Floyd J. Thompson

Feasibility and Safety of Neural Tissue Transplantation in Patients with Syringomyelia

Transplantation of fetal spinal cord (FSC) tissue has demonstrated significant potential in animal models for achieving partial anatomical and functional restoration following spinal cord injury (SCI). To determine whether this strategy can eventually be translated to humans with SCI, a pilot safety and feasibility study was initiated in patients with progressive posttraumatic syringomyelia (PPTS). A total of eight patients with PPTS have been enrolled to date, and this report presents findings for the first two patients through 18 months postoperative. The study design included detailed assessments of each subject at multiple pre- and postoperative time points. Outcome data were then compared with each subjects own baseline. The surgical protocol included detethering, cyst drainage, and implantation of 6-9-week postconception human FSC tissue. Immunosuppression with cyclosporine was initiated a few days prior to surgery and continued for 6 months postoperatively. Key outcome measures included: serial magnetic resonance imaging (MRI) exams, standardized measures of neurological impairment and functional disability, detailed pain assessment, and extensive neurophysiological testing. Through 18 months, the first two patients have been stable neurologically and the MRIs have shown evidence of solid tissue at the graft sites, without evidence of donor tissue overgrowth. Although it is still too soon to draw any firm conclusions, the findings from the initial two patients in this study suggest that intraspinal grafting of human FSC tissue is both feasible and safe.

Locomotor Training Restores Walking in a Nonambulatory Child With Chronic, Severe, Incomplete Cervical Spinal Cord Injury

Background and Purpose: Locomotor training (LT) enhances walking in adult experimental animals and humans with mild-to-moderate spinal cord injuries (SCIs). The animal literature suggests that the effects of LT may be greater on an immature nervous system than on a mature nervous system. The purpose of this study was to evaluate the effects of LT in a child with chronic, incomplete SCI. Subject: The subject was a nonambulatory 4½-year-old boy with an American Spinal Injury Association Impairment Scale (AIS) C Lower Extremity Motor Score (LEMS) of 4/50 who was deemed permanently wheelchair-dependent and was enrolled in an LT program 16 months after a severe cervical SCI. Methods: A pretest-posttest design was used in the study. Over 16 weeks, the child received 76 LT sessions using both treadmill and over-ground settings in which graded sensory cues were provided. The outcome measures were ASIA Impairment Scale score, gait speed, walking independence, and number of steps. Result: One month into LT, voluntary stepping began, and the child progressed from having no ability to use his legs to community ambulation with a rolling walker. By the end of LT, his walking independence score had increased from 0 to 13/20, despite no change in LEMS. The childs final self-selected gait speed was 0.29 m/s, with an average of 2,488 community-based steps per day and a maximum speed of 0.48 m/s. He then attended kindergarten using a walker full-time. Discussion and Conclusion: A simple, context-dependent stepping pattern sufficient for community ambulation was recovered in the absence of substantial voluntary isolated lower-extremity movement in a child with chronic, severe SCI. These novel data suggest that some children with severe, incomplete SCI may recover community ambulation after undergoing LT and that the LEMS cannot identify this subpopulation.

Projection of phrenic nerve afferents to the cat sensorimotor cortex

The projection of phrenic nerve afferents to the sensorimotor cortex was studied in cats. The results of these experiments demonstrate that stimulation of phrenic nerve afferents elicits cortical evoked potentials (CEPs) in the sensorimotor cortex of cats. Cortical foci for CEPs classified as primary were found in areas 3b, 3a and 4 gamma. These foci were located medial to forelimb and lateral to hindlimb afferent representations in the sensorimotor cortex.

Neurophysiological assessment of the feasibility and safety of neural tissue transplantation in patients with syringomyelia.

The feasibility and safety of a procedure involving fetal spinal cord tissue transplantation in patients with syringomyelia was assessed using a neurophysiological protocol designed to quantitate peripheral nerve function, spinal cord reflex excitability, and spinal cord conduction pathways essential for somatosensory evoked potentials. We report here data obtained before and for 18 months following the transplantation procedure performed on the first two patients in this study. The neurophysiological assessment protocols included measures of cortical and spinal cord evoked potentials, H-reflex excitability, and peripheral nerve conduction. Prior to the procedure, both patients had significant deficits on some of the neurophysiological measures, for example, lower extremity cortical evoked potentials. However, robust measures of intact pathways, such as upper extremity cortical evoked potentials, were also observed preoperatively in both patients. Thus, it was anticipated that conduction in these intact pathways could be at risk either from complications from the transplantation procedure and/or from continued expansion of the syrinx. Following the transplantation procedure, no negative changes were observed in any of the neurophysiological measures in either patient. In addition, patient 1 showed a decrease in the rate potentiation of tibial H-reflexes on the right side and an increase in the response probability of left tibial H-reflexes. The results of this postoperative longitudinal assessment provide a first-level demonstration of the safety of the intraspinal neural tissue transplantation procedure. However, the consideration of safety is currently limited to the grafting procedure itself, since the long-term fates of the donor tissue in these two patients remain to be shown more definitively.

