Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context
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This manuscript contains fundamental work on hormonal and neurobiological processing of social experience in humans. It sheds compelling new light on potential mechanisms underlying how humans place social experiences in context, demonstrating how oxytocin and cortisol might interact to modulate higher-level processing and contextualizing of familiar vs. stranger encounters.
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Abstract
Both oxytocin (OT) and touch are key mediators of social attachment. In rodents, tactile stimulation elicits the endogenous release of OT, potentially facilitating attachment and other forms of prosocial behavior, yet the relationship between endogenous OT and neural modulation remains unexplored in humans. Using a serial sampling of plasma hormone levels during functional neuroimaging across two successive social interactions, we show that contextual circumstances of social touch influence not only current hormonal and brain responses but also later responses. Namely, touch from a male to his female romantic partner enhanced her subsequent OT release for touch from an unfamiliar stranger, yet females’ OT responses to partner touch were dampened following stranger touch. Hypothalamus and dorsal raphe activation reflected plasma OT changes during the initial social interaction. In the subsequent interaction, precuneus and parietal-temporal cortex pathways tracked time- and context-dependent variables in an OT-dependent manner. This OT-dependent cortical modulation included a region of the medial prefrontal cortex that also covaried with plasma cortisol, suggesting an influence on stress responses. These findings demonstrate that modulation between hormones and the brain during human social interactions can flexibly adapt to features of social context over time.
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Author Response
Reviewer #1 (Public Review):
The authors sought to identify the relationship between social touch experiences and the endogenous release of oxytocin and cortisol. Female participants who received a touch from their romantic partner before a stranger exhibited a blunted hormonal response compared to when the stranger was the first toucher, suggesting that social touch history and context influence subsequent touch experiences. Concurrent fMRI recordings identified key brain networks whose activity corresponded to hormonal changes and self-report.
The strengths of the manuscript are in the power achieved by collecting multi-faceted metrics: plasma hormones across time, BOLD signal, and self-report. The experiment was cleverly designed and nicely counterbalanced. Data analysis was thorough and statistically …
Author Response
Reviewer #1 (Public Review):
The authors sought to identify the relationship between social touch experiences and the endogenous release of oxytocin and cortisol. Female participants who received a touch from their romantic partner before a stranger exhibited a blunted hormonal response compared to when the stranger was the first toucher, suggesting that social touch history and context influence subsequent touch experiences. Concurrent fMRI recordings identified key brain networks whose activity corresponded to hormonal changes and self-report.
The strengths of the manuscript are in the power achieved by collecting multi-faceted metrics: plasma hormones across time, BOLD signal, and self-report. The experiment was cleverly designed and nicely counterbalanced. Data analysis was thorough and statistically sophisticated, making the findings and conclusions convincing.
This work sheds new light on potential mechanisms underlying how humans place social experiences in context, demonstrating how oxytocin and cortisol might interact to modulate higher-level processing and contextualizing of familiar vs. stranger encounters.
Thank you very much for this generous evaluation of the study.
Reviewer #2 (Public Review):
To test how oxytocin impacts the brain and the psychological, neural, and hormonal response to touch, the authors tested human females during two counterbalanced fMRI sessions wherein females were stroked on the arm or the palm, by a real-world romantic partner or a stranger, while blood levels of oxytocin and cortisol were collected at multiple time points.
This combination of measures, and the number of hypotheses that could be tested with them, is remarkable - virtually unheard of. This impressive, difficult, and more ecological design than is typical for the field is a major strength of the study, which allowed the authors to test many important hypotheses concurrently and to show contextual effects that could not otherwise be observed. The only potential drawback perhaps is that with such a large design, including many measures, the authors produced so many significant interactions and results that it could be hard for the casual reader to appreciate the importance of each.
