Endogenous and exogenous oxytocin modulate interpersonal motor resonance in autism: A context-dependent and person-specific approach

Abstract

Understanding and interpreting non-verbal actions are critical components of social cognition, which are often challenging for autistic individuals. Oxytocin, a neuropeptide known to modulate social behavior and enhance the salience of social stimuli, is being explored as a therapeutic option for improving social mirroring. However, its effects are mediated by context- and person-dependent factors. This study examines the impact of a single intranasal dose of oxytocin (24 IU) on interpersonal motor resonance in young adult men with and without autism. Neurophysiological assessments of corticomotor excitability were performed using transcranial magnetic stimulation while participants observed real-time hand movements displayed by an experimenter demonstrating varying social intent (i.e. showing direct vs averted gaze). While no overall effect of oxytocin on interpersonal motor resonance was observed across groups, person-specific factors significantly influenced outcomes. In the autism group, individuals with higher endogenous oxytocin levels exhibited greater motor resonance during action observation. Autistic individuals with heightened social difficulties or avoidant attachment styles showed enhanced motor resonance following oxytocin administration. These findings highlight the nuanced role of both endogenous and exogenous oxytocin in shaping neurophysiological motor resonance and emphasize the importance of individual variability in assessing oxytocin’s therapeutic potential for addressing social challenges in autism.

Lay abstract

This study explores how oxytocin, a hormone that influences social behaviors, affects the ability to interpret and respond to non-verbal cues, particularly in autistic adults. Understanding others’ actions and intentions, often guided by observing body language and eye contact, is a critical part of social interaction. Autistic individuals frequently face challenges in these areas. Using a safe, non-invasive brain stimulation technique, the study measured participants’ brain responses as they observed real-time hand movements paired with the interaction partner’s direct eye contact or averted gaze. Participants included young autistic and non-autistic adult men who received a placebo and a single dose of oxytocin via nasal spray. Results showed no overall differences between the two groups in their brain responses to these movements. However, in the autism group, several factors significantly influenced the effects of oxytocin. Participants with higher natural oxytocin levels or those who reported greater social challenges showed stronger responses after oxytocin administration, particularly when observing hand movements combined with direct gaze. These findings suggest that oxytocin may enhance social understanding in autistic individuals, especially for those experiencing greater difficulties. This highlights the potential of personalized approaches when considering oxytocin as a therapeutic option to improve social interactions.

Keywords

action observation autism spectrum disorder mirror system motor simulation oxytocin transcranial magnetic stimulation

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References

Alvares

G. A.

Quintana

D. S.

Whitehouse

A. J. O.

(2017). Beyond the hype and hope: Critical considerations for intranasal oxytocin research in autism spectrum disorder. Autism Research, 10(1), 25–41. https://doi.org/10.1002/aur.1692

Artman

Reppert

Perlow

Swaminathan

Oddie

Fisher

(1982). Characterization of the daily oxytocin rhythm in primate cerebrospinal fluid. The Journal of Neuroscience, 2(5), 598–603. https://doi.org/10.1523/JNEUROSCI.02-05-00598.1982

Bartz

J. A.

Zaki

Bolger

Ochsner

K. N.

(2011). Social effects of oxytocin in humans: Context and person matter. Trends in Cognitive Sciences, 15, 301–309. https://doi.org/10.1016/j.tics.2011.05.002

Bernaerts

Berra

Wenderoth

Alaerts

(2016). Influence of oxytocin on emotion recognition from body language: A randomized placebo-controlled trial. Psychoneuroendocrinology, 72, 182–189. https://doi.org/10.1016/j.psyneuen.2016.07.002

Betti

Zani

Granziol

Guerra

Castiello

Sartori

(2018). Look at me: Early gaze engagement enhances corticospinal excitability during action observation. Frontiers in Psychology, 9, Article 1408. https://doi.org/10.3389/fpsyg.2018.01408

Caldwell

H. K.

(2018). Oxytocin and sex differences in behavior. Current Opinion in Behavioral Sciences, 23, 13–20. https://doi.org/10.1016/J.COBEHA.2018.02.002

Constantino

J. N.

Todd

R. D.

(2005). Intergenerational transmission of subthreshold autistic traits in the general population. Biological Psychiatry, 57(6), 655–660. https://doi.org/10.1016/j.biopsych.2004.12.014

Crockford

Deschner

Ziegler

T. E.

Wittig

R. M.

(2014). Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: A review. Frontiers in Behavioral Neuroscience, 8, Article 68. https://doi.org/10.3389/fnbeh.2014.00068

Daughters

Manstead

A. S. R.

Hubble

Rees

Thapar

van Goozen

S. H. M.

(2015). Salivary oxytocin concentrations in males following intranasal administration of oxytocin: A double-blind, cross-over study. PLOS ONE, 10(12), 1–11. https://doi.org/10.1371/journal.pone.0145104

10.