Velocity-Dependent Ankle Torque in Rats after Contusion Injury of the Midthoracic Spinal Cord: Time Course

Progressive neurophysiological changes in the excitability of the pathways that subserved ankle extensor stretch reflexes were observed following midthoracic contusion. The purpose of the present study was to determine the nature and time course of velocity-dependent changes in the excitability of the ankle stretch reflex following T(8) contusion injury. These studies were conducted in adult Sprague-Dawley rats using a 10-g 2.5-cm weight drop onto the exposed thoracic spinal cord (using an NYU injury device and a MASCIS protocol). Velocity-dependent ankle torques and triceps surae EMGs were measured in awake animals over a broad range of rotation velocities (49-612 deg/sec) using instrumentation and protocol previously reported. EMGs and ankle torques were measured before and at weekly intervals following injury. Statistical tests of the data included within group repeated measures ANOVA and between group one-way ANOVA comparisons with time-matched control animals. An alternating pattern of significant increase followed by significant decrease in velocity-dependent ankle torque was observed during the first postinjury month. An increase of 33% in the peak torque and 24% in peak EMG magnitude at 612 deg/sec was observed in the first week. EMG burst amplitudes, that were timed-locked to the dynamic phase of the rotation, were observed to increase and decrease in a manner, which indicated that the changes in torque included stretch-evoked active contractions of the ankle extensors. During the second and third postinjury months, consistent 24-40% increases in the peak torques and 17-107% increases in the EMG magnitudes at the highest velocity were observed. No significant increases in torques were observed in the slowest rotation velocity in these periods.

Modulation of triceps surae H-reflexes as a function of the reflex activation history during standing and stepping

The facilitatory effectiveness of spindle afferent feedback is controlled by modulation of segmental reflex excitability such that the level of muscle activation is appropriate for the task. Phase-dependent modes of reflex modulation have been well-characterized. We hypothesized that segmental reflex excitability of the triceps surae was also modulated in a manner associated with the activation history of the spindle afferents and the segmental reflex pathway during isometric contractions, standing and stepping. In the first experiment. pairs of soleus (S) H-reflexes were evoked 80 ms apart with equal strength stimuli at rest and while subjects isometrically contracted their S against loads of 10%. 20%. and 50% of their maximum voluntary efforts. The percent depression of the second H-reflex relative to the first was used as a measure of the effect of reflex activation history. At rest, the second H-reflexes were depressed an average of 73% relative to the first. The degree of depression was progressively reduced as the plantarflexion torque increased. In the second experiment, paired H-reflexes were obtained from the S and medial (MG) and lateral gastrocnemii (LG) muscles while subjects were standing and during the stance phase of step initiation. The degree of depression of the second H-reflex during standing ( > 78%) was similar in magnitude to that produced at rest in Experiment I. At the end of the stance phase of stepping. depression of the second H-reflex of all three muscles was reduced to less than 25%. We conclude that the segmental reflex excitability is modulated as a function of the reflex activation history during these tasks.

Morphological changes of the soleus motoneuron pool in chronic midthoracic contused rats

This study investigated the morphological features of the soleus motoneuron pool in rats with chronic (4 months), midthoracic (T8) contusions of moderate severity. Motoneurons were retrogradely labeled using unconjugated cholera toxin B (CTB) subunit solution injected directly into the soleus muscle of 10 contused and 6 age- and sex-matched, normal controls. Morphometric studies compared somal area, perimeter, diameter, dendritic length, and size distribution of labeled cells in normal and postcontusion animals. In normal animals, motoneurons with a mean of 110.4 +/- 5.2 were labeled on the toxin-injected side of the cord (left). By comparison, labeled cells with a mean of 93.0 +/- 8.4 (a 16% decrease, P = 0.006) were observed in the chronic spinal-injured animals. A significantly smaller frequency of very small (area, approximately 100 microm2) and medium (area, 545-914 microm2) neurons, and a significantly higher frequency of larger (area, >914 microm2) neurons was observed in the labeled soleus motoneuron pools of injured animals compared with the normal controls. Dendritic bundles in the contused animals were composed of thicker dendrites, were arranged in more closely aggregated bundles, and were organized in a longitudinal axis (rostrocaudal axis). Changes in soleus motoneuron dendritic morphology also included significant decrease of total number of dendrites, increased staining, hypertrophy of primary dendrites, and significant decreased primary, secondary, and tertiary branching. The changes in size distribution and dendritic morphology in the postcontusion animals possibly resulted from cell loss and transformation of medium cells to larger cells and/or injury-associated failure of medium cells to transport the immunolabel.

