Lateralized effects of vagus nerve stimulation on cortical spreading depression: insights from a mouse model

Vagus nerve stimulation (VNS) is increasingly recognized as a therapeutic approach for neurological disorders, such as epilepsy, migraine, and stroke rehabilitation. However, clinical outcomes vary considerably among individuals, underscoring the importance of elucidating the distinct effects of left versus right VNS. In this study, we aimed to investigate how lateralized VNS influences cortical spreading depression (CSD) in mice. Left or right VNS and sciatic nerve stimulation (SNS) were delivered directly by electrodes placed around the vagus or sciatic nerve. CSD was induced by both near-threshold (0.125 M) and supra-threshold (1 M) KCl, and hemispheric responses were assessed in 64 mice. A custom-built intrinsic optical signal (IOS) imaging system integrated with artificial intelligence algorithms was utilized to record and analyze the CSD. Notably, VNS significantly reduced the incidence and slowed CSD propagation at 0.125 M KCl, whereas only minimal effects were observed at 1 M KCl, suggesting that VNS efficacy may depend on the cortical excitability threshold. Right VNS effectively decreased CSD occurrence in the ipsilateral hemisphere, whereas left VNS selectively slowed propagation in the contralateral hemisphere. Additionally, left SNS exerted a modest yet significant reduction in CSD within the left hemisphere, reinforcing the importance of stimulation modality and site. Furthermore, reduced c-Fos expression following VNS, particularly within the stimulated hemisphere, indicates a dampened state of neuronal excitability, thereby supporting the hemisphere-specific neuromodulatory potential of VNS. These findings indicate that lateralized VNS may enable more precise, patient-specific interventions in neurological conditions characterized by cortical hyperexcitability.