Oxytocin modulates the effective connectivity between the precuneus and the dorsolateral prefrontal cortex

  • Jyothika Kumar
  • Sarina J. Iwabuchi
  • Birgit A. Völlm
  • Lena PalaniyappanEmail author
Original Paper


Our social activity is heavily influenced by the process of introspection, with emerging research suggesting a role for the Default Mode Network (DMN) in social cognition. We hypothesize that oxytocin, a neuropeptide with an important role in social behaviour, can effectively alter the connectivity of the DMN. We test this hypothesis using a randomized, double-blind, crossover, placebo-controlled trial where 15 healthy male participants received 24 IU oxytocin or placebo prior to a resting-state functional MRI scan. We used Granger Causality Analysis for the first time to probe the role of oxytocin on brain networks and found that oxytocin reverses the pattern of effective connectivity between the bilateral precuneus and the left dorsolateral prefrontal cortex (dlPFC), a key central executive network (CEN) region. Under placebo, the bilateral precuneus exerted a significant negative causal influence on the left dlPFC and the left dlPFC exerted a significant positive causal influence on the bilateral precuneus. However, under oxytocin, these patterns were reversed, i.e. positive causal influence from the bilateral precuneus to the left dlPFC and negative causal influence from the left dlPFC to the bilateral precuneus (with statistically significant effects for the right precuneus). We propose that these oxytocin-induced effects could be a mechanistic process by which it modulates social cognition. These results provide a measurable target for the physiological effects of oxytocin in the brain and offer oxytocin as a potential agent to enhance the cooperative role of the predominantly ‘task-inactive’ ‘default mode’ brain regions in both healthy and patient populations.


Oxytocin Resting fMRI Granger Causality Effective connectivity Default Mode Network 



This study was supported by an Early Career Research Knowledge and Transfer Award from the University of Nottingham to Prof Birgit Völlm. LP is supported by the Academic Medical Organization of Southwest Ontario (AMOSO) Opportunities Fund; Bucke Fund; Chrysalis Fund and the Canadian Institute of Health Research (CIHR Foundation Grant). The funding bodies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. We would like to acknowledge the assistance provided by Drs. Mehri Kaviani and Elizabeth Liddle and Professor Peter Liddle in setting up this study and acquiring data.

Compliance with ethical standards

Conflict of interest

Dr. Lena Palaniyappan is an employee of Western University, Ontario. He receives book royalties from Oxford University Press and income from the SPMM MRCPsych course. He has received travel support to speak at a meeting organized by Magstim Ltd. (UK); speaker and consultancy fees from Otsuka Canada, Janssen Canada, Canadian Psychiatric Association and Educational Grants from Janssen, Sunovion and Otsuka Canada. There are no other relevant conflicts of interest.

Informed consent

Informed consent was obtained from all participants and an inconvenience allowance was paid. This study received approval from the University of Nottingham Medical School Ethics Committee.

Supplementary material

406_2019_989_MOESM1_ESM.pdf (253 kb)
Supplementary material 1 (PDF 252 KB)


