order of increasing estimated importance) phasic reflexes, tonic reflexes, cutaneous reflexes, inappropriate coactivation in voluntary efforts, and spontaneous (triggered) spasms.

METHODOLOGY--The key questions are: Can the results of the BMCA examination be used to identify and classify altered motor control features in persons with SCI who have spastic paresis, while reducing their medications? Can differences in behavior between patients whose spasticity is managed by various medications be discriminated? Will those differences be restricted to one aspect of spastic paresis, or will these differences be global, representing an overall excitability change? Will SCI subjects who are well-satisfied with their anti-spastic medication regime differ in response to withdrawal of those medications from those who are not satisfied?

  By examining the responses to the elements of the BMCA (relaxation, reinforcement maneuvers, voluntary control, passive movements, tendon jerks, clonus elicitation, and plantar stimulation), we anticipate being able to identify different behaviors when anti-spastic medications are reduced. Emphasis is given to selection of subjects with problematic signs of upper motor neuron dysfunction and altered motor control (poor coordination, spasms, hypertonicity, hyperreflexia), and to careful examination of severity of the SCI. Following a carefully monitored washout phase, a comprehensive assessment battery is repeated to characterize the altered motor control in the subject. Data are analyzed and compared with the baseline, on-medication data and a profile of the main features of the altered motor control compiled. By comparing subjects on different medications and their response to reduction of those medications, conclusions regarding specific features of their spasticity and alteration of those features by pharmacologic intervention may be drawn.

PROGRESS--Relocation of the main data collection to the Dallas VA Medical Center has delayed progress toward the project goals. Initial efforts have focused on establishing protocols, demonstrating efficacy of new hardware through normative data collection, and collecting data in three series of studies in spastic SCI subjects.




George H. Kraft, MD, MS; Alan D. Alquist, MS
University of Washington, Departments of Rehabilitation Medicine and Radiology, Seattle, Washington 98195; email: ghkraft@u.washington.edu; flag@u.washington.edu

Sponsor: Multiple Sclerosis Association of America, Cherry Hill, NJ 08002

PURPOSE--Heat-sensitive multiple sclerosis patients (HSMS) are more adversely affected in certain activities than others; specifically, those activities requiring repeated effort. Typical "heat-induced" acute physiologic, motor, and self-perceived stress among HSMS include: the worsening of existing neurologic signs and symptoms, the development of new signs and symptoms, lassitude, and myriad fatigue symptoms. This study focused on active cooling-induced effects upon motor function, as measured by changes in: skeletal muscle strength and local endurance, systemic endurance, and dynamic and standing balance.

METHODOLOGY--We employed a one-group, two-treatment, repeated-measures, within-subjects design. Investigators and research subjects were blinded to the treatment conditions. Treatment conditions were randomly ordered and had two levels: low (sham) body cooling (LC) at 26.5 °C and high body cooling (HC) at 7 °C, and the order factor had two levels (second and third experiments). Treatment and order-effects and the interaction of these factors on the dependent variables were statistically tested through analysis of variance (ANOVA). A post-hoc Pearson r (product-moment correlation coefficient) was employed to measure the extent to which heat exchange was related to biologic and performance changes. Further analysis indicated differences due to treatment conditions (HC vs. LC) and differences between LC and HC due to order of testing or extraneous factors such as: accommodation to equipment, repeated testing, or behavioral differences, as well as correlations between heat exchange and the biologic and performance changes.

PROGRESS--Seventeen subjects have completed the treatment series.

  There were significant before and after evaluation, by treatment condition, interactions in several measurement domains: strength (quadriceps), F[1,15]4.53 (F=3.07, p<0.05), endurance task (leg cycling), F[1,15]8.84 (F=6.77, p<0.01), dynamic balance task (tandem gait), F[1,15]6.71 (F=3.07, p<0.05), single leg standing balance, F[1,15]7.48 (F=6.77, p<0.01), and ambulation velocity, F[1,15]3.18 (F=3.07, p<0.05). There were no pure order effects, however, an order by temperature by pre-post interaction in tandem gait, F[1,15]6.48 (F=3.07, p<0.05) and ambulation velocity, F[1,15]5.61 (F=3.07, p<0.05).

  There were no order effects that contributed to differences in the main effects.