De Coster

Mueller

S. C.

T’Sjoen

De Saedeleer

Brass

. (2014). The influence of oxytocin on automatic motor simulation. Psychoneuroendocrinology, 50, 220–226. https://doi.org/10.1016/j.psyneuen.2014.08.021

11.

Fadiga

Fogassi

Pavesi

Rizzolatti

(1995). Motor facilitation during action observation: A magnetic stimulation study. Journal of Neurophysiology, 73(6), 2608–2611. http://jn.physiology.org/content/jn/73/6/2608.full.pdf

12.

Feldman

(2017). The neurobiology of human attachments. Trends in Cognitive Sciences, 21(2), 80–99. https://doi.org/10.1016/j.tics.2016.11.007

13.

Festante

Ferrari

P. F.

Thorpe

S. G.

Buchanan

R. W.

Fox

N. A.

(2020). Intranasal oxytocin enhances EEG mu rhythm desynchronization during execution and observation of social action: An exploratory study. Psychoneuroendocrinology, 111, 104467. https://doi.org/10.1016/j.psyneuen.2019.104467

14.

Forbes

P. A. G.

Wang

Hamilton

A. F. D. C

. (2017). STORMy interactions: Gaze and the modulation of mimicry in adults on the autism spectrum. Psychonomic Bulletin and Review, 24(2), 529–535. https://doi.org/10.3758/s13423-016-1136-0

15.

Gallese

Rochat

M. J.

Berchio

(2013). The mirror mechanism and its potential role in autism spectrum disorder. Developmental Medicine & Child Neurology, 55(1), 15–22. https://doi.org/10.1111/j.1469-8749.2012.04398.x

16.

Gentner

Classen

(2006). Modular organization of finger movements by the human central nervous system. Neuron, 52(4), 731–742. https://doi.org/10.1016/J.NEURON.2006.09.038

17.

Gillath

Hart

Noftle

E. E.

Stockdale

G. D.

(2009). Development and validation of a state adult attachment measure (SAAM). Journal of Research in Personality, 43(3), 362–373. https://doi.org/10.1016/j.jrp.2008.12.009

18.

Gossen

Hahn

Westphal

Prinz

Schultz

R. T.

Gründer

Spreckelmeyer

K. N.

(2012). Oxytocin plasma concentrations after single intranasal oxytocin administration: A study in healthy men. Neuropeptides, 46, 211–215. https://doi.org/10.1016/j.npep.2012.07.001

19.

Guastella

A. J.

Boulton

K. A.

Whitehouse

A. J. O.

Song

Y. J.

Thapa

Gregory

S. G.

Pokorski

Granich

DeMayo

M. M.

Ambarchi

Wray

Thomas

E. E.

Hickie

I. B.

(2023). The effect of oxytocin nasal spray on social interaction in young children with autism: A randomized clinical trial. Molecular Psychiatry, 28(2), 834–842. https://doi.org/10.1038/s41380-022-01845-8

20.

Guastella

A. J.

Hickie

I. B.

McGuinness

M. M.

Otis

Woods

E. A.

Disinger

H. M.

Chan

H.-K.

Chen

T. F.

Banati

R. B.

(2013). Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology, 38(5), 612–625. https://doi.org/10.1016/j.psyneuen.2012.11.019

21.

Hamilton

A. F.

(2013). Reflecting on the mirror neuron system in autism: A systematic review of current theories. Developmental Cognitive Neuroscience, 3, 91–105. https://doi.org/10.1016/j.dcn.2012.09.008

22.

Kavanagh

L. C.

Suhler

C. L.

Churchland

P. S.

Winkielman

(2011). When it’s an error to mirror: The surprising reputational costs of mimicry. Psychological Science, 22(10), 1274–1276. https://doi.org/10.1177/0956797611418678/ASSET/0956797611418678.FP.PNG_V03

23.

