To identify VNS Therapy stimulation parameters associated with beneficial outcomes in a double-lesion rat model of Parkinson’s disease (PD).

Vagus nerve stimulation (VNS) is thought to affect the brain by modifying brain rhythms through the nucleus of the solitary tract (NTS). The NTS projects to the locus coeruleus (LC), and firing rates of noradrenergic (NE) neurons in the LC are increased relative to the duration of VNS, resulting in increased NE release in target regions, thereby protecting against neurotoxicity/neurodegeneration. Our hypothesis is that high-frequency stimulation parameters, which are more suitable to NTS and LC firing properties, might be ideal for driving strong NE response in the central nervous system (CNS) and could mitigate CNS inflammation and motor symptoms as seen in PD patients. 

Double-lesioned (6-OHDA + DSP-4) rats were assigned to 6 treatment groups, including VNS with various stimulation settings and traditional pharmacotherapy.  The rats were followed for 10 days with active therapy, during which gross motor assessments, fine motor assessments, and blood sampling for cortisol took place.  After 10 days of therapy, all rats were euthanized and tissue was collected for histological assessment.  Sections of striatum, substantia nigra, and locus coeruleus were assessed for general neuron health and glia activation, and a lysate of prefrontal cortex was assessed for NE concentration.

Higher stimulation frequencies were associated with the largest improvement in gross and fine motor function and neuron health as measured by cell counts in the SN and LC, and reduced intrasomal α-synuclein accumulation in SN.  All VNS Therapy settings were associated with improved neuron health and motor function, but low frequency VNS Therapy (10 Hz) was less associated with improvement in the CNS.

VNS Therapy, especially when delivered at high-frequency, is effective at relieving PD-like symptoms and provides a protective effect against neurodegeneration in the CNS.