Transcutaneous spinal cord stimulation improves spasticity after spinal cord injury by increasing motoneuronal KCC2 via activation of primary afferents

The National Institute of Neurological Disorders and Stroke awarded Drexel University $149,190 on July 14, 2026, under CFDA 93.853 (Extramural Research Programs in the Neurosciences and Neurological Disorders) to conduct research on transcutaneous spinal cord stimulation and its mechanisms for reducing spasticity following spinal cord injury.

The research investigates whether transcutaneous spinal cord stimulation improves spasticity after spinal cord injury by upregulating KCC2, a chloride extruder that maintains neuronal chloride homeostasis and GABAergic signaling. Current pharmacological treatments for spasticity, which emerges in approximately 75 percent of spinal cord injury patients, are limited and carry severe side effects. Preliminary data suggests transcutaneous spinal cord stimulation increases motoneuronal KCC2 protein levels and decreases spasticity, but the causal relationship remains unknown. The project will determine whether transcutaneous spinal cord stimulation improves spasticity by genetically increasing or decreasing motoneuronal KCC2, and will clarify direct evidence of how activation of large, myelinated primary afferents translates to therapeutic outcomes.

Work is performed in Philadelphia, Pennsylvania, with an ultimate completion date of February 29, 2028. The award is structured as a Project Grant, the standard assistance type for investigator-initiated research under NINDS extramural programs.

Abstract

After spinal cord injury (SCI), spasticity emerges in approximately 75% of individuals. Spasticity clinically manifests as hyperreflexia, CO-contraction of antagonistic muscles, muscle spasms, and clonus which are a result of disrupted spinal excitability and inhibition after SCI. Current available pharmacological treatments for spasticity are limited and often have severe side effects and dampen overall motor output. Transcutaneous spinal cord stimulation (tscs) has recently emerged as a promising clinical treatment for spasticity, however its mechanisms of action remain elusive. Our previous work suggests that KCC2, a chloride extruder, plays a critical role in decreasing spasticity following rehabilitation after SCI. KCC2 is a chloride extruder responsible for helping maintain low intracellular chloride in neurons to ensure proper hyperpolarizing gabaergic signaling. However, following SCI, KCC2 protein levels are decreased, disrupting chloride homeostasis and increasing motoneuronal hyperexcitability. Our preliminary data suggests that, similarly to activity-based therapies, tscs can both increase protein levels of motoneuronal membrane-bound (active) KCC2 and decrease spasticity. However, IT remains unknown whether this is coincidential or if there is a causal effect. In aim 1, we will determine if tscs improves spasticity after SCI by genetically increasing active motoneuronal KCC2 or knocking-down motoneuronal KCC2. We hypothesize that the upregulation of motoneuronal KCC2 via tscs underlies improvements in spasticity after SCI. While human and computational studies have provided indirect evidence that tscs activates large, myelinated primary afferents by quantifying motor responses, direct evidence is lacking. Additional studies are needed to further clarify how the activation of primary afferents through activity and stimulation-based therapies impacts functional recovery. In aim 2, we will assess the role of VGLUT1+ afferent activation on motor output, hyperreflexia, and KCC2 protein abundance and localization to assess the contribution of primary afferent activation during tscs to improvements in spasticity. We hypothesize that tscs activates VGLUT1 afferents to produce teps, decrease hyperreflexia, and increase KCC2 after SCI to improve spasticity. Overall, we hypothesize that tscs improves spasticity by increasing the amount of active, membrane-bound KCC2 in motoneurons following activation of VGLUT1+ afferents.