Inverse effects of oxytocin on attributing mental activity to others in depressed and healthy subjects: a double-blind placebo controlled FMRI study

David Pincus, Samet Kose, Ashley Arana, Kevin Johnson, Paul S Morgan, Jeffrey Borckardt, Tal Herbsman, Fran Hardaway, Mark S George, Jaak Panksepp, Ziad Nahas, David Pincus, Samet Kose, Ashley Arana, Kevin Johnson, Paul S Morgan, Jeffrey Borckardt, Tal Herbsman, Fran Hardaway, Mark S George, Jaak Panksepp, Ziad Nahas

Abstract

Background: Oxytocin is a stress-attenuating and pro-social neuropeptide. To date, no study has looked at the effects of oxytocin in modulating brain activity in depressed individuals nor attempted to correlate this activity with attribution of mental activity in others.

Method: We enrolled 10 unmedicated depressed adults and 10 matched healthy controls in a crossover, double blind placebo controlled fMRI 40 i.u. intra-nasal oxytocin study (20 i.u. per nostril). Each subject performed reading the mind in the eyes task (RMET) before and after inhalation of oxytocin or placebo control for a total of 80 scans.

Results: Before oxytocin administration, RMET engaged the medial and lateral prefrontal cortex, amygdala, insula and associative areas. Depressed subjects showed increased anterior ventral activation for the RMET minus gender identification contrast whereas matched controls showed increased dorsal and frontal activity. Compared to placebo, oxytocin in depressed subjects showed increased activity in the superior middle frontal gyrus and insula, while controls exhibited more activity in ventral regions. Oxytocin also led to inverse effects in reaction times on attribution task between groups, with controls getting faster and depressed individuals slower to respond.

Conclusion: Depression is associated with increased paralimbic activity during emotional mental attribution of others, appearing to be distinctly modulated by oxytocin when compared to healthy controls. Further studies are needed to explore long-term exposure to pro-social neuropeptides on mood in depressed populations and assess their clinical relevance.

Keywords: depression; fMRI; mentalization; oxytocin; theory of mind.

Figures

Figure 1
Figure 1
Reaction time slope changes with intra-nasal oxytocin in healthy matched controls (blue) and depressed subjects (red) across RMET, gender attribution and motor cued response.
Figure 2
Figure 2
Baseline RMET minus Gender Attribution: Predominant ventral activations in unmedicated depressed subjects at baseline (red) compared to superior frontal and temporal activations in healthy matched controls (blue).
Figure 3
Figure 3
Baseline (green) and added activations with oxytocin compared to placebo (red) in unmedicated depressed subjects during RMET.
Figure 4
Figure 4
Baseline (green) and added activations with oxytocin compared to placebo (red) in healthy matched controls during RMET.