  Heat exchange and motor performance gains are more highly correlated when HSMS are administered the HC treatment. Significant correlations between heat exchange and performance change occurred in 7 of the 9 motor tests with the HC treatment and only 1 of 9 with the LC treatment.

INDICATIONS--We conclude that acute, controlled microclimate body cooling among HSMS subjects at 7 °C for 60 min will effectively and safely decrease body temperature as measured by oral and tympanic methods; decrease systemic stress; and increase motor function. The motor function is measured by significant increases in strength of powerful ambulatory-muscles, in static (single leg standing balance test) and dynamic (tandem gait) coordination, and in local and systemic endurance capacity. This cooling produces heat loss within MS persons that is significantly correlated to motor function changes; that is, the greater the heat loss the greater the motor function gain. We believe these may be important findings for MS patients. Simultaneous symptomatic relief from fatigue and from loss of strength and coordination would benefit heat-sensitive MS persons.



Ken B. Waites, MD
University of Alabama at Birmingham, Department of Pathology, Birmingham, AL 35233; email: waites@wp.path.uab.edu

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Dept. of Education, Washington, DC 20202

PURPOSE--Pulmonary complications, with pneumonia being the most frequent, are a major cause of both morbidity and mortality in persons with spinal cord injury (SCI). Both bacterial and viral immunizations have been recommended to prevent these complications in those with neuromuscular disorders producing mechanical dysfunctions of the respiratory system. Although persons with SCI, particularly those with tetraplegia and high paraplegia, have been shown to be at increased risk for the development of serious pulmonary complications, including pneumonia, we are unaware of any studies documenting the efficacy of either bacterial or viral immunizations to reduce the incidence of these in this population. Our objectives are to document changes in immunologically related laboratory values of persons vaccinated at varying intervals after SCI; and to compare the incidence of pulmonary complications in those unimmunized with those vaccinated at varying times following injury.

METHODOLOGY--The original study entailed random assignment of persons with SCI into one of six groups following their entry into the University of Alabama at Birmingham (UAB) Hospital care system. Groups 1 and 2 were to receive pneumococcal vaccine or placebo at 72 hrs (±24 hrs) of injury. Groups 3 and 4 were to receive the vaccine or placebo at 17 days(±24 hrs) postinjury. Groups 5 and 6 were to receive vaccine or placebo at 4-6 mo postinjury. The groups were determined according to the time at which the patient was admitted to the UAB Hospital or Spain Rehabilitation Center. Following enrollment, four blood samples were collected: the first at the time of administration, the second 1 mo later, the third 2 mo later, and the fourth at 1 yr. Laboratory tests to be performed on each sample included: antipneumococcal antibody titers to four major representative serotypes, quantitative immunoglobulins, complete blood count with differential leukocyte count, liver profile, total serum protein and albumin. Subjects and controls were monitored during their initial hospitalization and by telephone postinjury at 3-mo intervals for the occurrence of respiratory or other systemic complications of pneumococcal disease. Appropriate microbiological and/or immunological diagnostic procedures were to be implemented whenever possible to determine whether or not such complications were indeed due to infection with Streptococcus pneumoniae.

  Recent developments in the acute care of persons with SCI made it necessary to alter the study design and eliminate Groups 1 and 2, immunized immediately postinjury, because of the high dose of methylprednisolone often given within 8 hrs of injury. Steroid presence negates the immunogenicity of the pneumococcal vaccine for 2 weeks. All new subjects are enrolled in Groups 3, 4, 5, or 6.

  Follow-up laboratory values and their scheduled obtainment were not altered otherwise. Emphasis is placed on the immunogenicity of pneumococcal vaccine, since measurable laboratory data are available. Only the reports from subjects themselves are available to document occurrence of pulmonary complications, and rarely were any attempts made to identify Streptococcus pneumoniae as an etiologic agent.

PROGRESS--Data collection instruments and accompanying syllabus have been completed and are in use. Subject identification, enrollment, administration of vaccine or placebo, follow-up, and collection of blood samples is complete. 95 persons have been enrolled in the study, none of whom experienced any adverse effects from the vaccination. Seven were lost to follow-up before all data were collected, and 48 refused to participate. Analyses of antibody levels have been performed.