Acute effects of locomotor training on overground walking speed and H-reflex modulation in individuals with incomplete spinal cord injury.

Abstract Objective: The purpose of this study was to assess the effect of a single bout of a locomotor-training paradigm on overground walking speed and H-reflex modulation of individuals with incomplete spinal cord injury (SCI). Methods: Self-selected and maximum walking speeds and soleus H-reflexes (H/M ratios) during standing and stance and swing phases of walking (self-selected velocity) were obtained from 4 individuals with American Spinal Injury Association impairment classification D. Data were collected immediately before and after a single bout of locomotor training with body weight support on a treadmill. The pretraining H/M ratios of the SCI subjects were also compared with values from 4 able-bodied subjects who did not receive the intervention. Maximum H/M ratios while standing and during midstance and midswing phases of overground walking were considerably greater in the SCI subjects than in the control subjects. Results: After the single bout of training, self-selected and maximum overground walking speeds of the subjects with SCI increased by 26% and 25%, respectively. Furthermore, H-reflexes were significantly more depressed in the SCI subjects during overground walking (28% less during stance, 34% less during swing). Conclusions: Although preliminary, these findings indicate that a single bout of locomotor training produced immediate increases in walking velocity and acute neurophysiologic changes in individuals with incomplete SCI.

Comparison of Single Bout Effects of Bicycle Training Versus Locomotor Training on Paired Reflex Depression of the Soleus H-Reflex After Motor Incomplete Spinal Cord Injury

OBJECTIVE To examine paired reflex depression changes post 20-minute bout each of 2 training environments: stationary bicycle ergometer training (bicycle training) and treadmill with body weight support and manual assistance (locomotor training). DESIGN Pretest-posttest repeated-measures. SETTING Locomotor laboratory. PARTICIPANTS Motor incomplete SCI (n=12; mean, 44+/-16y); noninjured subjects (n=11; mean, 30.8+/-8.3y). INTERVENTION All subjects received each type of training on 2 separate days. MAIN OUTCOME MEASURE Paired reflex depression at different interstimulus intervals (10 s, 1 s, 500 ms, 200 ms, and 100 ms) was measured before and after both types of training. RESULTS (1) Depression was significantly less post-SCI compared with noninjured subjects at all interstimulus intervals and (2) post-SCI at 100-millisecond interstimulus interval: reflex depression significantly increased postbicycle training in all SCI subjects and in the chronic and spastic subgroups (P<.05). CONCLUSIONS Phase-dependent regulation of reflex excitability, essential to normal locomotion, coordinated by pre- and postsynaptic inhibitory processes (convergent action of descending and segmental inputs onto spinal circuits) is impaired post-SCI. Paired reflex depression provides a quantitative assay of inhibitory processes contributing to phase-dependent changes in reflex excitability. Because bicycle training normalized reflex depression, we propose that bicycling may have a potential role in walking rehabilitation, and future studies should examine the long-term effects on subclinical measures of reflex activity and its relationship to functional outcomes.

Lumbar spinal cord responses to limb vein distention.

The purpose of this study was to determine if central neural responses were elicited by distention of limb veins, and to compare the pattern of these response to those produced in previous studies using electrical stimulation to excite limb venous afferent fibers. Spinal evoked potentials were measured in response to stretch of the wall of a segment of the femoral-saphenous vein by perfusion-distention or by mechanical stretch. These studies revealed that spinal cord evoked potentials were elicited by these procedures, and that the activated venous afferent fibers coursed through the saphenous nerve and entered the sixth lumber spinal cord segment. The minimum stretches which were required to elicit spinal evoked potentials were produced by perfusion pressures starting at 2-3 mm Hg, or by mechanical stretch of the wall of 5 micron/mm. A vein wall proprioceptor hypothesis is proposed and discussed in the light of these findings. In addition to the cord dorsum evoked potentials, distention or stretch of the vein wall elicited ventral root potentials (excitatory postsynaptic population potentials) which are known to be produced by excitatory inputs to motoneurons. A venous afferent mediated muscle-tonus venopressor mechanism hypothesis is proposed and discussed in the light of these and previous findings.