Kemmerer

(2021). What modulates the mirror neuron system during action observation? Progress in Neurobiology, 205, 102128. https://doi.org/10.1016/j.pneurobio.2021.102128

24.

Kéri

Benedek

(2009). Oxytocin enhances the perception of biological motion in humans. Cognitive, Affective & Behavioral Neuroscience, 9(3), 237–241. https://doi.org/10.3758/CABN.9.3.237

25.

Kilner

J. M.

Marchant

J. L.

Frith

C. D.

(2006). Modulation of the mirror system by social relevance. Social Cognitive and Affective Neuroscience, 1(2), 143–148. https://doi.org/10.1093/scan/nsl017

26.

Krings

Naujokat

Graf

Keyserlingk

(1998). Representation of cortical motor function as revealed by stereotactic transcranial magnetic stimulation. Electroence-phalography and Clinical Neurophysiology/Electromyo-graphy and Motor Control, 109(2), 85–93. https://doi.org/10.1016/S0924-980X(97)00078-7

27.

Levy

Goldstein

Zagoory-Sharon

Weisman

Schneiderman

Eidelman-Rothman

Feldman

(2016). Oxytocin selectively modulates brain response to stimuli probing social synchrony. NeuroImage, 124, 923–930. https://doi.org/10.1016/J.NEUROIMAGE.2015.09.066

28.

LoParo

Waldman

I. D.

(2014). The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis. Molecular Psychiatry, 20(5), 640–646. https://doi.org/10.1038/mp.2014.77

29.

Mariscal

M. G.

Oztan

Rose

S. M.

Libove

R. A.

Jackson

L. P.

Sumiyoshi

R. D.

Trujillo

T. H.

Carson

D. S.

Phillips

J. M.

Garner

J. P.

Hardan

A. Y.

Parker

K. J.

(2019). Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism Research, 12(8), 1156–1161. https://doi.org/10.1002/AUR.2135

30.

Martins

Gabay

A. S.

Mehta

Paloyelis

(2020). Salivary and plasmatic oxytocin are not reliable trait markers of the physiology of the oxytocin system in humans. eLife, 9, Article e62456. https://doi.org/10.7554/eLife.62456

31.

Martins

D. A.

Mazibuko

Zelaya

Vasilakopoulou

Loveridge

Oates

Maltezos

Mehta

Wastling

Howard

McAlonan

Murphy

Williams

S. C. R.

Fotopoulou

Schuschnig

Paloyelis

(2020). Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans. Nature Communications, 11(1), 1–16. https://doi.org/10.1038/s41467-020-14845-5

32.

Moerkerke

Bonte

M.-L.

Daniels

Chubar

Alaerts

Steyaert

Boets

(2021). Oxytocin receptor gene (OXTR) DNA methylation is associated with autism and related social traits-A systematic review. Research in Autism Spectrum Disorders, 85, 101785. https://doi.org/10.1016/j.rasd.2021.101785

33.

Moerkerke

Peeters

de Vries

Daniels

Steyaert

Alaerts

Boets

(2021). Endogenous oxytocin levels in autism—A meta-analysis. Brain Sciences, 11(11), 1545. https://doi.org/10.3390/BRAINSCI11111545/S1

34.

Oberman

L. M.

Ramachandran

V. S.

(2007). The simulating social mind: The role of the mirror neuron system and simulation in the social and communicative deficits of autism spectrum disorders. Psychological Bulletin, 133(2), 310–327. https://doi.org/10.1037/0033-2909.133.2.310

35.

Oldfield

R. C.

(1971). The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia, 9(1), 97–113. https://doi.org/10.1016/0028-3932(71)90067-4

36.

Ono

Hirosawa

Hasegawa

Ikeda

Kudo

Naito

Yoshimura

Kikuchi

(2021). Influence of oxytocin administration on somatosensory evoked magnetic fields induced by median nerve stimulation during hand action observation in healthy male volunteers. PLOS ONE, 16(3), Article e0249167. https://doi.org/10.1371/JOURNAL.PONE.0249167

37.