J. Scott Richards, PhD; Richard Shewchuck, PhD
University of Alabama at Birmingham, Spain Rehabilitation Center, Birmingham, AL 35233-7330; email: richards@sun.rehabm.uab.edu

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Dept. of Education, Washington, DC 20202

PURPOSE--Much of the research in spinal cord injury (SCI) has been focused on acute medical aspects of SCI, with relatively little emphasis being placed on follow-up concerns, particularly quality of life issues. Recent work has suggested that there is a strong relationship between both physical health and emotional well-being of the person with SCI and the existence of an effective social support system. There is very little information, however, on the impact of care demands on the caregiver who also most typically is the major source of social support. The purpose of this project is to investigate on a longitudinal basis, the relationship between the physical and emotional care needs of the person with SCI and the physical and emotional health of the caregiver at several intervals postinjury.

  We shall examine the relationship between factors of well-being in persons with SCI and their caregivers, measured at preselected times postinjury; determine the association between physical and psychosocial characteristics of the person with SCI and feelings-of-burden variables in caregiver(s) at preselected times postinjury; determine the interrelationships between feelings of well-being of the person with SCI and his caregiver(s) in different cohorts over time; and determine the interrelationships between physical and psychosocial characteristics of the person with SCI and the feeling of burden in the caregiver over time.

METHODOLOGY--This is a longitudinal study consisting of four waves of data. A sample size of 100 SCI/caregiver pairs has been targeted. Individuals who identify themselves as most likely to be the primary caregiver are approached regarding participation in the study. The caregivers are administered four structured interviews: one in-person during the rehabilitation phase prior to discharge, and three by mail at 1 and 6 mo, and 1 yr postdischarge. The predischarge interview serves as a baseline of caregiver mental and physical health, as well as an indicator of anticipated burden of care.

PROGRESS--To date, 105 caregivers have been enrolled in the project and 63 of them have completed all 4 phases. Follow-up is scheduled to be completed by the end of August, 1997. Eighty-eight percent of the caregiving sample is female, 66 percent have a high school education or better, and 47 percent were employed outside the home at the time of injury. With regard to relationship to the person with SCI, 32 percent are spouses, 29 percent mothers, and 12 percent brothers. Of the persons with SCI, 78 percent are male and 57 percent have a high school education or greater; 52 percent have a cervical injury, while the remaining 48 percent have paraplegia.

  Preliminary analysis of data reveals the caregivers are experiencing increasing negative affect secondary to caregiving over the first year postdischarge. Decreasing instrumental support is also apparent over the first year postdischarge.

FUTURE PLANS--Preliminary data analysis has begun. It will be descriptive and correlational. Longitudinal/causal analyses will not be able to be carried out until the project is completed.



Jay M. Meythaler, MD
University of Alabama at Birmingham, Spain Rehabilitation Center, Birmingham, AL 35233; email: meythaler@sun.rehabm.uab.edu

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Dept. of Education, Washington, DC 20202

PURPOSE--The development of severe upper motor neuron spasticity is among the most common secondary medical complications for persons with spinal cord injury (SCI). This spasticity is often severe enough to affect the ability to independently perform routine activities of daily living (ADL), thereby causing many individuals to remain homebound, in acute care hospitals, or in nursing facilities. Oral baclofen (Lioresal) has proven to be a relatively effective agent for treating this problem. Unfortunately, oral dosage is limited by systemic toxicity and cognitive side effects such as drowsiness and lethargy. Moreover, because of baclofen's incomplete penetration across the blood-brain barrier, the concentration of drug at the site of action within the nervous system is typically low. As a result, 25-35 percent of persons with SCI do not receive adequate therapy.

  Recent research has focused on the administration of baclofen intrathecally by means of a subcutaneously placed pump with a drug reservoir. This delivery system bypasses the blood-brain barrier and delivers baclofen directly into the cerebrospinal fluid surrounding the spinal cord. The purpose of this study is to examine the effects of intrathecal baclofen on cognition and the ability to conduct routine ADL independently. Incidence of any medical complications will also be determined. The cost-effectiveness of treating spasticity with intrathecal baclofen will also be addressed.

  We seek to determine the degree to which spasticity is reduced following administration of intrathecal baclofen; to determine whether intrathecal baclofen administration significantly improves the ability of individuals to function independently in ADL, mobility transfers, and bowel and bladder care; to determine whether the level of cognitive awareness changes after administration of intrathecal baclofen; to assess the cost-effectiveness of intrathecal baclofen administration; and to document systemic side effects secondary to intrathecal baclofen administration.