The authors supported their hypothesis that oxytocin effects are context-sensitive, as they found a key interaction wherein experiencing the partner first increased oxytocin for the partner relative to when they came first the OT levels were low but then increased if they were preceded by the partner (excepting one timepoint). Cortisol responses (which reflect hormonal stress) were also higher when the stranger came first than when he was preceded by the partner). In addition, touch was experienced more positively on the arm than on the palm, supporting the role of c-fibers in conveying specifically felt responses to warm, tender touch.
These data indicate significant context sensitivity with real-world implications. For example, experiencing warm touch on the arm can make us more receptive to other people in subsequent encounters. Conversely, when strangers try to approach and get close to us "out of the blue" people experience this as stressful, which reduces the pleasantness of the interaction and may reduce trust in the moment...perhaps even subsequently.
This research is critical to the basic science of neurohormonal modulation, given that most of this research occurs in rodents or in simplified studies in humans, usually through intranasal oxytocin administration with unclear impacts on circulating levels in the brain and blood. Oxytocin in particular has suffered from oversimplification as the "love drug" - wherein people assume that it always renders people more loving and trusting. The reality is more complex, as they showed, and these demonstrations are needed to clarify for the field and the public that neurohormones adaptively shift with the context, location, and identity of the social partner in an adaptive way. These results also help us understand the many null effects of oxytocin on trusting strangers in human neuroeconomic studies. In a modern world that is characterized by significant loneliness, interactions with strangers and outsiders, and touch-free digital interactions, our ability to understand the human need for genuine social contact and how it impacts our response to outsiders (welcomed in versus a source of stress) is critical to human health and the wellbeing of individuals and society.
Thank you very much for this nice summary of the study and its implications.
As you pointed out, the design was ambitious and involved a broad range of measures and levels of hypothesis-testing. This presented challenges in reporting the results. In this paper we have tried to provide interpretation of the basic results, such as that social encounters (even in the scanner environment) are sufficient to evoke changes in endogenous oxytocin levels over the course of the experimental session, and that various interactions arise due to an influence of contextual factors such as the familiarity of the person and the recent social interaction history. For the more complex results, such as the nature of relationships between BOLD signal change and the degree of change in individuals’ plasma oxytocin levels, we have tried to outline provisional interpretations.
We hope that the picture will gradually become more filled-in by work from ours and others’ labs—maybe these findings and interpretations will look very different in a few years’ time. We consider this study a starting point for future research into the dynamics and function of human endogenous oxytocin.
Reviewer #3 (Public Review):
In an ambitious, multimodal effort, Handlin, Novembre et al. investigated how the endogenous release of oxytocin and cortisol as well as functional brain activity are modulated by social touch under different contextual circumstances (e.g. palm vs. arm touch, stranger vs. partner touch) in neurotypical female participants.
Using serial sampling of plasma hormone levels in blood during concurrent functional MRI neuroimaging, the authors show that the familiarity of the interactant during social touch not only impacts current hormonal levels but also subsequent hormonal responses in a successive touch interaction. Specifically, endogenous oxytocin levels are significantly heightened (and cortisol levels dampened) during touch from a romantic partner compared to touch from an unfamiliar stranger, at least during the first touch interaction. During the second touch interaction, however, oxytocin levels plummeted when being touched by a stranger following partner touch (although a recovery was made), whereas the normally elevated oxytocin responses to partner touch were dampened when following stranger touch. These results are paralleled by similar familiarity- and order-related effects in neural regions involving the hypothalamus, dorsal raphe, and precuneus.
However, an important distinction to be made is that, although a significant main effect of familiarity was encountered in several brain regions when taking peak plasma oxytocin levels into account, subsequent t-tests showed no activation differences in the BOLD response between partner and stranger touch within the same subjects. Significant interaction maps seem thus mainly driven by between-subject effects at the different time points, which is arguably due to differences between subjects in their initial calibration of neural/hormonal responses, and not session-to-session changes within the same subjects.
A similar comment can be made for the reported covariance between (changes in) maximal oxytocin levels and (changes in) BOLD activity for the hypothalamus.
