Low-dose intranasal oxytocin delivered with Breath Powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study

Abstract

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.

“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

“…There is preliminary evidence for dose-dependent effects of oxytocin in both nonhuman 27,28 and human [29][30][31][32][33] species. This evidence was gathered in blood oxygen level-dependent (BOLD)-functional magnetic resonance imaging (fMRI) task-based studies, using paradigms that engage specific neural circuits, such as the amygdala, or measuring specific neurophysiological processes, such as pupil reactivity to emotional faces [29][30][31][32][33] .…”

“…There is preliminary evidence for dose-dependent effects of oxytocin in both nonhuman 27,28 and human [29][30][31][32][33] species. This evidence was gathered in blood oxygen level-dependent (BOLD)-functional magnetic resonance imaging (fMRI) task-based studies, using paradigms that engage specific neural circuits, such as the amygdala, or measuring specific neurophysiological processes, such as pupil reactivity to emotional faces [29][30][31][32][33] . Overall, these studies indicated that lower-to-medium doses (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) of oxytocin may be more efficacious than higher doses, inspiring the current working hypothesis that the intranasal oxytocin dose-response curve follows an inverted-U shape 34 .…”

Transport of oxytocin to the brain after peripheral administration by membrane‐bound or soluble forms of receptors for advanced glycation end‐products

“…OT. 65 These results appear to suggest that OT can travel to the brain via a nose-to-brain route, as well as be transported from the systemic circulation after permeating the nasal mucosal membrane, which contains rich microvessel networks. Therefore, we considered the related question of whether the nasal routes are inhibited in RAGE KO (Ager -/-) male mice with respect to the extent that nasal-specific or via-blood routes can contribute to OT transport from the nasal cavity.…”

The effect of intranasal oxytocin on visual processing and salience of human faces

“…This therapeutic option is appealing, given the relatively mild side effect profile of OT, and the ease of intranasal administration; however, the effect duration is relatively short. Substantial controversy remains about how and how much intranasally administered oxytocin reaches the brain in humans 67 , and the few human studies applying variable doses have yet to produce conclusive results 68 – 70 . The dose applied here (40IU) is the largest dose typically applied in human research.…”