Article | Published:

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Davis MC, Lee J, Horan WP, Clarke AD, McGee MR, Green MF, et al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res. 2013;147:393–7.

  2. 2.

    Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves “Mind-Reading” in humans. Biol Psychiatry. 2007b;61:731–3.

  3. 3.

    Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, et al. Intranasal Oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010;67:692–4.

  4. 4.

    Guastella AJ, Mitchell PB, Mathews F. Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry. 2008b;64:256–8.

  5. 5.

    Guastella AJ, Mitchell PB, Dadds MR. Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry. 2008a;63:3–5.

  6. 6.

    Yatawara C, Einfeld S, Hickie I, Davenport T, Guastella A. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry. 2016;21:1225–31.

  7. 7.

    Quintana DS, Guastella AJ, Westlye LT, Andreassen OA. The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders. Mol Psychiatry. 2016a;21:29–38.

  8. 8.

    Alvares GA, Quintana DS, Whitehouse AJ. Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder. Autism Res. 2017;10:25–41.

  9. 9.

    Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005;435:673–6.

  10. 10.

    MacDonald K, MacDonald TM. The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry. 2010;18:1–21.

  11. 11.

    Striepens N, Kendrick KM, Maier W, Hurlemann R. Prosocial effects of oxytocin and clinical evidence for its therapeutic potential. Front Neuroendocrinol. 2011;32:426–50.

  12. 12.

    Coghlan A. ‘Cuddle chemical’eases symptoms of schizophrenia. New Sci. 2010;207:10.

  13. 13.

    De Dreu CKW, Greer LL, Van Kleef GA, Shalvi S, Handgraaf MJJ. Oxytocin promotes human ethnocentrism. Proc Natl Acad Sci. 2011;108:1262–6.

  14. 14.

    Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y. Intranasal administration of oxytocin increases envy and schadenfreude (gloating). Biol Psychiatry. 2009;66:864–70.

  15. 15.

    Shamay-Tsoory SG, Abu-Akel A. The social salience hypothesis of oxytocin. Biol Psychiatry. 2016;79:194–202.

  16. 16.

    Kemp AH, Guastella AJ. The role of oxytocin in human affect a novel hypothesis. Curr Dir Psychol Sci. 2011;20:222–31.

  17. 17.

    Carver CS, Harmon-Jones E. Anger is an approach-related affect: evidence and implications. Psychol Bull. 2009;135:183.

  18. 18.

    Prehn K, Heekeren HR, Van der Meer E. Influence of affective significance on different levels of processing using pupil dilation in an analogical reasoning task. Int J Psychophysiol. 2011;79:236–43.

  19. 19.

    Bradley MM, Miccoli L, Escrig MA, Lang PJ. The pupil as a measure of emotional arousal and autonomic activation. Psychophysiology. 2008;45:602–7.

  20. 20.

    Alnaes D, Sneve MH, Espeseth T, Endestad T, van de Pavert SHP, Laeng B. Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus. J Vis. 2014;14:1–1.

  21. 21.

    Karatekin C, Couperus JW, Marcus DJ. Attention allocation in the dual‐task paradigm as measured through behavioral and psychophysiological responses. Psychophysiology. 2004;41:175–85.

  22. 22.

    Beatty J. Task-evoked pupillary responses, processing load, and the structure of processing resources. Psychol Bull. 1982;91:276.

  23. 23.

    Chatham CH, Frank MJ, Munakata Y. Pupillometric and behavioral markers of a developmental shift in the temporal dynamics of cognitive control. Proc Natl Acad Sci. 2009;106:5529–33.

  24. 24.

    Leknes S, Wessberg J, Ellingsen DM, Chelnokova O, Olausson H, Laeng B. Oxytocin enhances pupil dilation and sensitivity to ‘hidden’ emotional expressions. Soc Cogn Affect Neurosci. 2012;8:741–9.

  25. 25.

    Prehn K, Kazzer P, Lischke A, Heinrichs M, Herpertz SC, Domes G. Effects of intranasal oxytocin on pupil dilation indicate increased salience of socioaffective stimuli. Psychophysiology. 2013;50:528–37.

  26. 26.

    Sansone GR, Gerdes CA, Steinman JL, Winslow JT, Ottenweller JE, Komisaruk BR, et al. Vaginocervical stimulation releases oxytocin within the spinal cord in rats. Neuroendocrinology. 2002;75:306–15.

  27. 27.

    Sansone GR, Komisaruk BR. Evidence that oxytocin is an endogenous stimulator of autonomic sympathetic preganglionics: the pupillary dilatation response to vaginocervical stimulation in the rat. Brain Res. 2001;898:265–71.

