Contralesional Anodal Transcranial Direct Current Stimulation Promotes Intact Corticospinal Tract Axonal Sprouting and Functional Recovery After Traumatic Brain Injury in Mice

Abstract

Background Anodal transcranial direct current stimulation (AtDCS), a neuromodulatory technique, has been applied to treat traumatic brain injury (TBI) in patients and was reported to promote functional improvement. We evaluated the effect of contralesional AtDCS on axonal sprouting of the intact corticospinal tract (CST) and the underlying mechanism in a TBI mouse model to provide more preclinical evidence for the use of AtDCS to treat TBI. Methods TBI was induced in mice by a contusion device. Then, the mice were subjected to contralesional AtDCS 5 days per week followed by a 2-day interval for 7 weeks. After AtDCS, motor function was evaluated by the irregular ladder walking, narrow beam walking, and open field tests. CST sprouting was assessed by anterograde and retrograde labeling of corticospinal neurons (CSNs), and the effect of AtDCS was further validated by pharmacogenetic inhibition of axonal sprouting using clozapine-N-oxide (CNO). Results TBI resulted in damage to the ipsilesional cortex, while the contralesional CST remained intact. AtDCS improved the skilled motor functions of the impaired hindlimb in TBI mice by promoting CST axon sprouting, specifically from the intact hemicord to the denervated hemicord. Furthermore, electrical stimulation of CSNs significantly increased the excitability of neurons and thus activated the mechanistic target of rapamycin (mTOR) pathway. Conclusions Contralesional AtDCS improved skilled motor following TBI, partly by promoting axonal sprouting through increased neuronal activity and thus activation of the mTOR pathway.