Short-term transcutaneous vagus nerve stimulation increases pupil size but does not affect EEG alpha power: a replication

Abstract

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising brain stimulation method for the treatment of pharmaco-resistant epilepsy and depression. Its clinical efficacy is thought to depend on taVNS-induced activation of the locus coeruleus. However, unlike for invasive VNS, there is little evidence for an effect of taVNS on noradrenergic activity. Objective: We attempted to replicate recently published findings by Sharon et al. (2021), showing that short bursts of taVNS transiently increased pupil size and decreased EEG alpha power, two correlates of central noradrenergic activity. Methods: Following the original study, we used a single-blind, sham-controlled, randomized cross-over design. We applied short-term (3.4 s) taVNS in healthy human volunteers (n=29), while collecting resting-state pupil-size and EEG data. To analyze the data, we used scripts provided by Sharon and colleagues. Results: Consistent with Sharon et al. (2021), pupil dilation was significantly larger during taVNS than during sham stimulation (p = .009; Bayes factor supporting the difference = 7.45). However, we failed to replicate the effect of taVNS on EEG alpha power (p = .37); the data were four times more likely under the null hypothesis (BF10 = 0.28). Conclusion: Our findings support the effectiveness of short-term taVNS in inducing transient pupil dilation, a correlate of phasic noradrenergic activity. However, we failed to replicate the recent finding by Sharon et al. (2021) that taVNS attenuates EEG alpha activity. Overall, this study highlights the need for continued research on the neural mechanisms underlying taVNS efficacy and its potential as a treatment option for pharmaco-resistant conditions. It also highlights the need for direct replications of influential taVNS studies.

Non-invasive vagus nerve stimulation and the motivation to work for rewards: a replication

“…Third, in our study, only 8 out of 40 (20%) participants were men, whereas in Neuser et al [1] 34 out of 81 (42%) participants were men. Although this difference could potentially account for the discrepancy between our behavioral results, the limited available evidence suggests that female animals [22] and human participants [35] show larger effects of VNS than males, which is inconsistent with our null finding in a group of mainly female participants.…”

“…Several recent taVNS studies have not managed to replicate the effects of invasive VNS on psychophysiological measures such as pupil size and P300 amplitude, reporting null effects instead [15][16][17][18]34]. In the present work and another replication attempt [35], we find that even results of high-profile taVNS studies can be difficult to replicate. Parametric exploration of tVNS stimulation parameters [36,37] and demanding authors to report internal replications may help this nascent field of inquiry to overcome these challenges.…”

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

“…Additionally, there are several differences between the taVNS parameters used in this and in prior studies that may contribute to apparent differences in the relationship between taVNS intensity and pupil dilation. Nine of the prior 16 taVNS studies that examined effects on pupil size reported testing taVNS intensities that overlapped in part or in whole with the taVNS intensity range in the present study (Capone et al, 2021;D'Agostini et al, 2022D'Agostini et al, , 2023Keute et al, 2019;Lloyd et al, 2023;Pandža et al, 2020;Sharon et al, 2021;Skora et al, 2024;Urbin et al, 2021). Another four studies tested taVNS ranges below the minimum intensity in the present study (Burger, Van der Does, et al, 2020;D'Agostini et al, 2021;McHaney et al, 2023;Warren et al, 2019).…”

“…Location and configuration of the stimulating electrode may also be important. All three experiments in past studies that applied taVNS to the EAM found pupil effects (Capone et al, 2021;Pandža et al, 2020;Urbin et al, 2021), while one of the two experiments that targeted tragus found pupil effects (Villani et al, 2019), and only eight of the 18 experiments in prior studies that targeted the concha found an effect on pupil size (D'Agostini et al, 2023;Lloyd et al, 2023;Sharon et al, 2021;Skora et al, 2024;Urbin et al, 2021;Wienke et al, 2023). This suggests that stimulating the EAM is perhaps more consistently effective in increasing neuromodulatory activity.…”

“…These studies, summarized in Table 1, have targeted three regions of the external ear known to receive vagal innervation: the concha, tragus, and external acoustic meatus (EAM; Butt et al, 2020). Thirteen of the 16 published studies targeted the concha with 200-300μs taVNS pulses delivered at 25-30 Hz (Borges et al, 2021;Burger, Van der Does, et al, 2020;D'Agostini et al, 2021D'Agostini et al, , 2022D'Agostini et al, , 2023Keute et al, 2019;Lloyd et al, 2023;McHaney et al, 2023;Sharon et al, 2021;Skora et al, 2024;Urbin et al, 2021;Warren et al, 2019;Wienke et al, 2023). Of these studies, two also tested parameters that deviated from these ranges: Urbin et al (2021) included 300 Hz taVNS andD'Agostini et al (2023) included a 400 µs pulse-width condition.…”