Chronic oxytocin improves neural decoupling at rest in children with autism: an exploratory RCT.

Publisher: Blackwell Publishers Country of Publication: England NLM ID: 0375361 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-7610 (Electronic) Linking ISSN: 00219630 NLM ISO Abbreviation: J Child Psychol Psychiatry Subsets: MEDLINE

Publication: 2002- : Oxford : Blackwell Publishers
Original Publication: Oxford ; New York : Pergamon Press

Oxytocin*/pharmacology ; Oxytocin*/administration & dosage ; Autism Spectrum Disorder*/physiopathology ; Autism Spectrum Disorder*/drug therapy ; Administration, Intranasal*; Humans ; Child ; Male ; Female ; Theta Rhythm/drug effects ; Theta Rhythm/physiology ; Alpha Rhythm/drug effects ; Alpha Rhythm/physiology ; Electroencephalography

Background: Shifts in peak frequencies of oscillatory neural rhythms are put forward as a principal mechanism by which cross-frequency coupling/decoupling is implemented in the brain. During active neural processing, functional integration is facilitated through transitory formations of "harmonic" cross-frequency couplings, whereas "nonharmonic" decoupling among neural oscillatory rhythms is postulated to characterize the resting, default state of the brain, minimizing the occurrence of spurious, noisy, background couplings.
Methods: Within this exploratory, randomized, placebo-controlled trial, we assessed whether the transient occurrence of nonharmonic and harmonic relationships between peak-frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands is impacted by intranasal administration of oxytocin, a neuromodulator implicated in improving homeostasis and reducing stress/anxiety. To do so, resting-state electroencephalography was acquired before and after 4 weeks of oxytocin administration (12 IU twice-daily) in children with autism spectrum disorder (8-12 years, n = 33 oxytocin; n = 34 placebo). At the baseline, neural assessments of children with autism were compared with those of a matched cohort of children without autism (n = 40).
Results: Compared to nonautistic peers, autistic children displayed a lower incidence of nonharmonic alpha-theta cross-frequency decoupling, indicating a higher incidence of spurious "noisy" coupling in their resting brain (p = .001). Dimensionally, increased neural coupling was associated with more social difficulties (p = .002) and lower activity of the parasympathetic "rest & digest" branch of the autonomic nervous system (p = .018), indexed with high-frequency heart-rate-variability. Notably, after oxytocin administration, the transient formation of nonharmonic cross-frequency configurations was increased in the cohort of autistic children (p < .001), indicating a beneficial effect of oxytocin on reducing spurious cross-frequency-interactions. Furthermore, parallel epigenetics changes of the oxytocin receptor gene indicated that the neural effects were likely mediated by changes in endogenous oxytocinergic signaling (p = .006).
Conclusions: Chronic oxytocin induced important homeostatic changes in the resting-state intrinsic neural frequency architecture, reflective of reduced noisy oscillatory couplings and improved signal-to-noise properties.
(© 2024 Association for Child and Adolescent Mental Health.)