METHODOLOGY--This time-series experiment will collect baseline data on 35 persons with SCI, followed by an experimental intervention (intrathecal baclofen administration), and subsequent data collection to assess any changes as a result of the intervention. Participants will receive a bolus dosage intrathecally of 50 micrograms of baclofen to determine the response to the medication and observe any adverse effects. Those not responding adequately (average drop of two points on their muscle tone and reflex scores) or having any significant adverse effects will be ineligible for further study. From those responding adequately, baseline data will be collected during a routine clinic visit. Data will include demographics, measures of injury and spasticity severity, muscle strength, functional independence, cognition and economics. Follow-up data will be collected at mo 1, 3, 6, 9, and 1 yr after pump implantation, and annually thereafter.

  We expect to enroll an average of 10 persons annually. Data will be analyzed by paired comparisons within subjects pre- and postimplantation.

PROGRESS--Between 1994 and 1997, 28 new subjects received an intrathecal bolus of baclofen to determine response to the medication. Of these, 21 have undergone implantation of the pump. Data have been collected on their response to the medication, medical complications, functional independence, cognition, and economic impact up to 1 yr after implantation. For those who underwent bolus but not implantation, data regarding response to the medication and medical complications related to the bolus have been collected; 25 subjects responded sufficiently well to the bolus trial to be considered candidates for the implanted pump; 1 withdrew (moved); and 4 did not wish to proceed.

  Ashworth scores were recorded before administration of the bolus and at 1, 2, 4, and 6 hrs thereafter on all subjects undergoing bolus injections of intrathecal baclofen and are also documented for each subject at every follow-up clinic appointment (at least every 3 mo).

  All implanted subjects (except the one withdrawl) have been evaluated for each area prior to pump insertion and postoperatively at 1, 6, and 12 mo, and many of them have had a neuropsychological battery prior to surgery and at 3 mo postoperatively.

  Data regarding costs for medical care, medications, and supplies prior to surgery have been obtained for persons undergoing pump implantation. For subjects post implantation, data have been obtained for costs since surgery.

  Subject reports of side effects are documented at each follow-up clinic appointment. There has been one case of catheter failure and one pump site infection.

FUTURE PLANS--We shall continue following enrolled subjects described in protocol for data collections and implanting five to seven persons per year with pumps.




David F. Apple, Jr, MD; Mike Castro, MS; Ellen A. Hillegass, PT; Sandee Rogers, PT; Gary A. Dudley, PhD
Shepherd Center, Atlanta, GA 30309; Department of Physical Therapy, Georgia State University, Atlanta, GA 30303; Department of Exercise Science, The University of Georgia, Athens, GA 30602; email: david_apple@shepherd.org

Sponsor: Paralyzed Veterans of America: Spinal Cord Research Foundation

PURPOSE--The purpose of this study was to determine alterations of skeletal muscle during the first 6 mo after complete spinal cord injury (SCI). Cross-sectional studies of humans years after SCI suggest that complete SCI results in atrophy, conversion to more fast fibers, and less resistance to fatigue. Studies of lower mammals show that these responses are evident within 6 mo of injury. Whether humans present a comparable time frame is not known. This is important because conversion to fast muscle, with its high energy demand of contraction and limited ability to maintain force, is believed to limit the use of rehabilitation therapies.

METHODOLOGY--Subjects with complete SCI are studied 3 times; after they are clinically stable, about 6 wks after SCI (POST1); 1 mo later (POST2); and 3 mo later (POST3). On each occasion, magnetic resonance (MR) images of the thigh and calf are taken, the left m. quadriceps femoris is electrically stimulated and biopsies of the right m. quadriceps femoris are taken. Nonimpaired controls are studied at POST1 and POST3.

PROGRESS--Testing of five subjects and five controls is complete. Data from POST1 and POST3 are presented.

