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


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.

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We thank Natalia Tesli, Claire Poppy, Hanne Smevik, Martin Tesli, Line Gundersen, Siren Tønnensen, Martina Lund, Eivind Bakken (NORMENT, KG Jebsen Center for Psychosis Research, Institute of Clinical Medicine, University of Oslo), Marianne Røine, Nils Meland, Claudia Grasnick, and Kristin A. Bakke (Smerud Medical Research International AS) for their contributions. We also thank medical staff from Oslo University Hospital and staff from the Oslo University Hospital Hormone laboratory for their assistance with the study. We are grateful to Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. for their generous donation of the oxytocin used in the study.

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Correspondence to Ole A. Andreassen.

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Funding and disclosure:

This study was supported by the Research Council of Norway and OptiNose AS (Grant no. BIA 219483) and an Excellence Grant for the Novo Nordisk Foundation (NNF16OC0019856). P.G.D. is an employee of OptiNose AS, Oslo, Norway and owns stock and stock options in OptiNose. O.A.A. has received speaker’s honoraria from GSK, Lundbeck, and Otsuka for work not directly relevant to the submitted manuscript. R.A.M. is an employee of OptiNose US, Yardley, PA, USA and owns stock and stock options in OptiNose. K.T.S. is employed by Smerud Medical Research International AS, a CRO receiving fees for clinical trial services from OptiNose AS. The other authors declare no competing interests.

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