Effect of combined treadmill training and magnetic stimulation on spasticity and gait impairments after cervical spinal cord injury.

Spasticity and gait impairments are two common disabilities after cervical spinal cord injury (C-SCI). In this study, we tested the therapeutic effects of early treadmill locomotor training (Tm) initiated at postoperative (PO) day 8 and continued for 6 weeks with injury site transcranial magnetic stimulation (TMSsc) on spasticity and gait impairments after low C6/7 moderate contusion C-SCI in a rat model. The combined treatment group (Tm+TMSsc) showed the most robust decreases in velocity-dependent ankle torques and triceps surae electromyography burst amplitudes that were time locked to the initial phase of lengthening, as well as the most improvement in limb coordination quantitated using three-dimensional kinematics and CatWalk gait analyses, compared to the control or single-treatment groups. These significant treatment-associated decreases in measures of spasticity and gait impairment were also accompanied by marked treatment-associated up-regulation of dopamine beta-hydroxylase, glutamic acid decarboxylase 67, gamma-aminobutyric acid B receptor, and brain-derived neurotrophic factor in the lumbar spinal cord (SC) segments of the treatment groups, compared to tissues from the C-SCI nontreated animals. We propose that the treatment-induced up-regulation of these systems enhanced the adaptive plasticity in the SC, in part through enhanced expression of pre- and postsynaptic reflex regulatory processes. Further, we propose that locomotor exercise in the setting of C-SCI may decrease aspects of the spontaneous maladaptive segmental and descending plasticity. Accordingly, TMSsc treatment is characterized as an adjuvant stimulation that may further enhance this capacity. These data are the first to suggest that a combination of Tm and TMSsc across the injury site can be an effective treatment modality for C-SCI-induced spasticity and gait impairments and provided a pre-clinical demonstration for feasibility and efficacy of early TMSsc intervention after C-SCI.

Altered patterns of reflex excitability, balance, and locomotion following spinal cord injury and locomotor training.

Spasticity is an important problem that complicates daily living in many individuals with spinal cord injury (SCI). While previous studies in human and animals revealed significant improvements in locomotor ability with treadmill locomotor training, it is not known to what extent locomotor training influences spasticity. In addition, it would be of considerable practical interest to know how the more ergonomically feasible cycle training compares with treadmill training as therapy to manage SCI-induced spasticity and to improve locomotor function. Thus the main objective of our present studies was to evaluate the influence of different types of locomotor training on measures of limb spasticity, gait, and reflex components that contribute to locomotion. For these studies, 30 animals received midthoracic SCI using the standard Multicenter Animal Spinal cord Injury Studies (MASCIS) protocol (10 g 2.5 cm weight drop). They were divided randomly into three equal groups: control (contused untrained), contused treadmill trained, and contused cycle trained. Treadmill and cycle training were started on post-injury day 8. Velocity-dependent ankle torque was tested across a wide range of velocities (612-49°/s) to permit quantitation of tonic (low velocity) and dynamic (high velocity) contributions to lower limb spasticity. By post-injury weeks 4 and 6, the untrained group revealed significant velocity-dependent ankle extensor spasticity, compared to pre-surgical control values. At these post-injury time points, spasticity was not observed in either of the two training groups. Instead, a significantly milder form of velocity-dependent spasticity was detected at postcontusion weeks 8-12 in both treadmill and bicycle training groups at the four fastest ankle rotation velocities (350-612°/s). Locomotor training using treadmill or bicycle also produced significant increase in the rate of recovery of limb placement measures (limb axis, base of support, and open field locomotor ability) and reflex rate-depression, a quantitative assessment of neurophysiological processes that regulate segmental reflex excitability, compared with those of untrained injured controls. Light microscopic qualitative studies of spared tissue revealed better preservation of myelin, axons, and collagen morphology in both locomotor trained animals. Both locomotor trained groups revealed decreased lesion volume (rostro-caudal extension) and more spared tissue at the lesion site. These improvements were accompanied by marked upregulation of BDNF, GABA/GABA(b), and monoamines (e.g., norepinephrine and serotonin) which might account for these improved functions. These data are the first to indicate that the therapeutic efficacy of ergonomically practical cycle training is equal to that of the more labor-intensive treadmill training in reducing spasticity and improving locomotion following SCI in an animal model.

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.

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.

Chronic intrathecal baclofen treatment and withdrawal: I. Changes in ankle torque and hind limb posture in normal rats.

This study evaluated reflex excitability and locomotor changes during chronic intrathecal infusion of the GABAb agonist baclofen (ITB) and its withdrawal, in the rat. We observed sustained velocity dependent decreases in ankle torque during four weeks of ITB treatment. These changes were correlated with a significant reduction of the EMG burst magnitude time locked to the dynamic phase of ankle dorsiflexion during the first ITB treatment week. However, a considerable recovery of EMG magnitude was observed during the third and fourth weeks of treatment. During baclofen withdrawal, significantly increased velocity dependent ankle torque was observed for 4 weeks. These increases in ankle torque were correlated with increased magnitudes of EMG time locked to the dynamic phase of ankle rotation. Measures of hind limb axis and base of support were obtained using analysis of footprints on a treadmill during ITB treatment and withdrawal periods. During ITB treatment and for up to 7 weeks of withdrawal, hindlimb axis and base of support were significantly altered compared with vehicle controls. These studies were performed to provide a foundation for evaluation of treatment and withdrawal in the setting of experimental chronic contusion spinal cord injury.