Immediate effects and duration of a short and single application of transcutaneous auricular vagus nerve stimulation on P300 event related potential

Abstract

Introduction: Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that stimulates the auricular branch of the vagus nerve. The modulation of the locus coeruleus-norepinephrine (LC-NE) network is one of the potential working mechanisms of this method. Our aims were 1-to investigate if short and single applications of taVNS can modulate the P300 cognitive event-related potential (ERP) as an indirect marker that reflects NE brain activation under control of the LC, and 2-to evaluate the duration of these changes.

Methods: 20 healthy volunteers executed an auditory oddball paradigm to obtain P300 and reaction time (RT) values. Then a 7 min active or sham taVNS period was initiated and simultaneously a new P300 paradigm was performed. We successively repeated the paradigm on 4 occasions with different time intervals up to 56 min after the stimulation onset.

Results: During active taVNS an immediate and significant effect of increasing the amplitude and reducing the latency of P300, as well as a shortening in the RT was observed. This effect was prolonged in time up to 28 min. The values then returned to pre-stimulation levels. Sham stimulation did not generate changes.

Discussion: Our results, demonstrate differential facilitating effects in a concrete time window after taVNS. Literature about the modulatory effect of taVNS over P300 ERP shows a wide spread of results. There is not a standardized system for taVNS and currently the great heterogeneity of stimulation approaches concerning targets and parameters, make it difficult to obtain conclusions about this relationship. Our study was designed optimizing several stimulation settings, such as a customized earbud stimulator, enlarged stimulating surface, simultaneous stimulation over the cymba and cavum conchae, a Delayed Biphasic Pulse Burst and current controlled stimulation that adjusted the output voltage and guaranteed the administration of a preset electrical dose. Under our stimulation conditions, targeting vagal nerve fibers via taVNS modulates the P300 in healthy participants. The optimal settings of modulatory function of taVNS on P300, and their interdependency is insufficiently studied in the literature, but our data provides several easily optimizable parameters, that will produce more robust results in future.

Keywords: P300; auricular vagus nerve stimulation; event-related potentials; healthy volunteers; locus coeruleus; neurostimulation; norepinephrine; transcutaneous vagus nerve stimulation.

Figure 1

taVNS system. (A) Customized auricular device with stimulating platinum electrodes over cymba and cavum conchae physically connected to B; (B) electrical stimulus generator connected by Bluetooth to C; (C) stimulation control module in a smart phone app. That allowed to control the stimulating parameters.

Figure 2

Graphical representation of the main parameters of the DBP-type burst pacing pattern. Pulse width: the duration of a single electrical pulse. In this case, we used Delayed Biphasic Pulse (DBP), which consisted of three consecutive distinct periods: an initial 100 μs stimulation period, an intermediate 100 μs interphase delay phase and a final reversal phase 100 μs stimulation period. So, a total DBP duration was 300 μs. The time between each of these pulses or Inter-Pulse Interval (IPI) was 50 ms. The number of pulses in a train, their duration and the IPI determined the intra-train frequency (20 Hz). Total duration of each train was 0.2515 s. Thus, 5 pulses were applied every quarter of a second, which means a frequency of around 20 Hz. The Inter-Burst Interval (IBI) defined as the time that passes between one train and the next, was 1 s.

Figure 3

Stimulating protocol sequence. 12 consecutive periods with their respective duration are shown. Time 0, was considered at the beginning of taVNS or sham stimulation. Variables obtained along the periods are shown. Time (t) in minutes. Latency (Lat), Amplitude (A), Reaction time (RT), accuracy (% C) % of target sounds correctly indicated, Th, Threshold; ECG, electrocardiogram.

Figure 4

(A) Reaction time (RT); (B) amplitude; and (C) P300 latency, mean values along successive P300 blocks during active taVNS (dashed line) and sham (continuous line) conditions are represented, with their respective standard error of the mean. Sec: seconds; μV: microvolts; ms: milliseconds;

Figure 5

Wireless taVNS device. Image courtesy of Xana^® Smart Neurostimulation.