Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson’s disease

Abstract

BackgroundVagus nerve stimulation (VNS) modifies brain rhythms in the locus coeruleus (LC) via the solitary nucleus. Degeneration of the LC in Parkinson’s disease (PD) is an early catalyst of the spreading neurodegenerative process, suggesting that stimulating LC output with VNS has the potential to modify disease progression. We previously showed in a lesion PD model that VNS delivered twice daily reduced neuroinflammation and motor deficits, and attenuated tyrosine hydroxylase (TH)-positive cell loss. ObjectiveThe goal of this study was to characterize the differential effects of three clinically-relevant VNS paradigms in a PD lesion model. MethodsEleven days after DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, noradrenergic lesion, administered systemically)/6-OHDA (6-hydroxydopamine, dopaminergic lesion, administered intrastriatally) rats were implanted with VNS devices, and received either low-frequency VNS, standard-frequency VNS, or high-frequency microburst VNS. After 10 days of treatment and behavioral assessment, rats were euthanized, right prefrontal cortex (PFC) was dissected for norepinephrine assessment, and the left striatum, bilateral substantia nigra (SN), and LC were sectioned for immunohistochemical detection of catecholamine neurons, α-synuclein, astrocytes, and microglia. ResultsAt higher VNS frequencies, specifically microburst VNS, greater improvements occurred in motor function, attenuation of TH-positive cell loss in SN and LC, and norepinephrine concentration in the PFC. Additionally, higher VNS frequencies resulted in lower intrasomal α-synuclein accumulation and glial density in the SN. ConclusionsThese data indicate that higher stimulation frequencies provided the greatest attenuation of behavioral and pathological markers in this PD model, indicating therapeutic potential for these VNS paradigms.