In an effort to delineate the complex cascade of responses induced by afferent tactile stimulation, the authors report an exploratory regression analysis to identify BOLD activation that precedes the pattern of serial plasma changes in oxytocin levels (looking backwards; i.e. implying changes in brain activation drive changes in hormonal plasma levels). Although the authors are appropriately modest about the significance of the encountered effects, additional control analyses could bring further clarifications about the temporal (e.g., can similar covariations also be found when looking forward) and hormonal specificity (e.g. can similar findings be found for cortisol-variations) of the encountered results. Nevertheless, despite the 'dynamically' covarying relationships between BOLD and max plasma oxytocin levels (i.e. dynamic as in the sense across conditions, not across timepoints), claims about the directionality of this effect (i.e. 'hormonal neuromodulation' vs. 'neural modulation of hormonal levels') remain speculative.
A particular strength of this study is the employment of a "female-first" strategy since experimental data concerning endogenous oxytocin levels in women are sparse. Adequate control analyses are reported to take potential variability due to differences in contraception and phase in the hormonal cycle into account.
Thank you for your attentive reading of the study, and for raising several very important points.
You are right that the BOLD activation maps showing interactions between the change in OT levels and other factors (familiarity, order) reflect differences between subjects in the two runs of the experiment. The effect of familiarity emerged from the full model for the whole group (all participants, whether they started with partner or stranger), as an interaction between the partner/stranger factor and the change in OT. As you point out, this reflects interindividual-level covariation between OT changes and BOLD changes. For example, individuals showing greater OT increase were also more likely to show higher BOLD in certain clusters during partner compared to stranger touch. Similarly, the partner vs stranger contrast showing hypothalamus and Raphe reflects greater OT-BOLD covariance in the stranger first compared to the partner fist groups: in the stranger first group, BOLD was greater the lower the mean OT was across individuals.
The t-tests with OT as covariate further indicate that the interaction was driven by group differences in the second run. As you point out, within groups (partner or stranger first), there was no significant change in the OT-BOLD covariance from the first to the second run, though these relationships were different between groups. We agree with you that this lack of difference in within-group OT-BOLD covariance from the first to the second run is likely because responses in the first run biased responses in the second run—but in different ways depending on whether the partner or the stranger was presented first. Both groups did show a meaningful correlation in mean OT levels between the first and the second run (we have now included this information in the paper).
In general, we agree that it is very important to make clear that, as in many covariation/correlation effects in fMRI studies, the effects are driven by interindividual differences for a given covariant relationship, rather than the within-subject BOLD response increasing or decreasing.
We also agree that it is not possible to determine the direction of modulation from these results. The creation of the temporal OT regressor as “backward-looking” was informed by evidence from animal models for central-to-peripheral effects from hypothalamus to pituitary to bloodstream. We assumed this directionality in the analysis. Given the exploratory nature of this regressor, “looking forward” from temporal OT sample patterns to BOLD patterns with different time intervals would be an equally valid approach. It could reveal activation related to any systematic influence of peripheral OT levels on cortical responses. As the premise of the temporal OT regressor analysis in the present study was any assumed central-to-peripheral modulation, we have kept this as the focus but will explore any specific peripheral-to-central covariation in future work.
We believe that the full causal picture is likely to involve bidirectional modulation: a modulatory loop (or even loops) in which peripheral and central changes influence one another. Unfortunately, it is difficult to address such temporal feedback with the poor time resolution of fMRI.
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eLife assessment
This manuscript contains fundamental work on hormonal and neurobiological processing of social experience in humans. It sheds compelling new light on potential mechanisms underlying how humans place social experiences in context, demonstrating how oxytocin and cortisol might interact to modulate higher-level processing and contextualizing of familiar vs. stranger encounters.