Alaerts, K., Daniels, N., Moerkerke, M., Evenepoel, M., Tang, T., Donck, S.V.D., … & Prinsen, J. (2023). At the head and heart of oxytocin's stress‐regulatory neural and cardiac effects: A chronic administration RCT in children with autism. medRxiv, 2023.2004.2004.23288109.
Alaerts, K., Taillieu, A., Prinsen, J., & Daniels, N. (2021). Tracking transient changes in the intrinsic neural frequency architecture: Oxytocin facilitates non‐harmonic relationships between alpha and theta rhythms in the resting brain. Psychoneuroendocrinology, 133, 105397.
APA. (1994). DSM‐IV. Diagnostic and statistical manual of mental disorders. Washington, DC: Author.
APA. (2013). Diagnostic and statistical manual of mental disorders. Washington, DC: Author.
Bartz, J.A., Zaki, J., Bolger, N., & Ochsner, K.N. (2011). Social effects of oxytocin in humans: Context and person matter. Trends in Cognitive Sciences, 15, 301–309.
Bruining, H., Hardstone, R., Juarez‐Martinez, E.L., Sprengers, J., Avramiea, A.E., Simpraga, S., … & Linkenkaer‐Hansen, K. (2020). Measurement of excitation‐inhibition ratio in autism spectrum disorder using critical brain dynamics. Scientific Reports, 10, 9195.
Cheng, Y.C., Huang, Y.C., & Huang, W.L. (2020). Heart rate variability in individuals with autism spectrum disorders: A meta‐analysis. Neuroscience and Biobehavioral Reviews, 118, 463–471.
Constantino, J.N., Davis, S.A., Todd, R.D., Schindler, M.K., Gross, M.M., Brophy, S.L., … & Reich, W. (2003). Validation of a brief quantitative measure of autistic traits: Comparison of the social responsiveness scale with the autism diagnostic interview‐revised. Journal of Autism and Developmental Disorders, 33, 427–433.
Daniels, N., Moerkerke, M., Steyaert, J., Bamps, A., Debbaut, E., Prinsen, J., … & Alaerts, K. (2023). Effects of multiple‐dose intranasal oxytocin administration on social responsiveness in children with autism: A randomized, placebo‐controlled trial. Molecular Autism, 14, 16.
De Bruijn, E.R.A., Ruissen, M.I., & Radke, S. (2017). Electrophysiological correlates of oxytocin‐induced enhancement of social performance monitoring. Social Cognitive and Affective Neuroscience, 12, 1668–1677.
Evenepoel, M., Moerkerke, M., Daniels, N., Chubar, V., Claes, S., Turner, J., … & Alaerts, K. (2023). Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation. Translational Psychiatry, 13, 235.
Fathabadipour, S., Mohammadi, Z., Roshani, F., Goharbakhsh, N., Alizadeh, H., Palizgar, F., … & Vafaee, M.S. (2022). The neural effects of oxytocin administration in autism spectrum disorders studied by fMRI: A systematic review. Journal of Psychiatric Research, 154, 80–90.
Festante, F., 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.
Fries, P. (2005). A mechanism for cognitive dynamics: Neuronal communication through neuronal coherence. Trends in Cognitive Sciences, 9, 474–480.
Grace, S.A., Rossell, S.L., Heinrichs, M., Kordsachia, C., & Labuschagne, I. (2018). Oxytocin and brain activity in humans: A systematic review and coordinate‐based meta‐analysis of functional MRI studies. Psychoneuroendocrinology, 96, 6–24.
Guastella, A.J., Boulton, K.A., Whitehouse, A.J.O., Song, Y.J., Thapa, R., Gregory, S.G., … & 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, 834–842.
Horta, M., Kaylor, K., Feifel, D., & Ebner, N.C. (2020). Chronic oxytocin administration as a tool for investigation and treatment: A cross‐disciplinary systematic review. Neuroscience and Biobehavioral Reviews, 108, 1–23.
Huang, Y., Huang, X., Ebstein, R.P., & Yu, R. (2021). Intranasal oxytocin in the treatment of autism spectrum disorders: A multilevel meta‐analysis. Neuroscience and Biobehavioral Reviews, 122, 18–27.
Jain, V., Marbach, J., Kimbro, S., Andrade, D.C., Jain, A., Capozzi, E., … & Mendelowitz, D. (2017). Benefits of oxytocin administration in obstructive sleep apnea. American Journal of Physiology. Lung Cellular and Molecular Physiology, 313, L825–L833.
Johnson, M.H. (2017). Autism as an adaptive common variant pathway for human brain development. Developmental Cognitive Neuroscience, 25, 5–11.
Jurek, B., & Neumann, I.D. (2018). The oxytocin receptor: From intracellular signaling to behavior. Physiological Reviews, 98, 1805–1908.
Kemp, A.H., Quintana, D.S., Kuhnert, R.L., Griffiths, K., Hickie, I.B., & Guastella, A.J. (2012). Oxytocin increases heart rate variability in humans at rest: Implications for social approach‐related motivation and capacity for social engagement. PLoS One, 7, e44014.
Klimesch, W. (2012). α‐Band oscillations, attention, and controlled access to stored information. Trends in Cognitive Sciences, 16, 606–617.
