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.
| Leech, Kristan A; Kinnaird, Catherine R; Hornby, T George (2014) Effects of serotonergic medications on locomotor performance in humans with incomplete spinal cord injury. J Neurotrauma 31:1334-42 |
| Thompson, Christopher K; Hornby, T George (2013) Divergent modulation of clinical measures of volitional and reflexive motor behaviors following serotonergic medications in human incomplete spinal cord injury. J Neurotrauma 30:498-502 |
| Thompson, Christopher K; Lewek, Michael D; Jayaraman, Arun et al. (2011) Central excitability contributes to supramaximal volitional contractions in human incomplete spinal cord injury. J Physiol 589:3739-52 |
| Hornby, T George; Lewek, Michael D; Thompson, Christopher K et al. (2009) Repeated maximal volitional effort contractions in human spinal cord injury: initial torque increases and reduced fatigue. Neurorehabil Neural Repair 23:928-38 |