PRELIMINARY RESULTS--Subjects showed a 40 percent decline in fiber cross-sectional area (CSA). This was especially evident in type IIa fibers. Fiber type percent, based on histochemical analyses, showed no change. Succinate dehydrogenase and alpha-glycerolphosphate dehydrogenase activities tended to increase, especially in type I fibers. CSA for m. gastrocnemius, determined from MR images, decreased 26 percent. M. soleus and tibialis anterior showed decreases of 7 and 3 percent, respectively. Electromyostimulation (1 s 30 Hz trains of 450 µsec biphasic square wave pulses with 2 s rest between trains) for two bouts of 20 isometric actions with 2 min rest between bouts was used to assess contractile function. Subjects showed a 10 percent decline in torque for bouts 1 and 2 POST1. By POST3 torque decreased about 20 percent for each bout. They also showed greater fatigue over bouts with time, 15 percent at POST1 and 30 percent by POST3. Controls showed a 10 to 15 percent decline in torque within each bout and complete recovery between bouts at POST1 and POST3. Time to peak tension (TPT) and one-half relaxation time (1/2 R) were assessed during these tests: TPT increased about one-sixth for subjects over time and did not change during exercise; 1/2 R was also not influenced by exercise, but was longer at POST3 than POST1. SCI values at POST1 for TPT were comparable to those of able-bodied controls. Controls showed shorter 1/2 R, however, at POST1.

FUTURE PLANS--These results suggest that human skeletal muscle does not become more fast twitch, contract faster, show a decrease in aerobic enzyme content, or show preferential atrophy of slow muscle 6 mo after complete SCI. These data are at odds with general dogma. As a result, we will focus on the early responses of human skeletal muscle to SCI. More subjects are being recruited and followed the first 6 mo after SCI. If the preliminary results hold up, they will show that the major adaptive response of human skeletal muscle to extreme disuse for up to 6 mo is atrophy. This affords an excellent opportunity. Therapies for functional electrical stimulation and/or assisted standing and walking used early after injury will not need to be designed to maintain skeletal muscle fiber type composition, or attempt to convert fast fibers back to slow. Instead, they could concentrate on maintaining muscle mass.



C. Spinal Cord Regeneration


Talat Khan, PhD; Neelima Chauhan, PhD; Scott Sayers, PhD; Lian-Sheng Liu, MD
Rehabilitation Research and Development Center, Edward Hines Jr. VA Hospital, Hines, IL 60141

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B742-RA)

PURPOSE--The purpose of this study was to determine the effect of implantation of carbon filaments and fetal spinal cord tissues, both separately and together, on the growth of CGRP-positive sensory neurites and injury-associated astrogliosis, following severe spinal cord contusion injury in rats by in situ immunoflourescence.

METHODOLOGY--Adult rats were anesthetized and subjected to a severe contusion injury at the T8 level. The rats were divided into five groups: Group One consisted of normal controls (n=5); Group Two consisted of rats whose lesion sites were subsequently filled with a bundle of approximately 10,000 carbon filaments of 5 µm in diameter (AMOCO Thornel;tm) cultured with 15-day-old rat fetal spinal cord explants (n=5); Group Three consisted of rats that received fetal spinal cord tissue implants after injury (n=10); Group Four consisted of rats that received carbon filament implants after injury (n=5); and Group Five consisted of rats that sustained a contusion injury only (n=5). The implantation was performed 1 to 2 hrs postinjury. Following surgery, the animals were cared for in the intensive care area of our AAALAC-certified Animal Facility. After a 10-wk survival period, all animals were perfused with 4 percent buffered (l00 mM phosphate buffer, pH 7.2) paraformaldehyde. Immunofluorecence studies were performed on 12 µm-thick paraplast sections to assess immunoreactive CGRP for sensory neurites.

  The astroglial response was assessed by in situ expression of immunoreactive glial fibrillary acidic protein (GFAP), and the neuro-axonal profile was assessed by immunoreactive phosphoneurofilament protein (NF).

RESULTS--CGRP-immunoreactivity (CGRP-IR) was found to increase at the edges of the lesion, but not within the lesion, following severe contusion injury as compared to controls. The implantation of carbon filaments, or fetal spinal cord tissue, resulted in the attritional sprouting of CGRP-positive neurites within the lesion cavity. The co-implantation of carbon filaments together with fetal spinal cord tissue further enhanced the growth of CGRP-positive neurites within the lesion cavity. The dramatic increase of GFAP-IR surrounding the cyst at the site of the lesion following contusion injury, as compared to controls, indicated injury-associated astrogliosis. The increased expression of NF-IR in terminal clubs of the injured axons surrounding the cyst at the site of the lesion showed axonal swelling due to the accumulation of NF following contusion injury, as compared to controls. The implantation of carbon filaments, and carbon filaments co-cultured with fetal spinal cord tissue limited the astroglial response as evidenced by the depletion of GFAP-IR, and by the growth of NF-IR positive axons over the carbon filaments.