  28. 28.

    Domes G, Heinrichs M, Gläscher J, Büchel C, Braus DF, Herpertz SC. Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry. 2007a;62:1187–90.

  29. 29.

    Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M, et al. Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology. 2010;35:2403–13.

  30. 30.

    Petrovic P, Kalisch R, Singer T, Dolan RJ. Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J Neurosci. 2008;28:6607–15.

  31. 31.

    Quintana DS, Westlye LT, Alnæs D, Rustan Ø, Kaufmann T, Smerud K, et al. Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial. Psychoneuroendocrinology. 2016b;69:180–8.

  32. 32.

    Ousdal O, Jensen J, Server A, Hariri A, Nakstad P, Andreassen O. The human amygdala is involved in general behavioral relevance detection: evidence from an event-related functional magnetic resonance imaging Go-NoGo task. Neuroscience. 2008;156:450–5.

  33. 33.

    Ebitz RB, Platt MM. An evolutionary perspective on the behavioral consequences of exogenous oxytocin application. Front Behav Neurosci. 2014;7:225.

  34. 34.

    Koikegami H, Yoshida K. Pupillary dilatation induced by stimulation of amygdaloid nuclei. Psychiatry Clin Neurosci. 1953;7:109–26.

  35. 35.

    Ursin H, Kaada BR. Functional localization within the amygdaloid complex in the cat. Electroencephalogr Clin Neurophysiol. 1960;12:1–20.

  36. 36.

    Horowitz J, Sears M. Neurohypophyseal peptides and the eye: use of synthetic analogs in analyzing effects on the pupil. Graefes Arch Clin Exp Ophthalmol. 1983;220:253–6.

  37. 37.

    Somppi S, Törnqvist H, Topál J, Koskela A, Hänninen L, Krause CM, et al. Nasal oxytocin treatment biases dogs’ visual attention and emotional response toward positive human facial expressions. Front Psychol. 2017;8:1854.

  38. 38.

    Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry. 2016;79:243–50.

  39. 39.

    Striepens N, Kendrick KM, Hanking V, Landgraf R, Wüllner U, Maier W, et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep. 2013;3:3440.

  40. 40.

    Quintana D, Westlye L, Hope S, Nærland T, Elvsåshagen T, Dørum E, et al. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl Psychiatry. 2017;7:e1136.

  41. 41.

    Quintana DS, Westlye LT, Rustan ØG, Tesli N, Poppy CL, Smevik H, et al. Low dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized 4-way crossover trial with nasal cavity dimension assessment. Transl Psychiatry. 2015b;5:1–9.

  42. 42.

    Wechsler D. Weschsler abbreviated scale of intelligence. San Antonio, TX: Psychological Corporation; 1999.

  43. 43.

    Lecrubier Y, Sheehan D, Weiller E, Amorim P, Bonora I, Harnett Sheehan K, et al. The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. Eur Psychiatry. 1997;12:224–31.

  44. 44.

    Guastella AJ, Hickie IB, McGuinness MM, Otis M, Woods EA, Disinger HM, et al. Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology. 2013;38:612–25.

  45. 45.

    Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res. 2012;3:42–62.

  46. 46.

    Djupesland PG, Mahmoud RA, Messina JC. Accessing the brain: the nose may know the way. J Cereb Blood Flow . 2013;33:793–4.

  47. 47.

    Cole P. The four components of the nasal valve. Am J Rhinol. 2003;17:107–10.

  48. 48.

    Lundqvist D, Flykt A, Öhman A. The Karolinska directed emotional faces (KDEF). CD ROM from Department of Clinical Neuroscience, Psychology section, Karolinska Institutet: Stockholm. 1998;91–630.

  49. 49.

    Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002;33:341–55.

  50. 50.

    Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825–41.

  51. 51.

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23:S208–19.

  52. 52.

    Smith SM, Brady JM. SUSAN—A new approach to low level image processing. Int J Comput Vision. 1997;23:45–78.

  53. 53.

    Greve DN, Fischl B. Accurate and robust brain image alignment using boundary-based registration. Neuroimage. 2009;48:63–72.

  54. 54.

    Woolrich MW, Ripley BD, Brady M, Smith SM. Temporal autocorrelation in univariate linear modeling of FMRI data. Neuroimage. 2001;14:1370–86.

  55. 55.

    R Development Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2014.

  56. 56.

    Royall R. Statistical evidence: a likelihood paradigm. New York, USA: Routledge; 2017.

  57. 57.