Klimesch, W. (2013). An algorithm for the EEG frequency architecture of consciousness and brain body coupling. Frontiers in Human Neuroscience, 7, 766.
Klimesch, W. (2018). The frequency architecture of brain and brain body oscillations: An analysis. The European Journal of Neuroscience, 48, 2431–2453.
Laborde, S., Mosley, E., & Thayer, J.F. (2017). Heart rate variability and cardiac vagal tone in psychophysiological research – recommendations for experiment planning, data analysis, and data reporting. Frontiers in Psychology, 8, 213.
Lord, C., Rutter, M., Dilavore, P.C., & Risi, S. (1999). Autism diagnostic observation schedule. Los Angeles: Western Psychological Service.
Maier, P., Kaiser, M.E., Grinevich, V., Draguhn, A., & Both, M. (2016). Differential effects of oxytocin on mouse hippocampal oscillations in vitro. The European Journal of Neuroscience, 44, 2885–2898.
Martins, D.C., De Micheli, A., Oliver, D., Krawczun‐Rygmaczewska, A., Fusar‐Poli, P., & Paloyelis, Y. (2020). Intranasal oxytocin increases heart‐rate variability in men at clinical high risk for psychosis: A proof‐of‐concept study. Translational Psychiatry, 10, 227.
Mazurek, M.O., Vasa, R.A., Kalb, L.G., Kanne, S.M., Rosenberg, D., Keefer, A., … & Lowery, L.A. (2013). Anxiety, sensory over‐responsivity, and gastrointestinal problems in children with autism spectrum disorders. Journal of Abnormal Child Psychology, 41, 165–176.
Moerkerke, M., Daniels, N., Tibermont, L., Tang, T., Evenepoel, M., Van Der Donck, S., … & Alaerts, K. (2024). Chronic oxytocin administration stimulates the oxytocinergic system in children with autism. Nature Communications, 15, 58.
Moerkerke, M., Daniels, N., Van Der Donck, S., Tibermont, L., Tang, T., Debbaut, E., … & Boets, B. (2023). Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial. Journal of Child Psychology and Psychiatry, 64, 1583–1595.
Norman, G.J., Cacioppo, J.T., Morris, J.S., Malarkey, W.B., Berntson, G.G., & Devries, A.C. (2011). Oxytocin increases autonomic cardiac control: Moderation by loneliness. Biological Psychology, 86, 174–180.
Oettl, L.L., Ravi, N., Schneider, M., Scheller, M.F., Schneider, P., Mitre, M., … & Kelsch, W. (2016). Oxytocin enhances social recognition by modulating cortical control of early olfactory processing. Neuron, 90, 609–621.
Owen, S.F., Tuncdemir, S.N., Bader, P.L., Tirko, N.N., Fishell, G., & Tsien, R.W. (2013). Oxytocin enhances hippocampal spike transmission by modulating fast‐spiking interneurons. Nature, 500, 458–462.
Parker, K.J., Oztan, O., Libove, R.A., Sumiyoshi, R.D., Jackson, L.P., Karhson, D.S., … & 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, 8119–8124.
Peltola, M.J., Strathearn, L., & Puura, K. (2018). Oxytocin promotes face‐sensitive neural responses to infant and adult faces in mothers. Psychoneuroendocrinology, 91, 261–270.
Pletzer, B., Kerschbaum, H., & Klimesch, W. (2010). When frequencies never synchronize: The golden mean and the resting EEG. Brain Research, 1335, 91–102.
Quintana, D.S., & Guastella, A.J. (2020). An allostatic theory of oxytocin. Trends in Cognitive Sciences, 24, 515–528.
Rassi, E., Dorffner, G., Gruber, W., Schabus, M., & Klimesch, W. (2019). Coupling and decoupling between brain and body oscillations. Neuroscience Letters, 711, 134401.
Rodriguez‐Larios, J., & Alaerts, K. (2019). Tracking transient changes in the neural frequency architecture: Harmonic relationships between theta and alpha peaks facilitate cognitive performance. The Journal of Neuroscience, 39, 6291–6298.
Rodriguez‐Larios, J., & Alaerts, K. (2020). EEG alpha‐theta dynamics during mind wandering in the context of breath focus meditation: An experience sampling approach with novice meditation practitioners. The European Journal of Neuroscience, 53, 1855–1868.
Rodriguez‐Larios, J., Faber, P., Achermann, P., Tei, S., & Alaerts, K. (2020). From thoughtless awareness to effortful cognition: Alpha – theta cross‐frequency dynamics in experienced meditators during meditation, rest and arithmetic. Scientific Reports, 10, 5419.
Rodriguez‐Larios, J., Wong, K.F., Lim, J., & Alaerts, K. (2020). Mindfulness training is associated with changes in alpha‐theta cross‐frequency dynamics during meditation. Mindfulness, 11, 2695–2704.
Roopun, A.K., Kramer, M.A., Carracedo, L.M., Kaiser, M., Davies, C.H., Traub, R.D., … & Whittington, M.A. (2008). Temporal interactions between cortical rhythms. Frontiers in Neuroscience, 2, 145–154.
Rubenstein, J.L., & Merzenich, M.M. (2003). Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes, Brain, and Behavior, 2, 255–267.