  1. 1.
    Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M (2011) Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 12(9):524–538Google Scholar
  2. 2.
    Striepens N, Kendrick KM, Maier W, Hurlemann R (2011) Prosocial effects of oxytocin and clinical evidence for its therapeutic potential. Front Neuroendocrinol 32(4):426–450Google Scholar
  3. 3.
    Brüne M, Ebert A, Kolb M, Tas C, Edel MA, Roser P (2013) Oxytocin influences avoidant reactions to social threat in adults with borderline personality disorder. Hum Psychopharmacol 28(6):552–561Google Scholar
  4. 4.
    Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N et al (2015) Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain 138(11):3400–3412Google Scholar
  5. 5.
    Guastella AJ, Ward PB, Hickie IB, Shahrestani S, Hodge MA, Scott EM et al (2015) A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. Schizophr Res 168(3):628–633Google Scholar
  6. 6.
    Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ (2016) The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry 21(9):1225–1231Google Scholar
  7. 7.
    Brambilla M, Cotelli M, Manenti R, Dagani J, Sisti D, Rocchi M et al (2016) Oxytocin to modulate emotional processing in schizophrenia: a randomized, double-blind, cross-over clinical trial. Eur Neuropsychopharmacol 26(10):1619–1628Google Scholar
  8. 8.
    Perez-Rodriguez MM, Derish NE, New AS (2014) The use of oxytocin in personality disorders: rationale and current status. Curr Treat Options Psychiatry 1(4):345–357Google Scholar
  9. 9.
    Shilling PD, Feifel D (2016) Potential of oxytocin in the treatment of schizophrenia. CNS Drugs 30(3):193–208Google Scholar
  10. 10.
    Zink CF, Meyer-Lindenberg A (2012) Human neuroimaging of oxytocin and vasopressin in social cognition. Horm Behav 61(3):400–409Google Scholar
  11. 11.
    Wigton R, Radua J, Allen P, Averbeck B, Meyer-Lindenberg A, McGuire P et al (2015) Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci 40(1):E1–E22Google Scholar
  12. 12.
    Kumar J, Völlm B, Palaniyappan L (2015) Oxytocin affects the connectivity of the precuneus and the amygdala: a randomized, double-blinded, placebo-controlled neuroimaging trial. Int J Neuropsychopharmacol 18(5):pyu051Google Scholar
  13. 13.
    Schilbach L, Eickhoff SB, Rotarska-Jagiela A, Fink GR, Vogeley K (2008) Minds at rest? Social cognition as the default mode of cognizing and its putative relationship to the “default system” of the brain. Conscious Cogn 17(2):457–467Google Scholar
  14. 14.
    Mars RB, Neubert FX, Noonan MP, Sallet J, Toni I, Rushworth MF (2012) On the relationship between the “default mode network” and the “social brain”. Front Hum Neurosci 6:189Google Scholar
  15. 15.
    Li W, Mai X, Liu C (2014) The default mode network and social understanding of others: what do brain connectivity studies tell us. Front Hum Neurosci 8:74Google Scholar
  16. 16.
    Xie X, Bratec SM, Schmid G, Meng C, Doll A, Wohlschläger A et al (2016) How do you make me feel better? Social cognitive emotion regulation and the default mode network. Neuroimage 134:270–280Google Scholar
  17. 17.
    Spreng RN, Stevens WD, Chamberlain JP, Gilmore AW, Schacter DL (2010) Default network activity, coupled with the frontoparietal control network, supports goal-directed cognition. Neuroimage 53(1):303–317Google Scholar
  18. 18.
    Fornito A, Harrison BJ, Zalesky A, Simons JS (2012) Competitive and cooperative dynamics of large-scale brain functional networks supporting recollection. Proc Natl Acad Sci USA 109(31):12788–12793Google Scholar
  19. 19.
    Andrews-Hanna JR, Smallwood J, Spreng RN (2014) The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann N Y Acad Sci 1316(1):29–52Google Scholar
  20. 20.
    Beaty RE, Benedek M, Kaufman SB, Silvia PJ (2015) Default and executive network coupling supports creative idea production. Sci Rep 5:10964Google Scholar
  21. 21.
    Krieger-Redwood K, Jefferies E, Karapanagiotidis T, Seymour R, Nunes A, Ang JW (2016) Down but not out in posterior cingulate cortex: deactivation yet functional coupling with prefrontal cortex during demanding semantic cognition. Neuroimage 141:366–377Google Scholar
  22. 22.
    Riem MM, van IJzendoorn MH, Tops M, Boksem MA, Rombouts SA, Bakermans-Kranenburg MJ (2013) Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal. Eur Neuropsychopharmacol 23(10):1288–1295Google Scholar
  23. 23.
    Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG (2013) Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 16(2):255–260Google Scholar
  24. 24.
    Ebner NC, Chen H, Porges E, Lin T, Fischer H, Feifel D et al (2016) Oxytocin’s effect on resting-state functional connectivity varies by age and sex. Psychoneuroendocrinology 69:50–59Google Scholar
  25. 25.
    Brodmann K, Gruber O, Goya-Maldonado R (2017) Intranasal oxytocin selectively modulates large-scale brain networks in humans. Brain Connect 7(7):454–463Google Scholar
  26. 26.
    Palaniyappan L, Simmonite M, White TP, Liddle EB, Liddle PF (2013) Neural primacy of the salience processing system in schizophrenia. Neuron 79(4):814–828Google Scholar
  27. 27.
    Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25(49):11489–11493Google Scholar
  28. 28.
    Domes G, Heinrichs M, Gläscher J, Büchel C, Braus DF, Herpertz SC (2007) Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62(10):1187–1190Google Scholar
  29. 29.
    Chao-Gan Y, Yu-Feng Z (2010) DPARSF: a MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Front Syst Neurosci 4:13Google Scholar
  30. 30.
    Friston KJ, Williams S, Howard R, Frackowiak RS, Turner R (1996) Movement-related effects in fMRI time-series. Magn Reson Med 35(3):346–355Google Scholar
  31. 31.
    Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE (2012) Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage 59(3):2142–2154Google Scholar
  32. 32.
    Iwabuchi SJ, Peng D, Fang Y, Jiang K, Liddle EB, Liddle PF et al (2014) Alterations in effective connectivity anchored on the insula in major depressive disorder. Eur Neuropsychopharmacol 24(11):1784–1792Google Scholar
  33. 33.
    Sridharan D, Levitin DJ, Menon V (2008) A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci USA 105(34):12569–12574Google Scholar
  34. 34.
    Deshpande G, Santhanam P, Hu X (2011) Instantaneous and causal connectivity in resting state brain networks derived from functional MRI data. Neuroimage 54(2):1043–1052Google Scholar
  35. 35.
    Moran LV, Tagamets MA, Sampath H, O’Donnell A, Stein EA, Kochunov P et al (2013) Disruption of anterior insula modulation of large-scale brain networks in schizophrenia. Biol Psychiatry 74(6):467–474Google Scholar
  36. 36.
    Brookes MJ, Liddle EB, Hale JR, Woolrich MW, Luckhoo H, Liddle PF et al (2012) Task induced modulation of neural oscillations in electrophysiological brain networks. Neuroimage 63(4):1918–1930Google Scholar
  37. 37.
    Chand GB, Dhamala M (2016) The salience network dynamics in perceptual decision-making. Neuroimage 134:85–93Google Scholar
  38. 38.
    Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N et al (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15:273–289Google Scholar
  39. 39.
    Song XW, Dong ZY, Long XY, Li SF, Zuo XN, Zhu CZ et al (2011) REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PloS One 6(9):e25031Google Scholar
  40. 40.
    Utevsky AV, Smith DV, Huettel SA (2014) Precuneus is a functional core of the default-mode network. J Neurosci 34(3):932–940Google Scholar
  41. 41.
    Amft M, Bzdok D, Laird AR, Fox PT, Schilbach L, Eickhoff SB (2015) Definition and characterization of an extended social-affective default network. Brain Struct Funct 220(2):1031–1049Google Scholar
  42. 42.
    Uddin LQ, Clare Kelly AM, Biswal BB, Xavier Castellanos F, Milham MP (2009) Functional connectivity of default mode network components: correlation, anticorrelation, and causality. Hum Brain Mapp 30(2):625–637Google Scholar
  43. 43.
    Chen AC, Oathes DJ, Chang C, Bradley T, Zhou ZW, Williams LM et al (2013) Causal interactions between fronto-parietal central executive and default-mode networks in humans. Proc Natl Acad Sci 110(49):19944–19949Google Scholar
  44. 44.
    Greicius MD, Krasnow B, Reiss AL, Menon V (2003) Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci USA 100(1):253–258Google Scholar
  45. 45.
    Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME (2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 102(27):9673–9678Google Scholar
  46. 46.
    Pu W, Luo Q, Palaniyappan L, Xue Z, Yao S, Feng J et al (2016) Failed cooperative, but not competitive, interaction between large-scale brain networks impairs working memory in schizophrenia. Psychol Med 46(06):1211–1224Google Scholar
  47. 47.
    Whitfield-Gabrieli S, Ford JM (2012) Default mode network activity and connectivity in psychopathology. Annu Rev Clin Psychol 8:49–76Google Scholar
  48. 48.
