Vagus nerve stimulation parameters evoke differential neuronal responses in the locus coeruleus

Abstract

Vagus nerve stimulation (VNS) is used to treat drug‐resistant epilepsy and depression, with additional applications under investigation. The noradrenergic center locus coeruleus (LC) is vital for VNS effects; however, the impact of varying stimulation parameters on LC activation is poorly understood. This study characterized LC activation across VNS parameters. Extracellular activity was recorded in rats' left LC while 11 VNS paradigms, utilizing variable frequencies and bursting characteristics, were pseudorandomly delivered to the left cervical vagus for five cycles. Neurons' change from baseline firing rate and timing response profiles were assessed. The proportion of neurons categorized as responders over 5 VNS cycles doubled in comparison to the first VNS cycle (p < 0.001) for all VNS paradigms, demonstrating an amplification effect. The percentage of positively consistent/positive responders increased for standard VNS paradigms with frequencies ≥10 Hz and for bursting paradigms with shorter interburst intervals and more pulses per burst. The synchrony between pairs of LC neurons increased during bursting VNS but not standard paradigms. Also, the probability of evoking a direct response during bursting VNS was higher with longer interburst intervals and a higher number of pulses per burst. Standard paradigms between 10–30 Hz best positively activates LC with consistency to VNS while the best bursting paradigm to increase activity was 300 Hz, seven pulses per burst separated by 1 s. Bursting VNS was effective in increasing synchrony between pairs of neurons, suggesting a common network recruitment originating from vagal afferents. These results indicate differential activation of LC neurons depending on the VNS parameters delivered.

300 Hz transcutaneous auricular vagus nerve stimulation (taVNS) impacts pupil size nonlinearly as a function of intensity

“…Although the pulse width in the current study is one-fifth to one-sixth the length used in prior studies, the pulse rate is ten times higher. Additional support for this idea comes from findings in rats that iVNS delivered at 300 Hz and above increased the synchrony of LC neuron firing compared to iVNS at 30 Hz and below (Farrand et al, 2023). In line with this, 100 Hz taVNS delivered to the cymba concha elicited stronger activation of the NTS and LC in humans compared to 2, 10, and 25 Hz stimulation (Sclocco et al, 2020).…”

Tonic and phasic transcutaneous auricular vagus nerve stimulation both evoke rapid and transient pupil dilation

“…Given a recent report of different patterns of LC activation depending on specific combination of VNS parameters [60], another possible reason behind the absence of a sustained effect of tonic stimulation in the presence of the transient effect could be parameter choice. Firstly, it is possible that the stimulation session (24 minutes per Active/Sham mode) may have been too short to observe tonic pupil effects.…”

Optimized microburst VNS elicits fMRI responses beyond thalamic‐specific response from standard VNS

“… 12 While the standard VNS paradigm elicited the most consistent locus coeruleus response, a microburst paradigm with seven pulses per second separated by 1 sec between bursts was best for eliciting increased response. 12 Another study implicated the afferent connections of the nucleus tractus solitarius in the VNS response. 13 In a different study, VNS increased immediate and 1‐week seizure threshold in a kindling model of epilepsy in rodents when using standard and microburst stimulation parameters.…”

“…In one study, VNS stimulation resulted in cellular and metabolic changes in thalamus and other regions in stimulated rodents 11 . In another study, stimulation of locus coeruleus (an important nucleus associated with vagus nerve) via burst paradigms improved neuronal synchronization, a finding that was not replicated with standard VNS paradigm 12 . While the standard VNS paradigm elicited the most consistent locus coeruleus response, a microburst paradigm with seven pulses per second separated by 1 sec between bursts was best for eliciting increased response 12 .…”

“…In another study, stimulation of locus coeruleus (an important nucleus associated with vagus nerve) via burst paradigms improved neuronal synchronization, a finding that was not replicated with standard VNS paradigm 12 . While the standard VNS paradigm elicited the most consistent locus coeruleus response, a microburst paradigm with seven pulses per second separated by 1 sec between bursts was best for eliciting increased response 12 . Another study implicated the afferent connections of the nucleus tractus solitarius in the VNS response 13 .…”