Archival Report| Volume 4, ISSUE 7, P655-663, July 2019

Amygdala–Hippocampal Connectivity Is Associated With Endogenous Levels of Oxytocin and Can Be Altered by Exogenously Administered Oxytocin in Adults With Autism

  • Kaat Alaerts
    Address correspondence to Kaat Alaerts, Ph.D., Neurorehabilitation Research Group, Department of Rehabilitation Sciences, Group Biomedical Sciences, University of Leuven, Katholieke Universiteit Leuven, Belgium, Tervuursevest 101, B-3001 Heverlee, Belgium.
    Department of Rehabilitation Sciences, Group Biomedical Sciences, Neuromotor Rehabilitation Research Group, University of Leuven, Katholieke Universiteit Leuven, Belgium
    Search for articles by this author
  • Sylvie Bernaerts
    Department of Rehabilitation Sciences, Group Biomedical Sciences, Neuromotor Rehabilitation Research Group, University of Leuven, Katholieke Universiteit Leuven, Belgium
    Search for articles by this author
  • Bart Vanaudenaerde
    Department of Chronic Diseases, Metabolism and Ageing, Group Biomedical Sciences, Pneumology Research Group, University of Leuven, Katholieke Universiteit Leuven, Belgium
    Search for articles by this author
  • Nicky Daniels
    Department of Rehabilitation Sciences, Group Biomedical Sciences, Neuromotor Rehabilitation Research Group, University of Leuven, Katholieke Universiteit Leuven, Belgium
    Search for articles by this author
  • Nicole Wenderoth
    Department of Health Sciences and Technology, Neural Control of Movement Lab, Eidgenössische Technische Hochschule, Zurich, Switzerland
    Search for articles by this author
Published:February 04, 2019DOI:



      Oxytocin (OT) plays a pivotal role in interpersonal bonding, affiliation, and trust, and its intranasal administration is increasingly considered as a potential treatment for autism spectrum disorder.


      We explored whether variations in endogenous salivary OT concentration are related to interindividual differences in core autism symptoms and expressions of attachment in 38 male adults with autism spectrum disorder. Further, resting-state functional magnetic resonance imaging was adopted to specifically explore whether interindividual differences are reflected in the intrinsic network organization of key regions of the central oxytocinergic system.


      Positive correlations were identified between peripheral OT and expressions of secure attachment (the State Adult Attachment Measure and the Inventory of Peer Attachment), but no significant relationships were identified with scales assessing core autism symptom domains (the Social Responsiveness Scale and the Repetitive Behavior Scale). At the neural level, higher levels of endogenous OT were associated with lower degrees of interregional functional coupling between the amygdala and hippocampal regions. Interestingly, a single dose of exogenously administered OT induced a further reduction in amygdala–hippocampal connectivity, indicating that a higher availability of OT can alter the degree of amygdala–hippocampal connectivity.


      The identified associations between the oxytocinergic system, expressions of secure attachment, and amygdala–hippocampal pathways are anticipated to be of relevance for understanding the role of OT in modulating appropriate neural and physiological responses to stress and restoring homeostasis.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Bakermans-Kranenburg M.J.
        • van IJzendoorn M.H.
        Sniffing around oxytocin: Review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy.
        Transl Psychiatry. 2013; 3: e258
        • Bartz J.A.
        • Zaki J.
        • Bolger N.
        • Ochsner K.N.
        Social effects of oxytocin in humans: Context and person matter.
        Trends Cogn Sci. 2011; 15: 301-309
        • Guastella A.J.
        • MacLeod C.
        A critical review of the influence of oxytocin nasal spray on social cognition in humans: Evidence and future directions.
        Horm Behav. 2012; 61: 410-418
        • Hollander E.
        • Novotny S.
        • Hanratty M.
        • Yaffe R.
        • DeCaria C.M.
        • Aronowitz B.R.
        • Mosovich S.
        Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders.
        Neuropsychopharmacology. 2003; 28: 193-198
        • Hollander E.
