Thomas G. Hornby, Ph.D. - US grants

DESCRIPTION (provided by applicant): There is extensive experimental history demonstrating that alteration in motor behaviors following spinal cord injury (SCI) may be partly a result of damage to descending neuromodulatory (in particular serotonergic and noradrenergic) inputs to spinal circuits. Agonists to these monoamines act on specific spinal pathways to modulate motor behaviors (including locomotion) and their responses to sensory information, and have been shown to play a critical role in enhancement of neural plasticity in locomotor circuits. While spontaneous healing and specific physical interventions (i.e., body-weight supported treadmill training, BWSTT) can facilitate return of motor control following motor incomplete SCI in humans, the combination of physical and pharmacological agents to alter motor recovery has yet to be studied in detail. Accordingly, we propose to study the role of selective serotonin reuptake inhibitors (i.e., SSRIs, fluoxetine) on volitional and spastic motor behaviors following chronic (> 1 yr. post) motor incomplete SCI in humans and their effects in combination with specific physical interventions (i.e., BWSTT). Aim 1 will provide quantitative assessment of isometric volitional motor output (maximal torque output, agonist/antagonist co-activation), involuntary spastic behaviors (parameters associated with hyperexcitable flexor and stretch reflexes), and kinematics and EMG activity during locomotion to be compared with clinical measurements of muscle strength, spasticity and quality of overground ambulation (level of assistance, devices used, speed and gait pattern) before and following administration of fluoxetine. Aim 2 will investigate the plasticity of these motor behaviors following 12 weeks of BWSTT using robotic assistance in combination with pharmacological manipulations. Changes in behaviors will be compared to a control group of subjects with motor incomplete SCI that do not receive pharmacological interventions. We expect the monoaminergic agents to depress excitability of selected afferent pathways, but enhance circuitry responsible for volitional motor output and locomotion, thereby expediting the recovery of locomotor capability with BWSTT. As a consequence of these findings, a radical change in pharmacological management of motor incomplete SCI will be indicated.

The objective of this study is to identify how the suppression of reflex function by antispastic agents affects volitional movement in people with incomplete spinal cord injury (SCI). Spastic reflexes are commonly treated using medications or other therapeutic approaches without a good understanding of how the subsequent changes in reflex function affect volitional movements, including gait. This study aims to improve our understanding of how reflexes affect functional movements and the impact that oral medications have on reflex regulation of movement in people with incomplete SCI. We will test the effect of two commonly prescribed antispastic oral medications, baclofen and tizanidine, on the reflex regulation of volitional muscle activity and gait. We expect that reflex excitation contributes to the generation of muscle activity during volitional tasks, and antispastic agents will depress reflexes and reduce muscle activity of the legs during gait. A comparison of the effects of reflexes on volitional movements, including gait, and sensitivity to antispastic agents will be made to gain an improved understanding of how different types of incomplete SCI patients utilize reflex activation of muscles to facilitate movement. We anticipate that subjects with greater weakness might rely heavily on reflexes for the generation of muscle activity during movement, and could be detrimentally affected by antispastic medications. This study has important implications for therapies aimed at restoring movement in SCI and for the treatment of spasticity to improve functional movements.

DESCRIPTION (provided by applicant): The regulation of cardiovascular systems during muscle activity is poorly understood in people with incomplete spinal cord injury (SCI). In the past, disruptions in somatomotor and sympathetic control have been investigated separately in SCI. We propose to investigate the coupling of sympathetic and somatomotor control because it is relevant to exercise training paradigms that are designed to improve somatomotor function or enhance physical fitness. Our approach will be to measure tendon tap reflexes, voluntary muscle activation, and blood flow of the knee (below injury) and elbow (above injury) before and after sympathetic stimuli consisting of cold pressor tests, mental math and an acute bout of exercise. These data will provide information about sympathetic control of blood flow during muscle activity. Plasticity of the sympathetic- somatomotor coupling will also be investigated by making measurements before and after a treadmill training exercise program. These experiments will enable us to address three aims. Aim 1 will be to characterize coupling of sympathetic and somatomotor systems below the level of spinal injury. This aim will examine spinal sympathetic and motor reflexes and their interactions. It will also examine how descending somatomotor coupling is disrupted by the spinal injury. In Aim 2, we will identify changes in the interactions of sympathetic and somatomotor systems above a spinal injury. Because of the injury and the changes that occur below the injury, the sympathetic-somatomotor coupling is also likely to be disrupted in the arm. Aim 3 will then demonstrate plasticity of sympathetic-somatomotor coupling after exercise training. Three different eight week exercise training programs will be tested including 1) upper body ergometry, 2) treadmill training with exertion level matched to the upper body ergometry and 3) treadmill training with heart rate matched to an initial test of upper body ergometry. The exercise training will be tested in a randomized crossover study design with three months between exercise training paradigms. We anticipate that there will be plasticity of sympathetic-somatomotor coupling and that the exercise training effects will normalize control of these systems. However, because of the injury, we anticipate that adaptations will differ from non-injured controls. This study has implications for exercise training in human SCI. The coupling of sympathetic and somatomotor systems is expected to depend on whether exercise targets the upper or lower body. The recovery of function requires both the improvement in the control of movement as well as in the regulation of blood flow to active muscle groups. In addition, this study is important for understanding the potential impact of treadmill exercise training on cardiovascular fitness, a topic of increasing interest in people with limitations to physical activity.

Project Summary The objective of this project is to identify the trajectory of neurological and locomotor recovery in patients early post-stroke and the biomechanical strategies used by patients to accomplish independent locomotion. These patterns of recovery and underlying movement strategies used to accomplish independent ambulation will be assessed during both conventional rehabilitation strategies, and following application of physical interventions, specifically high intensity training (HIT) of stepping tasks, that have been shown to strongly influence multiple measures of neurological and locomotor recovery. Our previous work suggests consistent relationships between the amount of intensity of stepping practice and locomotor recovery (walking gains) following training. However, these findings contrast directly with research that indicates a relative consistent pattern of neurological recovery (measured using specific assessments of movement capability, fractionation of individual joints, or reflex activity), irrespective of the types of interventions provided. These discrepancies may be due to differences in definitions utilized for neurological vs locomotor recovery, but also highlight the potential use of alternative movement patterns post-stroke, during which full restitution of neurological function may not occur in most patients. Rather, compensatory movement strategies must be utilized to accomplish locomotor tasks. The present project will attempt to delineate changes in neurological and locomotor recovery and the underlying strategies used to perform walking tasks (Aim 1). We will subsequently evaluate alterations in specific patterns of neurological and functional recovery in response HIT applied in the later stages post-stroke to ascertain the relative plasticity of these patterns (Aim 2). In a separate cohort, we will apply such training early post-stroke and identify alterations in movement capability and neuromuscular strategies through the recovery phases post-stroke (Aim 3). If neurological recovery is indeed predictable and deterministic, we believe patterns of locomotor recovery and compensation are also deterministic and can be categorized by the amount of movement capability and compensations observed. We further postulate that these patterns are likely malleable with specific interventions and can provide greater insight into long-term functional and neuromuscular outcomes in patients early post-stroke.