  We therefore conclude that the implantation of carbon filaments may facilitate neuronal regeneration by reducing astrogliosis and providing scaffolding and directionality to axons.

FUTURE PLANS--Previously we have reported electrophysiological recovery, as determined by somatosensory-evoked potentials and motor-evoked potentials, in the group of animals that received carbon filament implants cultured with fetal spinal cord tissue. In addition, retrograde labelling showed labelled axons and cells across the lesion in the group that received carbon filament implants cultured with fetal spinal cord tissue, as compared to the other three injury groups. These results of our study suggest that the transplantation of the combination of carbon filaments and fetal spinal cord tissue play an important role in promoting spinal cord functional recovery after injury. We are currently in the progress of further evaluating the use of these implants for the repair of the spinal cord after injury.




Talat Khan, PhD; Joel B. Myklebust, PhD; Scott Sayers PhD; Robert Havey, BS; Neelima Chauhan, PhD
Rehabilitation Research and Development Center, Edward Hines Jr. VA Hospital, Hines, IL 60141; Zablocki V.A. Medical Center, Milwaukee WI 53295

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B423-3RA).

PURPOSE--Last year, we noted that various degrees of electrophysiological recovery were achieved after the application of a small 25 µA current around the lesion area in severely injured cat spinal cord. Furthermore, the animals receiving carbon filament implants, in addition to electrical stimulation of the injury site, have shown some weight bearing in addition to electrophysiological recovery. This study is designed to evaluate the functional benefit of the application of different amplitudes of pulsed DC electrical currents following severe contusion injury to the spinal cord in cats.

METHODOLOGY--Seventeen cats were anesthetized, and sustained a severe contusion injury to their spinal cord at the T8 level by dropping a 30 g weight from a height of 18 cm. A mid-dorsal myelotomy was performed 1-2 hrs after the contusion injury; by this time edema and hemorrhage develop extensively in the center of the injured spinal cord. Utilizing an operating microscope, the hemorrhagic and edematous tissue was removed by aspiration leaving a small cavity. The dura was sutured using 7-O suture.

  The animals were divided into five groups. In Groups One and Two, cats received a dorsal myelotomy and subsequently received implantable stimulators 2 hrs after injury. In Group Three, cats received a dorsal myelotomy and carbon filament implants 2 hrs after injury. In Group Four, cats received a dorsal myelotomy and carbon filament implants, in addition to implantable electrical stimulators 2 hrs after injury. Group Five served as a control group in which cats underwent a dorsal myelotomy 2 hrs after injury.

  In Group One, battery-powered stimulators, with 2 mm diameter platinum disc electrodes, were surgically implanted with the electrodes for current application configured to produce current flow parallel to the long tracts of the spinal cord across the injury site. The stimulation parameters were 25 µA pulsed direct current, which results in a 100 Hz unipolar square wave with a 20 percent duty cycle. In Groups Two and Four, the stimulation parameters were the same as in Group One; however, the current level was increased to 33 µA.

  All animals received daily care in AAALAC certified Animal Facility. Electrophysiological and behavioral tests were performed before injury and then monthly after injury throughout the duration of the 1 yr experimental period.

RESULTS--Various degrees of electrophysiological recovery have been observed in the animals that received implantable stimulators with 25 µA current after severe contusion injury. However, the animals receiving electrical stimulation with 33 µA at the injury site have consistently shown weight-bearing and minimum ambulation, in addition to electrophysiological recovery within 6 to 8 mo after surgery and electrical stimulation. No difference in functional and electrophysiological status was observed between groups Two and Four. The control animals, and animals receiving carbon filament implants, have all remained paraplegic at the end of the experimental period.

  These preliminary findings indicate that the application of an electrical field provides a favorable environment at the lesion site which results in functional recovery, and that this recovery is dependent on the current level.