        • Bartz J.
        • Chaplin W.
        • Phillips A.
        • Sumner J.
        • Soorya L.
        • et al.
        Oxytocin increases retention of social cognition in autism.
        Biol Psychiatry. 2007; 61: 498-503
        • Guastella A.J.
        • Einfeld S.L.
        • Gray K.M.
        • Rinehart N.J.
        • Tonge B.J.
        • Lambert T.J.
        • Hickie I.B.
        Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.
        Biol Psychiatry. 2010; 67: 692-694
        • Andari E.
        • Duhamel J.R.
        • Zalla T.
        • Herbrecht E.
        • Leboyer M.
        • Sirigu A.
        Promoting social behavior with oxytocin in high-functioning autism spectrum disorders.
        Proc Natl Acad Sci U S A. 2010; 107: 4389-4394
        • Auyeung B.
        • Lombardo M.V.
        • Heinrichs M.
        • Chakrabarti B.
        • Sule A.
        • Deakin J.B.
        • et al.
        Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism.
        Transl Psychiatry. 2015; 5: e507
        • Anagnostou E.
        • Soorya L.
        • Chaplin W.
        • Bartz J.
        • Halpern D.
        • Wasserman S.
        • et al.
        Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: A randomized controlled trial.
        Mol Autism. 2012; 3: 16
        • Watanabe T.
        • Kuroda M.
        • Kuwabara H.
        • Aoki Y.
        • Iwashiro N.
        • Tatsunobu N.
        • et al.
        Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism.
        Brain. 2015; 138: 3400-3412
        • Yatawara C.J.
        • Einfeld S.L.
        • Hickie I.B.
        • Davenport T.A.
        • Guastella A.J.
        The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: A randomized clinical crossover trial.
        Mol Psychiatry. 2015; 21: 1225-1231
        • Dadds M.R.
        • MacDonald E.
        • Cauchi A.
        • Williams K.
        • Levy F.
        • Brennan J.
        Nasal oxytocin for social deficits in childhood autism: A randomized controlled trial.
        J Autism Dev Disord. 2014; 44: 521-531
        • Guastella A.J.
        • Gray K.M.
        • Rinehart N.J.
        • Alvares G.A.
        • Tonge B.J.
        • Hickie I.B.
        • et al.
        The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: A randomized controlled trial.
        J Child Psychol Psychiatry. 2015; 56: 444-452
        • Parker K.J.
        • Oztan O.
        • Libove R.A.
        • Sumiyoshi R.D.
        • Jackson L.P.
        • Karhson D.S.
        • et al.
        Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism.
        Proc Natl Acad Sci U S A. 2017; 114: 8119-8124
        • Modahl C.
        • Green L.
        • Fein D.
        • Morris M.
        • Waterhouse L.
        • Feinstein C.
        • Levin H.
        Plasma oxytocin levels in autistic children.
        Biol Psychiatry. 1998; 43: 270-277
        • Al-Ayadhi L.Y.
        Altered oxytocin and vasopressin levels in autistic children in Central Saudi Arabia.
        Neurosciences (Riyadh). 2005; 10: 47-50
        • Green L.
        • Fein D.
        • Modahl C.
        • Feinstein C.
        • Waterhouse L.
        • Morris M.
        Oxytocin and autistic disorder: Alterations in peptide forms.
        Biol Psychiatry. 2001; 50: 609-613
        • Jacobson J.D.
        • Ellerbeck K.A.
        • Kelly K.A.
        • Fleming K.K.
        • Jamison T.R.
        • Coffey C.W.
        • et al.
        Evidence for alterations in stimulatory G proteins and oxytocin levels in children with autism.
        Psychoneuroendocrinology. 2014; 40: 159-169
        • Miller M.
        • Bales K.L.
        • Taylor S.L.
        • Yoon J.
        • Hostetler C.M.
        • Carter C.S.
        • Solomon M.
        Oxytocin and vasopressin in children and adolescents with autism spectrum disorders: Sex differences and associations with symptoms.