    Quintana DS, Williams DR. Bayesian alternatives for common null-hypothesis significance tests in psychiatry: A non-technical guide using JASP. BMC Psychiatry. 2018;18:178.

  58. 58.

    Wagenmakers E-J, Marsman M, Jamil T, Ly A, Verhagen J, Love J, et al. Bayesian inference for psychology. Part I: Theoretical advantages and practical ramifications. Psychon Bull Rev. 2018;25:35–57.

  59. 59.

    Wetzels R, Wagenmakers E-J. A default Bayesian hypothesis test for correlations and partial correlations. Psychon Bull Rev. 2012;19:1057–64.

  60. 60.

    Jeffreys H. The theory of probability. Oxford, UK: Oxford University Press; 1961.

  61. 61.

    Dienes Z. Using Bayes to get the most out of non-significant results. Front Psychol. 2014;5:1–17.

  62. 62.

    Quintana DS, Alvares GA, Hickie IB, Guastella AJ. Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev. 2015a;49:182–92.

  63. 63.

    Barrett LF. Are emotions natural kinds? Perspect Psychol Sci. 2006;1:28–58.

  64. 64.

    Harari-Dahan O, Bernstein A. A general approach-avoidance hypothesis of oxytocin: accounting for social and non-social effects of oxytocin. Neurosci Biobehav Rev. 2014;47:506–19.

  65. 65.

    Bethlehem RAI, van Honk J, Auyeung B, Baron-Cohen S. Oxytocin, brain physiology, and functional connectivity: A review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology. 2013;38:962–74.

  66. 66.

    Angrilli A, Mauri A, Palomba D, Flor H, Birbaumer N, Sartori G, et al. Startle reflex and emotion modulation impairment after a right amygdala lesion. Brain. 1996;119:1991–2004.

  67. 67.

    Phelps EA, O’Connor KJ, Gatenby JC, Gore JC, Grillon C, Davis M. Activation of the left amygdala to a cognitive representation of fear. Nat Neurosci. 2001;4:437.

  68. 68.

    Wright CI, Fischer H, Whalen PJ, McInerney SC, Shin LM, Rauch SL. Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli. Neuroreport. 2001;12:379–83.

  69. 69.

    Samson WK. Oxytocin redux. Am J Physiol-Regulat Integrat Comp Physiol: ajpregu. 00307.02016; 2016.

  70. 70.

    Stoehr JD, Cramer CP, North WG. Oxytocin and vasopressin hexapeptide fragments have opposing influences on conditioned freezing behavior. Psychoneuroendocrinology. 1992;17:267–71.

  71. 71.

    Liberzon I, Trujillo KA, Akil H, Young EA. Motivational properties of oxytocin in the conditioned place preference paradigm. Neuropsychopharmacology. 1997;17:353–9.

  72. 72.

    Yang J, Yang Y, Chen J-M, Liu W-Y, Wang C-H, Lin B-C. Central oxytocin enhances antinociception in the rat. Peptides. 2007;28:1113–9.

  73. 73.

    Singer T, Snozzi R, Bird G, Petrovic P, Silani G, Heinrichs M, et al. Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain. Emotion. 2008;8:781.

  74. 74.

    Gross J, De Dreu CK. Oxytocin conditions trait-based rule adherence. Soc Cogn Affect Neurosci. 2017;12:427–35. 

  75. 75.

    Gilzenrat MS, Nieuwenhuis S, Jepma M, Cohen JD. Pupil diameter tracks changes in control state predicted by the adaptive gain theory of locus coeruleus function. Cogn Affect Behav Neurosci. 2010;10:252–69.

  76. 76.

    Walum H, Waldman ID, Young LJ. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatry. 2016;79:251–7.

  77. 77.

    Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M, et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology. 2010;35:83–93.

  78. 78.

    Lischke A, Gamer M, Berger C, Grossmann A, Hauenstein K, Heinrichs M, et al. Oxytocin increases amygdala reactivity to threatening scenes in females. Psychoneuroendocrinology. 2012;37:1431–8.

  79. 79.

    Ousdal OT, Reckless GE, Server A, Andreassen OA, Jensen J. Effect of relevance on amygdala activation and association with the ventral striatum. Neuroimage. 2012;62:95–101.

  80. 80.

    Sander D, Grafman J, Zalla T. The human amygdala: an evolved system for relevance detection. Rev Neurosci. 2003;14:303–16.

Download references

Acknowledgements

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.

Author information

Correspondence to Ole A. Andreassen.

Ethics declarations

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Author Approvals

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1
Fig. 2