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Reviewer #1 (Public Review):
The authors sought to identify the relationship between social touch experiences and the endogenous release of oxytocin and cortisol. Female participants who received a touch from their romantic partner before a stranger exhibited a blunted hormonal response compared to when the stranger was the first toucher, suggesting that social touch history and context influence subsequent touch experiences. Concurrent fMRI recordings identified key brain networks whose activity corresponded to hormonal changes and self-report.
The strengths of the manuscript are in the power achieved by collecting multi-faceted metrics: plasma hormones across time, BOLD signal, and self-report. The experiment was cleverly designed and nicely counterbalanced. Data analysis was thorough and statistically sophisticated, making the …
Reviewer #1 (Public Review):
The authors sought to identify the relationship between social touch experiences and the endogenous release of oxytocin and cortisol. Female participants who received a touch from their romantic partner before a stranger exhibited a blunted hormonal response compared to when the stranger was the first toucher, suggesting that social touch history and context influence subsequent touch experiences. Concurrent fMRI recordings identified key brain networks whose activity corresponded to hormonal changes and self-report.
The strengths of the manuscript are in the power achieved by collecting multi-faceted metrics: plasma hormones across time, BOLD signal, and self-report. The experiment was cleverly designed and nicely counterbalanced. Data analysis was thorough and statistically sophisticated, making the findings and conclusions convincing.
This work sheds new light on potential mechanisms underlying how humans place social experiences in context, demonstrating how oxytocin and cortisol might interact to modulate higher-level processing and contextualizing of familiar vs. stranger encounters.
-
Reviewer #2 (Public Review):
To test how oxytocin impacts the brain and the psychological, neural, and hormonal response to touch, the authors tested human females during two counterbalanced fMRI sessions wherein females were stroked on the arm or the palm, by a real-world romantic partner or a stranger, while blood levels of oxytocin and cortisol were collected at multiple time points.
This combination of measures, and the number of hypotheses that could be tested with them, is remarkable - virtually unheard of. This impressive, difficult, and more ecological design than is typical for the field is a major strength of the study, which allowed the authors to test many important hypotheses concurrently and to show contextual effects that could not otherwise be observed. The only potential drawback perhaps is that with such a large …
Reviewer #2 (Public Review):
To test how oxytocin impacts the brain and the psychological, neural, and hormonal response to touch, the authors tested human females during two counterbalanced fMRI sessions wherein females were stroked on the arm or the palm, by a real-world romantic partner or a stranger, while blood levels of oxytocin and cortisol were collected at multiple time points.
This combination of measures, and the number of hypotheses that could be tested with them, is remarkable - virtually unheard of. This impressive, difficult, and more ecological design than is typical for the field is a major strength of the study, which allowed the authors to test many important hypotheses concurrently and to show contextual effects that could not otherwise be observed. The only potential drawback perhaps is that with such a large design, including many measures, the authors produced so many significant interactions and results that it could be hard for the casual reader to appreciate the importance of each.
The authors supported their hypothesis that oxytocin effects are context-sensitive, as they found a key interaction wherein experiencing the partner first increased oxytocin for the partner relative to when they came first the OT levels were low but then increased if they were preceded by the partner (excepting one timepoint). Cortisol responses (which reflect hormonal stress) were also higher when the stranger came first than when he was preceded by the partner). In addition, touch was experienced more positively on the arm than on the palm, supporting the role of c-fibers in conveying specifically felt responses to warm, tender touch.
These data indicate significant context sensitivity with real-world implications. For example, experiencing warm touch on the arm can make us more receptive to other people in subsequent encounters. Conversely, when strangers try to approach and get close to us "out of the blue" people experience this as stressful, which reduces the pleasantness of the interaction and may reduce trust in the moment...perhaps even subsequently.