        Autism Res. 2013; 6: 91-102
        • Jansen L.M.
        • Gispen-de Wied C.C.
        • Wiegant V.M.
        • Westenberg H.G.
        • Lahuis B.E.
        • van E.H.
        Autonomic and neuroendocrine responses to a psychosocial stressor in adults with autistic spectrum disorder.
        J Autism Dev Disord. 2006; 36: 891-899
        • Feldman R.
        • Weller A.
        • Zagoory-Sharon O.
        • Levine A.
        Evidence for a neuroendocrinological foundation of human affiliation: Plasma oxytocin levels across pregnancy and the postpartum period predict mother-infant bonding.
        Psychol Sci. 2007; 18: 965-970
        • Feldman R.
        • Gordon I.
        • Zagoory-Sharon O.
        Maternal and paternal plasma, salivary, and urinary oxytocin and parent-infant synchrony: Considering stress and affiliation components of human bonding.
        Dev Sci. 2011; 14: 752-761
        • Gordon I.
        • Zagoory-Sharon O.
        • Schneiderman I.
        • Leckman J.F.
        • Weller A.
        • Feldman R.
        Oxytocin and cortisol in romantically unattached young adults: Associations with bonding and psychological distress.
        Psychophysiology. 2008; 45: 349-352
        • Gordon I.
        • Zagoory-Sharon O.
        • Leckman J.F.
        • Feldman R.
        Oxytocin and the development of parenting in humans.
        Biol Psychiatry. 2010; 68: 377-382
        • Mielke E.L.
        • Neukel C.
        • Bertsch K.
        • Reck C.
        • Mohler E.
        • Herpertz S.C.
        Alterations of brain volumes in women with early life maltreatment and their associations with oxytocin.
        Horm Behav. 2018; 97: 128-136
        • Andari E.
        • Schneider F.C.
        • Mottolese R.
        • Vindras P.
        • Sirigu A.
        Oxytocin’s fingerprint in personality traits and regional brain volume.
        Cereb Cortex. 2014; 24: 479-486
        • Lord C.
        • Rutter M.
        • DiLavore P.C.
        • Risi S.
        Autism Diagnostic Observation Schedule.
        Western Psychological Service, Los Angeles, CA1999
        • Constantino J.N.
        • Davis S.A.
        • Todd R.D.
        • Schindler M.K.
        • Gross M.M.
        • Brophy S.L.
        • et al.
        Validation of a brief quantitative measure of autistic traits: Comparison of the social responsiveness scale with the autism diagnostic interview-revised.
        J Autism Dev Disord. 2003; 33: 427-433
        • Noens I.
        • De La Marche W.
        • Holte E.
        SRS-A: Screeningslijst voor autismespectrumstoornissen.
        Hogrefe Uitgevers, Amsterdam, The Netherlands2012
        • Lam K.S.
        • Aman M.G.
        The Repetitive Behavior Scale-Revised: Independent validation in individuals with autism spectrum disorders.
        J Autism Dev Disord. 2007; 37: 855-866
        • Gillath O.
        • Hart J.
        • Noftle E.E.
        • Stockdale G.D.
        Development and validation of a state adult attachment measure (SAAM).
        J Res Pers. 2009; 43: 362-373
        • Armsden G.C.
        • Greenberg M.T.
        The inventory of parent and peer attachment: Individual differences and their relationship to psychological well-being in adolescence.
        J Youth Adolesc. 1987; 16: 427-454
        • Bernaerts S.
        • Berra E.
        • Wenderoth N.
        • Alaerts K.
        Influence of oxytocin on emotion recognition from body language: A randomized placebo-controlled trial.
        Psychoneuroendocrinology. 2016; 72: 182-189
        • Bernaerts S.
        • Prinsen J.
        • Berra E.
        • Bosmans G.
        • Steyaert J.
        • Alaerts K.
        Long-term oxytocin administration enhances the experience of attachment.
        Psychoneuroendocrinology. 2017; 78: 1-9
        • Spengler F.B.
