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

Award Number: F31NS147874
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $49,538 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	2/6/2026	NEW	$0
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/6/2026	NEW	$49,538
														Subtotal = $49,538

Grand Total All Awards = $49,538

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

Award Number: F31NS147874

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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