    Anticevic A, Cole MW, Murray JD, Corlett PR, Wang XJ, Krystal JH (2012) The role of default network deactivation in cognition and disease. Trends Cogn Sci 16(12):584–592Google Scholar
  49. 49.
    Spencer MD, Chura LR, Holt RJ, Suckling J, Calder AJ, Bullmore ET et al (2012) Failure to deactivate the default mode network indicates a possible endophenotype of autism. Mol Autism 3(1):15Google Scholar
  50. 50.
    Abbott AE, Nair A, Keown CL, Datko M, Jahedi A, Fishman I et al (2016) Patterns of atypical functional connectivity and behavioral links in autism differ between default, salience, and executive networks. Cereb Cortex 26(10):4034–4045Google Scholar
  51. 51.
    Uddin LQ, Supekar K, Lynch CJ, Cheng KM, Odriozola P, Barth ME et al (2014) Brain state differentiation and behavioral inflexibility in autism. Cereb Cortex 25(12):4740–4747Google Scholar
  52. 52.
    Reniers RL, Corcoran R, Völlm BA, Mashru A, Howard R, Liddle PF (2012) Moral decision-making, ToM, empathy and the default mode network. Biol Psychol 90(3):202–210Google Scholar
  53. 53.
    Freeman SM, Clewett DV, Bennett CM, Kiehl KA, Gazzaniga MS, Miller MB (2015) The posteromedial region of the default mode network shows attenuated task-induced deactivation in psychopathic prisoners. Neuropsychology 29(3):493–500Google Scholar
  54. 54.
    Kluetsch RC, Schmahl C, Niedtfeld I, Densmore M, Calhoun VD, Daniels J et al (2012) Alterations in default mode network connectivity during pain processing in borderline personality disorder. Arch Gen Psychiatry 69(10):993–1002Google Scholar
  55. 55.
    Yang W, Cun L, Du X, Yang J, Wang Y, Wei D et al (2015) Gender differences in brain structure and resting-state functional connectivity related to narcissistic personality. Sci Rep 5:10924Google Scholar
  56. 56.
    Jankowiak-Siuda K, Zajkowski W (2013) A neural model of mechanisms of empathy deficits. Med Sci Monit 19:934–941Google Scholar
  57. 57.
    Gorka SM, Fitzgerald DA, Labuschagne I, Hosanagar A, Wood AG, Nathan PJ et al (2015) Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder. Neuropsychopharmacology 40(2):278–286Google Scholar
  58. 58.
    Andari E, Richard N, Leboyer M, Sirigu A (2016) Adaptive coding of the value of social cues with oxytocin, an fMRI study in autism spectrum disorder. Cortex 76:79–88Google Scholar
  59. 59.
    Nawijn L, van Zuiden M, Koch SB, Frijling JL, Veltman DJ, Olff M (2017) Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder. Soc Cogn Affect Neurosci 12:212–223Google Scholar
  60. 60.
    Bethlehem RA, Lombardo MV, Lai MC, Auyeung B, Crockford SK, Deakin J et al (2017) Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women. Transl Psychiatry 7(4):e1099Google Scholar
  61. 61.
    Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M et al (2010) Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 35(1):83–93Google Scholar
  62. 62.
    Lischke A, Gamer M, Berger C, Grossmann A, Hauenstein K, Heinrichs M et al (2012) Oxytocin increases amygdala reactivity to threatening scenes in females. Psychoneuroendocrinology 37(9):1431–1438Google Scholar
  63. 63.
    Rilling JK, DeMarco AC, Hackett PD, Chen X, Gautam P, Stair S et al (2014) Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 39:237–248Google Scholar
  64. 64.
    Bartz JA, Zaki J, Bolger N, Ochsner KN (2011) Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci 15(7):301–309Google Scholar
  65. 65.
    Steinbeis N, Bernhardt BC, Singer T (2012) Impulse control and underlying functions of the left DLPFC mediate age-related and age-independent individual differences in strategic social behavior. Neuron 73(5):1040–1051Google Scholar
  66. 66.
    Breukelaar IA, Antees C, Grieve SM, Foster SL, Gomes L, Williams LM et al (2017) Cognitive control network anatomy correlates with neurocognitive behavior: a longitudinal study. Hum Brain Mapp 38(2):631–643Google Scholar
  67. 67.
    Walum H, Waldman ID, Young LJ (2016) Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatry 79(3):251–257Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Psychiatry and Applied PsychologyUniversity of NottinghamNottinghamUK
  2. 2.Radiological Sciences, Division of Clinical NeuroscienceUniversity of NottinghamNottinghamUK
  3. 3.Nottinghamshire Healthcare NHS TrustNottinghamUK
  4. 4.Department of Psychiatry and Robarts Research InstituteUniversity of Western Ontario & Lawson Health Research InstituteLondonCanada

Personalised recommendations