Parker

K. J.

Oztan

Libove

R. A.

Sumiyoshi

R. D.

Jackson

L. P.

Karhson

D. S.

Summers

J. E.

Hinman

K. E.

Motonaga

K. S.

Phillips

J. M.

Carson

D. S.

Garner

J. P.

Hardan

A. Y.

(2017). Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America, 114(30), 8119–8124. https://doi.org/10.1073/pnas.1705521114

38.

Pek

Flora

D. B.

(2018). Reporting effect sizes in original psychological research: A discussion and tutorial. Psychological Methods, 23(2), 208–225. https://doi.org/10.1037/MET0000126

39.

Perry

Bentin

Shalev

Israel

Uzefovsky

Bar-On

Ebstein

R. P.

(2010). Intranasal oxytocin modulates EEG mu/alpha and beta rhythms during perception of biological motion. Psychoneuroendocrinology, 35(10), 1446–1453. https://doi.org/10.1016/j.psyneuen.2010.04.011

40.

Prinsen

(2022). Interpersonal motor resonance during social gaze conditions (v1). KU Leuven RDR. https://doi.org/10.48804/N6G7IF

41.

Prinsen

Alaerts

(2019). Eye contact enhances interpersonal motor resonance: Comparing video stimuli to a live two-person action context. Social Cognitive and Affective Neuroscience, 14(9), 967–976. https://doi.org/10.1093/scan/nsz064

42.

Prinsen

Alaerts

(2020). Enhanced mirroring upon mutual gaze: Multimodal evidence from TMS-assessed corticospinal excitability and the EEG mu rhythm. Scientific Reports, 10(1), 20449. https://doi.org/10.1038/s41598-020-77508-x

43.

Prinsen

Alaerts

(2022). Broken or socially mistuned mirroring in ASD ? An investigation via transcranial magnetic stimulation. Autism Research, 15(6), 1056–1067. https://doi.org/10.1002/aur.2720

44.

Prinsen

Alaerts

(2024). In the eye of the beholder: Social traits predict motor simulation during naturalistic action perception. Neuropsychologia, 199, 108889. https://doi.org/10.1016/j.neuropsychologia.2024.108889

45.

Prinsen

Bernaerts

Wang

de Beukelaar

T. T.

Cuypers

Swinnen

S. P.

Alaerts

(2017). Direct eye contact enhances mirroring of others’ movements: A transcranial magnetic stimulation study. Neuropsychologia, 95, 111–118. https://doi.org/10.1016/j.neuropsychologia.2016.12.011

46.

Prinsen

Brams

Alaerts

(2018). To mirror or not to mirror upon mutual gaze, oxytocin can pave the way: A cross-over randomized placebo-controlled trial. Psychoneuroendocrinology, 90, 148–156. https://doi.org/10.1016/j.psyneuen.2018.02.016

47.

Quintana

D. S.

Glaser

B. D.

Kang

Kildal

E. S. M.

Audunsdottir

Sartorius

A. M.

Barth

(2024). The interplay of oxytocin and sex hormones. Neuroscience & Biobehavioral Reviews, 163, 105765. https://doi.org/10.1016/j.neubiorev.2024.105765

48.

Rights

J. D.

Sterba

S. K.

(2019). Quantifying explained variance in multilevel models: An integrative framework for defining R-squared measures. Psychological Methods, 24(3), 309–338. https://doi.org/10.1037/MET0000184

49.

Rizzolatti

Sinigaglia

(2016). The mirror mechanism: A basic principle of brain function. Nature Reviews Neuroscience, 17(12), 757–765. https://doi.org/10.1038/NRN.2016.135

50.

Rossi

Hallett

Rossini

P. M.

Pascual-Leone

(2012). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology, 120(12), 323–330. https://doi.org/10.1016/j.clinph.2009.08.016.Rossi

51.

Rossini

P. M.

Barker

A. T.

Berardelli

Caramia

M. D.

Caruso

Cracco

R. Q.

Dimitrijević

M. R.

Hallett

Katayama

Lücking

C. H.

Maertens

Noordhout

A. L.

Marsden

C. D.

Murray

N. M. F.

Rothwell

J. C.

Swash

Tomberg

(1994). Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: Basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalography and Clinical Neurophysiology, 91(2), 79–92. https://doi.org/10.1016/0013-4694(94)90029-9

52.

Shamay-Tsoory

S. G.

Abu-Akel

(2016). The social salience hypothesis of oxytocin. Biological Psychiatry, 79(3), 194–202. https://doi.org/10.1016/j.biopsych.2015.07.020

53.

