Oxytocin, brain physiology, and functional connectivity: A review of intranasal oxytocin fMRI studies
Abstract
In recent years the neuropeptide oxytocin (OT) has become one of the most studied peptides of the human neuroendocrine system. Research has shown widespread behavioural effects and numerous potential therapeutic benefits. However, little is known about how OT triggers these effects in the brain. Here, we discuss some of the physiological properties of OT in the human brain including the long half-life of neuropeptides, the diffuse projections of OT throughout the brain and interactions with other systems such as the dopaminergic system. These properties indicate that OT acts without clear spatial and temporal specificity. Therefore, it is likely to have widespread effects on the brain's intrinsic functioning. Additionally, we review studies that have used functional magnetic resonance imaging (fMRI) concurrently with OT administration. These studies reveal a specific set of 'social' brain regions that are likely to be the strongest targets for OT's potential to influence human behaviour. On the basis of the fMRI literature and the physiological properties of the neuropeptide, we argue that OT has the potential to not only modulate activity in a set of specific brain regions, but also the functional connectivity between these regions. In light of the increasing knowledge of the behavioural effects of OT in humans, studies of the effects of OT administration on brain function can contribute to our understanding of the neural networks in the social brain.
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Previous oxytocin studies are male biased and often constrained by task-based inferences.
“Previous oxytocin studies are male biased and often constrained by task-based inferences.”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [9]
The widespread effects of oxytocin on complex human social behavior may be due to distributed influence at a neural circuit level.
“We have theorized that the widespread effects of oxytocin on complex human social behavior may be due to distributed influence at a neural circuit level.9”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [9]
fMRI techniques require study subjects to be restrained during examination, rendering them impractical for examining natural triggers or effects of oxytocin on animals and humans when engaged in contexts representative of natural social and environmental life.
“fMRI techniques are also not yet at a point where study subjects can be anything other than restrained during the examination (e.g., Bethlehem et al., 2012; Rilling et al., 2012), rendering them impractical for examining natural triggers or effects of oxytocin on animals and humans when engaged in contexts representative of natural social and environmental life.”
From Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: a review (2014) · cites this paper as Bethlehem et al., 2012
The hypothesis that central OTR activation modulates correlated activity across distributed brain networks is consistent with continually emerging data from experiments in primates.
“The hypothesis that central OTR activation modulates correlated activity across distributed brain networks is consistent with continually emerging data from experiments in primates.”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as Bethlehem et al., 2013
Intranasal OT administration modulates correlated fluctuations in BOLD responses across limbic, striatal, cortical, and/or brainstem nuclei during a variety of social contexts in rhesus macaques and humans.
“For example, fMRI experiments in both rhesus macaques and humans have found that intranasal OT administration modulates correlated fluctuations in BOLD responses across limbic, striatal, cortical, and/or brainstem nuclei during a variety of social contexts (Bethlehem et al., 2013; Gorka et al., 2015; Kirsch et al., 2005; Liu et al., 2015; Riem et al., 2012; Rilling et al., 2012).”
From Oxytocin receptors modulate a social salience neural network in male prairie voles (2017) · cites this paper as Bethlehem et al., 2013
OT reduces anxiety, fear, and stress, in part by dampening amygdala activity.
“there are increasing evidence for the role of OT in reducing anxiety, fear, and stress, in part by dampening amygdala activity”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Bethlehem et al. 2013
A larger neural network that goes beyond the amygdala likely underlies the effect of OT on social cognition.
“There was no significant relationship between anger ratings and amygdala activity, which indicates that a larger neural network that goes beyond the amyg-dala likely underlies the effect of OT on social cognition (Bethlehem et al., 2013).”
From 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 (2016) · cites this paper as Bethlehem et al., 2013
Despite the small increases in CSF OXT levels after intranasal administration, intranasal OXT has profound and widespread effects on several features of social living.
“Despite the small increases in CSF OXT levels after intranasal administration, intranasal OXT has profound and widespread effects on several features of social living (Bethlehem et al., 2013).”
From Marmosets treated with oxytocin are more socially attractive to their long-term mate (2015) · cites this paper as Bethlehem et al., 2013
It is predicted that intranasal OXT crosses the BBB via the olfactory bulb and the maxillary branch of the trigeminal nerve.
“While it is predicted that intranasal OXT crosses the BBB via the olfactory bulb and the maxillary branch of the trigeminal nerve (Macdonald and Macdonald, 2010; Bethlehem et al., 2013)”
From Marmosets treated with oxytocin are more socially attractive to their long-term mate (2015) · cites this paper as Bethlehem et al., 2013
Peptides administered intranasally are quickly absorbed into the bloodstream via the nasal passage and appear to bypass the blood-brain barrier to access the central nervous system via the olfactory bulb and the maxillary branch of the trigeminal nerve.
“Peptides administered intranasally are quickly absorbed into the bloodstream via the nasal passage, and appear to bypass the blood-brain barrier (BBB) to access the central nervous system (CNS) via the olfactory bulb and the maxillary branch of the trigeminal nerve (MacDonald and MacDonald, 2010; Bethlehem et al., 2013).”
From Oxytocin facilitates fidelity in well-established marmoset pairs by reducing sociosexual behavior toward opposite-sex strangers (2014) · cites this paper as Bethlehem et al., 2013
OXT's established role in promoting affiliative behavior and social bonds is more consistent with it acting to decrease self-interest and to increase interest in others.
“Indeed, OXT's established role in promoting affiliative behavior and social bonds [Bartz et al., 2011;Bethlehem et al., 2013;Guastella and MacLeod, 2012;Striepens et al., 2011] would seem more consistent with it acting to decrease self-interest and to increase interest in others.”
From Oxytocin blurs the self-other distinction during trait judgments and reduces medial prefrontal cortex responses: Oxytocin Blurs Self-Other Distinction (2016) · cites this paper as Bethlehem et al., 2013
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References 96 · Cited by 285
- Authors
- Bethlehem, R. A. I., van Honk, J., Auyeung, B., & Baron-Cohen, S.
- Affiliations
- Utrecht University (NL)
- Corresponding author
- Bethlehem, Richard A.I.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 38
- Issue
- 7
- Pages
- 962-974
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2025822303
- Cited by
- 285
- References
- 96
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 6 · 2023: 16 · 2022: 10 · 2021: 12 · 2020: 19 · 2019: 25 · 2018: 31 · 2017: 39 · 2016: 32 · 2015: 34 · 2014: 22 · 2013: 15
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin, intranasal administration, functional connectivity, social brain, dopaminergic system, brain regions, artificial neural networks, social behavior, neuroendocrine system
- MeSH terms
- Administration, Intranasal, Brain, Humans, Magnetic Resonance Imaging, Nerve Net, Oxytocin, Functional Neuroimaging
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