        • Schultz J.
        • Scheele D.
        • Essel M.
        • Maier W.
        • Heinrichs M.
        • Hurlemann R.
        Kinetics and dose dependency of intranasal oxytocin effects on amygdala reactivity.
        Biol Psychiatry. 2017; 82: 885-894
        • Paloyelis Y.
        • Doyle O.M.
        • Zelaya F.O.
        • Maltezos S.
        • Williams S.C.
        • Fotopoulou A.
        • Howard M.A.
        A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans.
        Biol Psychiatry. 2016; 79: 693-705
        • Kiem S.A.
        • Andrade K.C.
        • Spoormaker V.I.
        • Holsboer F.
        • Czisch M.
        • Samann P.G.
        Resting state functional MRI connectivity predicts hypothalamus-pituitary-axis status in healthy males.
        Psychoneuroendocrinology. 2013; 38: 1338-1348
        • Vaisvaser S.
        • Lin T.
        • Admon R.
        • Podlipsky I.
        • Greenman Y.
        • Stern N.
        • et al.
        Neural traces of Stress: cortisol related sustained enhancement of amygdala-hippocampal functional connectivity.
        Front Hum Neurosci. 2013; 7: 313
        • Herman J.P.
        • Ostrander M.M.
        • Mueller N.K.
        • Figueiredo H.
        Limbic system mechanisms of stress regulation: Hypothalamo-pituitary-adrenocortical axis.
        Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 1201-1213
        • Fan Y.
        • Pestke K.
        • Feeser M.
        • Aust S.
        • Pruessner J.C.
        • Boker H.
        • et al.
        Amygdala-hippocampal connectivity changes during acute psychosocial stress: Joint effect of early life stress and oxytocin.
        Neuropsychopharmacology. 2015; 40: 2736-2744
        • Risold P.Y.
        • Swanson L.W.
        Structural evidence for functional domains in the rat hippocampus.
        Science. 1996; 272: 1484-1486
        • Tasker J.G.
        • Boudaba C.
        • Schrader L.A.
        Local glutamatergic and GABAergic synaptic circuits and metabotropic glutamate receptors in the hypothalamic paraventricular and supraoptic nuclei.
        Adv Exp Med Biol. 1998; 449: 117-121
        • Striepens N.
        • Kendrick K.M.
        • Hanking V.
        • Landgraf R.
        • Wullner U.
        • Maier W.
        • Hurlemann R.
        Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans.
        Sci Rep. 2013; 3: 3440
        • Chang S.W.
        • Barter J.W.
        • Ebitz R.B.
        • Watson K.K.
        • Platt M.L.
        Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta).
        Proc Natl Acad Sci U S A. 2012; 109: 959-964
        • Modi M.E.
        • Connor-Stroud F.
        • Lndgraf R.
        • Young L.J.
        • Parr L.A.
        Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques.
        Psychoneuroendocrinology. 2014; 45: 49-57
        • Dal M.O.
        • Noble P.L.
        • Turchi J.
        • Cummins A.
        • Averbeck B.B.
        CSF and blood oxytocin concentration changes following intranasal delivery in macaque.
        PLoS One. 2014; 9: e103677
        • Neumann I.D.
        • Maloumby R.
        • Beiderbeck D.I.
        • Lukas M.
        • Landgraf R.
        Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice.
        Psychoneuroendocrinology. 2013; 38: 1985-1993
        • Quintana D.S.
        • Smerud K.T.
        • Andreassen O.A.
        • Djupesland P.G.
        Evidence for intranasal oxytocin delivery to the brain: Recent advances and future perspectives.
        Ther Deliv. 2018; 9: 515-525
        • Knobloch H.S.
        • Charlet A.
        • Hoffmann L.C.
        • Eliava M.
        • Khrulev S.
        • Cetin A.H.
        • et al.
        Evoked axonal oxytocin release in the central amygdala attenuates fear response.
        Neuron. 2012; 73: 553-566
        • Wang D.
        • Yan X.
        • Li M.