FUTURE PLANS--We will continue to evaluate the different parameters of the electric fields (frequency, duty cycle, and current) in search of the ideal parameters which will bring about optimal functional recovery after severe contusion injury to the spinal cord. Recovery will be evaluated electrophysiologically, behaviorally, and histologically in order to determine the beneficial effects of electrical stimulation of the injury site as a means of repairing the damaged spinal cord.




Ioannis V. Yannas, PhD; Myron Spector, PhD; Lila J. Chamberlain, MS
Massachusetts Institute of Technology, Department of Mechanical Engineering, Cambridge, MA 02139; Rehabilitation Engineering R&D, Brockton/West Roxbury VA Medical Center, West Roxbury, MA 02401; email: yannas@mit.edu; spector@ortho.bwh.harvard.edu; lilajo@mit.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #B687-2RA)

PURPOSE--The purpose of this project is to develop a prosthesis that will enhance nerve regeneration in the event of a nerve transection. Previous experiments have shown that a collagen-glycosaminoglycan (CG) matrix, ensheathed in a silicone tube, promotes regeneration across a 15-mm gap in the rat sciatic nerve. The current effort is to evaluate the long-term regeneration through collagen tubes, either empty or filled with the CG matrix, based on structural and functional measurements.

METHODOLOGY--Collagen-glycosaminoglycan (CG) matrices with axial pores 5-10 µm in diameter, were prepared following an established laboratory protocol. The matrices were implanted into 10-mm gap injuries in the rat sciatic nerve within silicone or collagen tubes. Empty collagen and silicone tubes and sciatic nerve autografts were used as controls. To assess the performance of the implants, a variety of methods were employed, including light and electron microscopy, computerized image analysis, immunohistochemical staining, in vivo and in vitro electrophysiology, gait analysis, and sensory functional testing. Regeneration was assessed at 6, 30, and 60 wks.

PROGRESS--The long-term evaluation of the fully resorbable devices has been completed.

RESULTS--The CG matrix, ensheathed by silicone and collagen tubes, was shown to enhance the morphological and electrophysiological recovery of nerves regenerated across 10-mm gaps at 30 and 60 wks, compared to empty tube controls. Morphologically, analysis of variance (ANOVA) revealed that the matrix significantly increased the total number of myelinated axons per nerve, the total number of large diameter (d;me6 µm) myelinated fibers and the mean fiber diameter of the regenerated nerves (p<0.001 for each) when compared to empty tubes. Large axons are important since axons larger than 6 µm have likely reached a distal target. By 60 wks, the regenerated nerves in all groups contained many more axons than normal, but significantly fewer large diameter fibers. The compound nerve action potentials, recorded in vitro, revealed significant increases in the conduction velocity and amplitude in matrix-filled tubes, compared to empty tubes (p<0.01 for each, ANOVA).

  Several differences were apparent when comparing silicone and collagen tubes. In the collagen tubes, both empty and matrix-filled, the regenerated tissue completely filled the interior of the tubes. In contrast, the regenerated tissue filled only half the tube cross-section in the matrix-filled silicone tubes and less than 10 percent in the empty silicone tubes. The collagen tubes also resulted in regenerates which were significantly closer to normal in structure and function than nerves regenerated through the silicone tubes.

  Using the total number of large myelinated fibers (d;me6 µm) per nerve, a linear relationship was established between 6 and 60 wks for each prosthesis group. ANOVA indicated that the regression was significant for each implant group (p<0.001). The CG matrix significantly increased the slope in the silicone and collagen tubes compared to the empty tubes (p<0.01).

  By 60 wks post-operative, the matrix-filled collagen implants had the largest number of axons per nerve (16,000±1,800), significantly more large diameter axons (2,400±200), and a significantly higher conduction velocity (50±2 m/s) than all other tube groups (p<0.001). More importantly, the nerves regenerated through the matrix-filled collagen devices were not significantly different from the autograft group based on all measurements at 30 and 60 wks.

IMPLICATIONS--These findings suggest that a CG matrix-filled collagen device can be used clinically as an alternative treatment to the autograft, resulting in similar morphological and electrophysiological recovery. However, the performance of the best prostheses resulted in only a 50-75 percent recovery of normal structure and function. This indicates that devices need further optimization to fully restore normal function.



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Last revised Fri 04/30/1999