Higher pupillary dilation during phasic transcutaneous vagus nerve stimulation (taVNS) and its relevance to the noradrenergic system of the locus coeruleus (LC‐NE)

Abstract Background Transcutaneous auricular vagus nerve stimulation (taVNS) may affect the locus coeruleus‐norepinephrine system (LC‐NE system) via modulation of the vagus nerve. The LC is our main source of NE in the brainstem and declines with age and is a potential epicentre of tau pathology in Alzheimer´s diseases (AD). Besides the excessive NE release leading to the formation of amyloid plaques, the severity and duration of AD are also related to LC cell death, decreased cortical NE levels, and accelerated tau spread. An increase in NE release in the LC accompanied by reduced inflammatory markers was achieved in animal models using phasic invasive (i)VNS. In humans, phasic taVNS leads to an increase in pupil dilation, which can serve as a proxy for LC activation. Therefore, taVNS may have the potential to increase NE release and thereby impact LC function and related links to tau pathology. Method Twenty‐four subjects (50% women; 22.96 +/‐ 2.24 years) received time‐synchronous phasic taVNS during a fixation task (∼ 18min) while recording pupillary dilation changes, which allowed systematic testing of phasic taVNS (3 sec) with low (3 mA) and high (5 mA) intensities and low (10 Hz) and high (25 Hz) frequencies at constant pulse width (250 µs). Result During on stimulation pupil dilation was higher during real (0.18±0.03) as compared to sham (0.09±0.03) stimulation (χ 2 = 10.29, p = 0.001) (see Fig. 1). Likewise higher (0.21±0.03) compared to lower (0.06±0.03) intensity (χ 2 = 23.02, p < 0.001) led to higher pupil dilation, while there was no significant difference between higher (0.13±0.03) and lower (0.14±0.03) frequencies (χ 2 = 0.11, p = 0.74). Conclusion Systematic testing of different frequencies and intensities, while keeping the pulse width constant, showed that phasic real taVNS and higher intensity lead to higher pupillary dilation, which is consistent with animal and human studies. Furthermore, the results suggest that the influence of intensity on pupil dilation might be stronger than that of frequency. The increased pupillary dilation during phasic taVNS could be an indication of LC involvement, however, more detailed studies e.g., functional magnetic resonance imaging (fMRI) during taVNS are needed to confirm this association.