        • Ma Y.
        Neural substrates underlying the effects of oxytocin: a quantitative meta-analysis of pharmaco-imaging studies.
        Soc Cogn Affect Neurosci. 2017; 12: 1565-1573
        • Sripada C.S.
        • Phan K.L.
        • Labuschagne I.
        • Welsh R.
        • Nathan P.J.
        • Wood A.G.
        Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex.
        Int J Neuropsychopharmacol. 2013; 16: 255-260
        • Dodhia S.
        • Hosanagar A.
        • Fitzgerald D.A.
        • Labuschagne I.
        • Wood A.G.
        • Nathan P.J.
        • Phan K.L.
        Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder.
        Neuropsychopharmacology. 2014; 39: 2061-2069
        • Ebner N.C.
        • Chen H.
        • Porges E.
        • Lin T.
        • Fischer H.
        • Feifel D.
        • Cohen R.A.
        Oxytocin's effect on resting-state functional connectivity varies by age and sex.
        Psychoneuroendocrinology. 2016; 69: 50-59
        • Eckstein M.
        • Markett S.
        • Kendrick K.M.
        • Ditzen B.
        • Liu F.
        • Hurlemann R.
        • Becker B.
        Oxytocin differentially alters resting state functional connectivity between amygdala subregions and emotional control networks: Inverse correlation with depressive traits.
        Neuroimage. 2017; 149: 458-467
        • Koch S.B.
        • van Z.M.
        • Nawijn L.
        • Frijling J.L.
        • Veltman D.J.
        • Olff M.
        Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder.
        Neuropsychopharmacology. 2016; 41: 2041-2051
        • Frijling J.L.
        • van Z.M.
        • Koch S.B.
        • Nawijn L.
        • Veltman D.J.
        • Olff M.
        Effects of intranasal oxytocin on amygdala reactivity to emotional faces in recently trauma-exposed individuals.
        Soc Cogn Affect Neurosci. 2016; 11: 327-336
        • Kumar J.
        • Vollm B.
        • Palaniyappan L.
        Oxytocin affects the connectivity of the precuneus and the amygdala: a randomized, double-blinded, placebo-controlled neuroimaging trial.
        Int J Neuropsychopharmacol. 2014; 18
        • Riem M.M.
        • van IJzendoorn M.H.
        • Tops M.
        • Boksem M.A.
        • Rombouts S.A.
        • Bakermans-Kranenburg M.J.
        Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal.
        Eur Neuropsychopharmacol. 2013; 23: 1288-1295
        • Fan Y.
        • Herrera-Melendez A.L.
        • Pestke K.
        • Feeser M.
        • Aust S.
        • Otte C.
        • et al.
        Early life stress modulates amygdala-prefrontal functional connectivity: implications for oxytocin effects.
        Hum Brain Mapp. 2014; 35: 5328-5339
        • Seeley S.H.
        • Chou Y.H.
        • O'Connor M.F.
        Intranasal oxytocin and OXTR genotype effects on resting state functional connectivity: A systematic review.
        Neurosci Biobehav Rev. 2018; 95: 17-32
        • Hill K.T.
        • Warren M.
        • Roth T.L.
        The influence of infant-caregiver experiences on amygdala Bdnf, OXTr, and NPY expression in developing and adult male and female rats.
        Behav Brain Res. 2014; 272: 175-180
        • Bartz J.A.
        • Lydon J.E.
        • Kolevzon A.
        • Zaki J.
        • Hollander E.
        • Ludwig N.
        • Bolger N.
        Differential effects of oxytocin on agency and communion for anxiously and avoidantly attached individuals.
        Psychol Sci. 2015; 26: 1177-1186
        • Martin J.
        • Kagerbauer S.M.
        • Gempt J.
        • Podtschaske A.
        • Hapfelmeier A.
        • Schneider G.
        Oxytocin levels in saliva correlate better than plasma levels with concentrations in the cerebrospinal fluid of patients in neurocritical care.
        J Neuroendocrinole12596. 2018;