Non-invasive deep brain stimulation therapies for neuroregeneration

Abstract Neurodegenerative diseases, such as Alzheimer’s disease, constitute a major socioeconomic burden. As clinical prevalence dramatically increases, the need for disease-modifying therapies is pressing. In this context, regenerative medicine therapies are considered a promising strategy for the treatment of these patients, due to the low turnover of neural tissues and the extensive neurodegeneration. The transplant of exogenous stem cells has been demonstrated to improve symptoms and lead to functional recovery.However, high immunogenicity and low cell survival limit clinical efficacy (Duncan et al.,2017). Electrical stimulation has been shown to modulate the proliferation and differentiation of neural stem cells (NSC), and thus, it holds high therapeutic potential (Thrivikraman et al.,2018). Although stimulation therapies, such as deep brain stimulation (DBS) have been widely used in the clinic, the invasiveness of the approach precludes translation.Moreover, the mechanisms underlying clinical efficacy remain unknown (Lozano et al.,2019). DBS via temporally interfering (TI) electric fields has emerged as a promising strategy for non-invasive stimulation (Grossman et al.,2017). However, its effect on neuroregeneration and neural biology remains unexplored. Here, the influence of TI stimulation on the biology of primary NSCs was investigated in vitro. Transcriptome analysis using mRNA-seq was carried out to investigate changes in gene expression following stimulation. It was demonstrated that TI stimulation induced changes in the expression of genes involved in neural development and cellular metabolism. In addition, immunostaining showed that TI stimulation led to the upregulation of biomarkers associated with cell proliferation and neural differentiation. Taken together, our results suggest that TI stimulation could be used to direct NSC fate through the modulation of metabolic pathways involved in neural differentiation and proliferation. This mechanism of action could partly explain the clinical benefits associated with stimulation therapies, and could constitute the basis for the development of targeted non-invasive strategies for the treatment of neurodegenerative disorders. Research Category and Technology and Methods Translational Research: 25. Therapeutics Keywords: Neuroregeneration, Deep Brain Stimulation, Non-invasive stimulation, Stimulation therapies