This research is critical to the basic science of neurohormonal modulation, given that most of this research occurs in rodents or in simplified studies in humans, usually through intranasal oxytocin administration with unclear impacts on circulating levels in the brain and blood. Oxytocin in particular has suffered from oversimplification as the "love drug" - wherein people assume that it always renders people more loving and trusting. The reality is more complex, as they showed, and these demonstrations are needed to clarify for the field and the public that neurohormones adaptively shift with the context, location, and identity of the social partner in an adaptive way. These results also help us understand the many null effects of oxytocin on trusting strangers in human neuroeconomic studies. In a modern world that is characterized by significant loneliness, interactions with strangers and outsiders, and touch-free digital interactions, our ability to understand the human need for genuine social contact and how it impacts our response to outsiders (welcomed in versus a source of stress) is critical to human health and the wellbeing of individuals and society.
-
Reviewer #3 (Public Review):
In an ambitious, multimodal effort, Handlin, Novembre et al. investigated how the endogenous release of oxytocin and cortisol as well as functional brain activity are modulated by social touch under different contextual circumstances (e.g. palm vs. arm touch, stranger vs. partner touch) in neurotypical female participants.
Using serial sampling of plasma hormone levels in blood during concurrent functional MRI neuroimaging, the authors show that the familiarity of the interactant during social touch not only impacts current hormonal levels but also subsequent hormonal responses in a successive touch interaction. Specifically, endogenous oxytocin levels are significantly heightened (and cortisol levels dampened) during touch from a romantic partner compared to touch from an unfamiliar stranger, at least …
Reviewer #3 (Public Review):
In an ambitious, multimodal effort, Handlin, Novembre et al. investigated how the endogenous release of oxytocin and cortisol as well as functional brain activity are modulated by social touch under different contextual circumstances (e.g. palm vs. arm touch, stranger vs. partner touch) in neurotypical female participants.
Using serial sampling of plasma hormone levels in blood during concurrent functional MRI neuroimaging, the authors show that the familiarity of the interactant during social touch not only impacts current hormonal levels but also subsequent hormonal responses in a successive touch interaction. Specifically, endogenous oxytocin levels are significantly heightened (and cortisol levels dampened) during touch from a romantic partner compared to touch from an unfamiliar stranger, at least during the first touch interaction. During the second touch interaction, however, oxytocin levels plummeted when being touched by a stranger following partner touch (although a recovery was made), whereas the normally elevated oxytocin responses to partner touch were dampened when following stranger touch. These results are paralleled by similar familiarity- and order-related effects in neural regions involving the hypothalamus, dorsal raphe, and precuneus.
However, an important distinction to be made is that, although a significant main effect of familiarity was encountered in several brain regions when taking peak plasma oxytocin levels into account, subsequent t-tests showed no activation differences in the BOLD response between partner and stranger touch within the same subjects. Significant interaction maps seem thus mainly driven by between-subject effects at the different time points, which is arguably due to differences between subjects in their initial calibration of neural/hormonal responses, and not session-to-session changes within the same subjects.
A similar comment can be made for the reported covariance between (changes in) maximal oxytocin levels and (changes in) BOLD activity for the hypothalamus.In an effort to delineate the complex cascade of responses induced by afferent tactile stimulation, the authors report an exploratory regression analysis to identify BOLD activation that precedes the pattern of serial plasma changes in oxytocin levels (looking backwards; i.e. implying changes in brain activation drive changes in hormonal plasma levels). Although the authors are appropriately modest about the significance of the encountered effects, additional control analyses could bring further clarifications about the temporal (e.g., can similar covariations also be found when looking forward) and hormonal specificity (e.g. can similar findings be found for cortisol-variations) of the encountered results. Nevertheless, despite the 'dynamically' covarying relationships between BOLD and max plasma oxytocin levels (i.e. dynamic as in the sense across conditions, not across timepoints), claims about the directionality of this effect (i.e. 'hormonal neuromodulation' vs. 'neural modulation of hormonal levels') remain speculative.
A particular strength of this study is the employment of a "female-first" strategy since experimental data concerning endogenous oxytocin levels in women are sparse. Adequate control analyses are reported to take potential variability due to differences in contraception and phase in the hormonal cycle into account.
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