Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation

Vagus nerve stimulation (VNS) has emerged as a therapy to treat a wide range of neurological disorders, including epilepsy, depression, stroke, and tinnitus. Activation of neurons in the locus coeruleus (LC) is believed to mediate many of the effects of VNS in the central nervous system. Despite the importance of the LC, there is a dearth of direct evidence characterizing neural activity in response to VNS. A detailed understanding of the brain activity evoked by VNS across a range of stimulation parameters may guide selection of stimulation regimens for therapeutic use. In this study, we recorded neural activity in the LC and the mesencephalic trigeminal nucleus (Me5) in response to VNS over a broad range of current amplitudes, pulse frequencies, train durations, inter-train intervals, and pulse widths. Brief 0.5s trains of VNS drive rapid, phasic firing of LC neurons at 0.1mA. Higher current intensities and longer pulse widths drive greater increases in LC firing rate. Varying the pulse frequency substantially affects the timing, but not the total amount, of phasic LC activity. VNS drives pulse-locked neural activity in the Me5 at current levels above 1.2mA. These results provide insight into VNS-evoked phasic neural activity in multiple neural structures and may be useful in guiding the selection of VNS parameters to enhance clinical efficacy.