Little is known about how intranasally administered oxytocin reaches the brain and modulates social behavior and cognition. Pupil dilation is a sensitive index of attentional allocation and effort, and inter-individual variability in pupil diameter during performance of social-cognitive tasks may provide a better assessment of pharmacological effects on the brain than behavioral measures. Here, we leverage the close relationship between pupil and neural activity to inform our understanding of nose-to-brain oxytocin routes and possible dose-response relationships. To this end, we assessed pupil diameter data from a previously reported functional magnetic resonance imaging (fMRI) study under four treatment conditions – including two different doses of intranasal oxytocin using a novel Breath Powered nasal device, intravenous (IV) oxytocin, and placebo – and investigated the association with amygdala activation in response to emotional stimuli. The study used a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. A significant main effect of treatment condition on pupil diameter was observed. Posthoc tests revealed reduced pupil diameter after 8IU intranasal oxytocin compared to placebo, but no significant difference between 8IU intranasal oxytocin and either 24IU intranasal oxytocin or IV oxytocin treatment conditions. Analysis also showed a significant relationship between pupil diameter and right amygdala activation after 8IU intranasal oxytocin. Although there was no significant difference between 8IU intranasal oxytocin and IV oxytocin on right amygdala activity and pupil diameter, the significant difference between 8IU intranasal oxytocin and placebo is consistent with the hypothesis that oxytocin can travel to the brain via a nose-to-brain route.
Quintana, D.S., Westlye, L.T., Alnæs, D., Kaufmann, T., Mahmoud, R.A., Smerud, K.T., Djupesland, P.G., & Andreassen, O.A. (2019). Low dose intranasal oxytocin delivered with Breath Powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study. Neuropsychopharmacology, 44(2),