Singh

Nunag

Muldoon

Cadenhead

K. S.

Pineda

J. A.

Feifel

(2016). Effects of intranasal oxytocin on neural processing within a socially relevant neural circuit. European Neuropsychopharmacology, 26(3), 626–630. https://doi.org/10.1016/j.euroneuro.2015.12.026

54.

Striepens

Kendrick

K. M.

Hanking

Landgraf

Wüllner

Maier

Hurlemann

(2013). Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Scientific Reports, 3(3440), 1–5. https://doi.org/10.1038/srep03440

55.

Tabak

B. A.

Leng

Szeto

Parker

K. J.

Verbalis

J. G.

Ziegler

T. E.

Lee

M. R.

Neumann

I. D.

Mendez

A. J.

(2023). Advances in human oxytocin measurement: Challenges and proposed solutions. Molecular Psychiatry, 28(1), 127–140. https://doi.org/10.1038/s41380-022-01719-z

56.

Taurines

Schwenck

Lyttwin

Schecklmann

Jans

Reefschläger

Geissler

Gerlach

Romanos

(2014). Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: Correlation with autistic symptomatology. ADHD Attention Deficit and Hyperactivity Disorders, 6(3), 231–239. https://doi.org/10.1007/S12402-014-0145-Y/FIGURES/1

57.

Wadsworth

H. M.

Maximo

J. O.

Donnelly

R. J.

Kana

R. K.

(2018). Action simulation and mirroring in children with autism spectrum disorders. Behavioural Brain Research, 341, 1–8. https://doi.org/10.1016/j.bbr.2017.12.012

58.

Wang

Zhao

Liu

Teng

Fan

Wang

Xia

Sun

(2022). Integrative analysis prioritised oxytocin-related biomarkers associated with the aetiology of autism spectrum disorder. EBioMedicine, 81, 104091. https://doi.org/10.1016/j.ebiom.2022.104091

59.

Wang

Hamilton

A. F.

(2014). Why does gaze enhance mimicry? Placing gaze-mimicry effects in relation to other gaze phenomena. The Quarterly Journal of Experimental Psychology, 67(4), 747–762. https://doi.org/https://dx-doi-org.web.bisu.edu.cn/10.1080/17470218.2013.828316

60.

Wang

Newport

Hamilton

A. F.

(2011). Eye contact enhances mimicry of intransitive hand movements. Biology Letters, 7(1), 7–10. https://doi.org/10.1098/rsbl.2010.0279

61.

Wang

Ramsey

Hamilton

A. F.

(2011). The control of mimicry by eye contact is mediated by medial prefrontal cortex. Journal of Neuroscience, 31(33), 12001–12010. https://doi.org/10.1523/JNEUROSCI.0845-11.2011

62.

Wechsler

(2012). WAIS-IV-NL: Wechsler Adult Intelligence Scale-Fourth Edition-Nederlandse Bewerking. Afname- en scoringshandleiding. Pearson Assessment and Information.

63.

Winter

Jurek

(2019). The interplay between oxytocin and the CRF system: Regulation of the stress response. Cell and Tissue Research, 375(1), 85–91. https://doi.org/10.1007/s00441-018-2866-2

64.

World Medical Association. (2013). Declaration of Helsinki. Ethical principles for medical research involving human subjects. Journal of the American Medical Association, 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053

65.

Wynn

J. K.

Green

M. F.

Hellemann

Reavis

E. A.

Marder

S. R.

(2018). A dose-finding study of oxytocin using neurophysiological measures of social processing. Neuropsychopharmacology, 44(2), 289–294. https://doi.org/10.1038/s41386-018-0165-y

66.

Yatawara

C. J.

Einfeld

S. L.

Hickie

I. B.

Davenport

T. A.

Guastella

A. J.

(2016). The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: A randomized clinical crossover trial. Molecular Psychiatry, 21(9), 1225–1231. https://doi.org/10.1038/mp.2015.162

67.

Yates

Hobson

(2020). Continuing to look in the mirror: A review of neuroscientific evidence for the broken mirror hypothesis, EP-M model and STORM model of autism spectrum conditions. Autism : The International Journal of Research and Practice, 24(8), 1945–1959. https://doi.org/10.1177/1362361320936945