Ruissen, M.I., & De Bruijn, E.R. (2015). Is it me or is it you? Behavioral and electrophysiological effects of oxytocin administration on self‐other integration during joint task performance. Cortex, 70, 146–154.
Rutherford, H.J.V., Guo, X.M., Wu, J., Graber, K.M., Hayes, N.J., Pelphrey, K.A., & Mayes, L.C. (2018). Intranasal oxytocin decreases cross‐frequency coupling of neural oscillations at rest. International Journal of Psychophysiology, 123, 143–151.
Schiller, B., Koenig, T., & Heinrichs, M. (2019). Oxytocin modulates the temporal dynamics of resting EEG networks. Scientific Reports, 9, 13418.
Shaffer, F., Mccraty, R., & Zerr, C.L. (2014). A healthy heart is not a metronome: An integrative review of the heart's anatomy and heart rate variability. Frontiers in Psychology, 5, 1040.
Shamay‐Tsoory, S.G., & Abu‐Akel, A. (2016). The social salience hypothesis of oxytocin. Biological Psychiatry, 79, 194–202.
Singh, F., Nunag, J., Muldoon, G., Cadenhead, K.S., Pineda, J.A., & Feifel, D. (2016). Effects of intranasal oxytocin on neural processing within a socially relevant neural circuit. European Neuropsychopharmacology, 26, 626–630.
Soriano, J., Daniels, N., Prinsen, J., & Alaerts, K. (2020). Intranasal oxytocin enhances approach‐related EEG frontal alpha asymmetry during engagement of direct eye contact. Brain Communications, 2, fcaa093.
Stoop, R. (2012). Neuromodulation by oxytocin and vasopressin. Neuron, 76, 142–159.
Tarvainen, M.P., Niskanen, J.P., Lipponen, J.A., Ranta‐Aho, P.O., & Karjalainen, P.A. (2014). Kubios HRV – heart rate variability analysis software. Computer Methods and Programs in Biomedicine, 113, 210–220.
Tenke, C.E., & Kayser, J. (2005). Reference‐free quantification of EEG spectra: Combining current source density (CSD) and frequency principal components analysis (fPCA). Clinical Neurophysiology, 116, 2826–2846.
Van De Cruys, S., Evers, K., Van Der Hallen, R., Van Eylen, L., Boets, B., De‐Wit, L., & Wagemans, J. (2014). Precise minds in uncertain worlds: Predictive coding in autism. Psychological Review, 121, 649–675.
Van Der Donck, S., Moerkerke, M., Dlhosova, T., Vettori, S., Dzhelyova, M., Alaerts, K., & Boets, B. (2022). Monitoring the effect of oxytocin on the neural sensitivity to emotional faces via frequency‐tagging EEG: A double‐blind, cross‐over study. Psychophysiology, 59, e14026.
Waller, C., Wittfoth, M., Fritzsche, K., Timm, L., Wittfoth‐Schardt, D., Rottler, E., … & Gündel, H. (2015). Attachment representation modulates oxytocin effects on the processing of own‐child faces in fathers. Psychoneuroendocrinology, 62, 27–35.
Wechsler, D. (1999). Wechsler abbreviated scale of intelligence (WASI). San Antonio, TX: Psychological Corporation.
Wigton, R., Radua, J., Allen, P., Averbeck, B., Meyer‐Lindenberg, A., Mcguire, P., … & Fusar‐Poli, P. (2015). Neurophysiological effects of acute oxytocin administration: Systematic review and meta‐analysis of placebo‐controlled imaging studies. Journal of Psychiatry & Neuroscience, 40, E1–E22.
World Medical Association. (2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 310, 2191–2194.
Wynn, J.K., Green, M.F., Hellemann, G., Reavis, E.A., & Marder, S.R. (2019). A dose‐finding study of oxytocin using neurophysiological measures of social processing. Neuropsychopharmacology, 44, 289–294.
Ye, Z., Stolk, A., Toni, I., & Hagoort, P. (2017). Oxytocin modulates semantic integration in speech comprehension. Journal of Cognitive Neuroscience, 29, 267–276.
Zaninetti, M., & Raggenbass, M. (2000). Oxytocin receptor agonists enhance inhibitory synaptic transmission in the rat hippocampus by activating interneurons in stratum pyramidale. The European Journal of Neuroscience, 12, 3975–3984.
Zelenina, M., Kosilo, M., Da Cruz, J., Antunes, M., Figueiredo, P., Mehta, M.A., & Prata, D. (2022). Temporal dynamics of intranasal oxytocin in human brain electrophysiology. Cerebral Cortex, 32, 3110–3126.
Zhang, X., Li, P., Otieno, S., Li, H., & Leppänen, P.H.T. (2021). Oxytocin reduces romantic rejection‐induced pain in online speed‐dating as revealed by decreased frontal‐midline theta oscillations. Psychoneuroendocrinology, 133, 105411.

1257621N Fonds Wetenschappelijk Onderzoek; FWO-TBM T001821N Fonds Wetenschappelijk Onderzoek; 2019-J1811190-212989 Doctor Gustave Delport fund of the King Baudouin Foundation; Branco-Weiss Fellowship; C14/17/102 Onderzoeksraad, KU Leuven; ELG-D2857 Onderzoeksraad, KU Leuven

Keywords: Oxytocin; alpha; autism spectrum disorder; electroencephalography; heart rate variability; neural rhythms; signal to noise; theta

50-56-6 (Oxytocin)

Date Created: 20240224 Date Completed: 20241029 Latest Revision: 20241120

20250114

10.1111/jcpp.13966

38400592