Spasticity is a debilitating condition which emerges in up to ~75% of individuals with spinal cord injury (SCI), with most experiencing spastic episodes one year after injury. Current pharmacological approaches to decrease spasticity (i.e. baclofen, tizanidine, botulinum toxin) lead to significant undesirable side effects such as sedation and dizziness. More importantly, they also induce a profound depression of spinal reflex excitability which significantly reduces muscle activity and impedes conventional rehabilitative efforts. There is therefore a critical need to identify alternate avenues. The last decade has seen a critical breakthrough in the SCI field with the use of stimulation-based therapies, in particular epidural stimulation, to further modulate the excitability of spinal networks and enhance functional recovery after SCI. Although promising, these treatments are invasive, costly, and require highly skilled and specialized teams. In contrast, non-invasive transcutaneous spinal cord stimulation (tSCS) has the potential to be rapidly adapted in clinical rehabilitation settings. This project is designed to advance our understanding of the neuroplasticity triggered by 6 weeks of repeated lumbar tSCS initiated acutely, to prevent the development of spasticity, or chronically, to decrease spasticity once spinal hyperexcitability has fully developed.
Aim 1 will determine if tSCS contributes to decrease spasticity/hyperreflexia through restoring spinal inhibition in lumbar spinal networks. Behavioral correlates of spasticity will be monitored over time. In a terminal experiment, the effect of tSCS on spinal inhibitory pathways (homosynaptic depression, reciprocal inhibition, and presynaptic inhibition) will be correlated to the reorganization of inhibitory/excitatory inputs to motoneurons and primary afferents.
Aim 2 will determine if tSCS restores motor-evoked potentials (MEPs) originating from above and below the injury after SCI. During a terminal experiment, MEPs initiated by a stimulation to the spinal cord below or above the injury will be recorded as well as synaptic transmission in the cortico-reticulospinal pathway. The modulatory effect of proprioceptive feedback on the MEPs of various origin will also be evaluated. The contribution of primary afferents (VGlut1+/paravalbumin) and descending tracts (vGi) to increased motor output and normalization of the SCI-induced facilitation of proprioceptive afferents will be evaluated. Because spastic symptoms, such as spasms and uncontrollable reflexes, render rehabilitation and activity-based therapies such as locomotor training challenging and less effective, Aim 3 will determine if decreasing spasticity with tSCS prior to the initiation of a step-training program improves locomotor recovery. Spasticity and locomotor recovery will be evaluated over time and will be correlated to the return of spinal inhibition and cortico-reticulospinal transmission. The proposed research project is consistent with the goals of the NIH/NINDS by addressing a current gap in knowledge and delineating the mechanisms of tSCS. Understanding the mechanisms underlying the beneficial effect of non-invasive interventions is critical to optimize evidence-based clinical practice and fast-track its use in the SCI community.

Public Health Relevance

We will pursue studies in an incomplete model of chronic spinal cord injury (SCI), examining how a repeated treatment of transcutaneous stimulation contributes to decrease spasticity, hyperreflexia and improve motor function. We will determine if 6 weeks of repeated transcutaneous stimulation initiated acutely after injury before spasticity develops, or chronically once spasticity is established, leads to 1) a return in spinal inhibition, 2) an increase in motor output 3) improves locomotor recovery when delivered prior to a step-training program. Understanding the mechanisms underlying the beneficial effect of non-invasive interventions is critical to optimize clinical intervention and fast-track its use in the SCI community.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Bambrick, Linda Louise
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Drexel University
Anatomy/Cell Biology
Schools of Medicine
United States
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