External stimulation of the trigeminal nerve causes pupil dilation in healthy volunteers, suggesting locus coeruleus modulation.

BACKGROUND

: External trigeminal nerve stimulation (eTNS) is a non-invasive neuromodulation method being investigated as a treatment for epilepsy, depression, and stress-related disorders. eTNS has already received approval for treating migraines and ADHD in children. While there is evidence that eTNS is clinically beneficial, the underlying mechanisms are poorly understood. The trigeminal nerve gives input to several nuclei in the brainstem, which then activate the locus coeruleus (LC), regulating norepinephrine (NE) levels. LC activation has been shown to cause pupil dilation, while NE is involved in regulating processes such as arousal and memory. Thus, the LC-NE system may be important in eTNS mechanisms.

OBJECTIVE

: We hypothesize that eTNS will cause pupil dilation by activating the LC-NE system. Therefore, we investigated the effect of eTNS on pupil responses in healthy volunteers.

METHOD

: Participants (n=20) underwent three stimulation conditions (eTNS, sham and median nerve stimulation – MNS) while pupil diameter was recorded. MNS was applied as an additional control.

RESULTS

: eTNS and MNS elicited larger pupil responses compared to sham, with eTNS causing the largest pupil dilation. Additionally, the number of pupil dilations was significantly higher after eTNS than after MNS and sham. Latency of pupil responses did not differ between eTNS and MNS, but was significantly later after sham. Response size was associated with baseline pupil diameter.

CONCLUSION

: eTNS causes significantly larger pupil dilation than MNS-control stimulation. This suggests that eTNS modulates the release of NE leading to pupil dilation. Accordingly, the LC-NE system could be a key component in mediating eTNS effects.