References

    1. Anisman H. (1984). “Vulnerability to depression: contribution of stress,” in Neurobiology of Mood Disorders edsR. M. Post R. M., Ballenger J. C.(Baltimore: Williams and Wilkins; ), 407–431
    1. Baron-Cohen S., Ring H., Chitnis X., Wheelwright S., Gregory L., Williams S., Brammer M., Bullmore E. (2006). fMRI of parents of children with Asperger syndrome: a pilot study. Brain Cogn. 61, 122–13010.1016/j.bandc.2005.12.011
    1. Baron-Cohen S., Wheelwright S., Hill J., Raste Y., Plumb I. (2001). The “Reading the Mind in the Eyes” test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J. Child. Psychol. Psychiatry 42, 241–25110.1111/1469-7610.00715
    1. Bell C. (2006). Plasma oxytocin levels in depression and their correlation with the temperament dimension of reward dependence. J. Psychopharmacol. 20, 656–66010.1177/0269881106060512
    1. Burbach J. P., Schoots O., Hernando F. (1998). Biochemistry of vasopressin fragments. Prog. Brain Res. 119, 127–13610.1016/S0079-6123(08)61566-6
    1. Choi-Kain L. W., Gunderson J. G. (2008). Mentalization: ontogeny, assessment, and application in the treatment of borderline personality disorder. Am. J. Psychiatry 165, 1127–113510.1176/appi.ajp.2008.07081360
    1. Claybaugh J. R., Uyehara C. F. (1993). Metabolism of neurohypophysial hormones. Ann. N. Y. Acad. Sci. 689, 250–26810.1111/j.1749-6632.1993.tb55552.x
    1. de Leeuw J., Kreft I. G. (1995). Questioning multilevel models. J. Educ. Behav. Stat. 20, 171–189
    1. Ditzen B., Neumann I. D., Bodenmann G., von Dawans B., Turner R. A., Ehlert U., Heinrichs M. (2007). Effects of different kinds of couple interaction on cortisol and heart rate responses to stress in women. Psychoneuroendocrinology 32, 565–57410.1016/j.psyneuen.2007.03.011
    1. Domes G., Heinrichs M., Michel A., Berger C., Herpertz S. (2007). Oxytocin improves “mind-reading” in humans. Biol. Psychiatry 61, 731–73310.1016/j.biopsych.2006.07.015
    1. Epperson C. N., McDougle C. J., Price L. H. (1996a). Intranasal oxytocin in obsessive-compulsive disorder. Biol. Psychiatry 40, 547–54910.1016/0006-3223(96)00120-5
    1. Epperson C. N., McDougle C. J., Price L. H. (1996b). Intranasal oxytocin in trichotillomania. Biol. Psychiatry 40, 559–56010.1016/0006-3223(96)00165-5
    1. Fonagy P., Target M. (2007). The rooting of the mind in the body: new links between attachment theory and psychoanalytic thought. J. Am. Psychoanal. Assoc. 55, 411–456
    1. Gallagher H. L., Happe F., Brunswick N., Fletcher P. C., Frith U., Frith C. D. (2000). Reading the mind in cartoons and stories: an fMRI study of ‘theory of mind’ in verbal and nonverbal tasks. Neuropsychologia 38, 11–2110.1016/S0028-3932(99)00053-6
    1. George M. S., Kimbrell T. A., Parekh P. I., Ketter T. A., Pazzaglia P. J., Callahan A., Frye M., Marangell L., Herscovitch P., Post R. M. (1995). Actively Depressed Subjects Have Difficulty Inducing, and Blunted Limbic rCBF During, Transient Sadness. Miami: APA New Research; Abstracts 99-NR167.
    1. Green M. J., Cahill C. M., Malhi G. S. (2007). The cognitive and neurophysiological basis of emotion dysregulation in bipolar disorder. J. Affect. Disord. 103, 29–4210.1016/j.jad.2007.01.024
    1. Guastella A. J., Mitchell P. B., Dadds M. R. (2008). Oxytocin increases gaze to the eye region of human faces. Biol. Psychiatry 63, 3–510.1016/j.biopsych.2007.06.026
    1. Happe F., Ehlers S., Fletcher P., Frith U., Johansson M., Gillberg C., Dolan R., Frackowiak R., Frith C. (1996). ‘Theory of mind’ in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 8, 197–20110.1097/00001756-199612200-00040
    1. Happe F. G. (1994). An advanced test of theory of mind: understanding of story characters’ thoughts and feelings by able autistic, mentally handicapped, and normal children and adults. J. Autism Dev. Disord. 24, 129–15410.1007/BF02172093
    1. Hartmann H. P. (2009). Psychoanalytic self psychology and its conceptual development in light of developmental psychology, attachment theory, and neuroscience. Ann. N. Y. Acad. Sci. 1159, 86–10510.1111/j.1749-6632.2009.04476.x
    1. Hoffman D. A., Gavin M. B. (1998). Centering decisions in hierarchical linear models: implications for research in organizations. J. Manage. 24, 623–641
    1. Hurlemann R., Patin A., Onur O. A., Cohen M. X., Baumgartner T., Metzler S., Dziobek I., Gallinat J., Wagner M., Maier W., Kendrick K. M. (2010). Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans. J. Neurosci. 30, 4999–500710.1523/JNEUROSCI.5538-09.2010
    1. Jenkinson M., Bannister P., Brady M., Smith S. (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17, 825–84110.1016/S1053-8119(02)91132-8
    1. Jenkinson M., Smith S. (2001). A global optimisation method for robust affine registration of brain images. Med. Image Anal. 5, 143–15610.1016/S1361-8415(01)00036-6
    1. Johnston P. J., Stojanov W., Devir H., Schall U. (2005). Functional MRI of facial emotion recognition deficits in schizophrenia and their electrophysiological correlates. Eur. J. Neurosci. 22, 1221–123210.1111/j.1460-9568.2005.04294.x
    1. Kirsch P., Esslinger C., Chen Q., Mier D., Lis S., Siddhanti S., Gruppe H., Mattay V. S., Gallhofer B., Meyer-Lindenberg A. (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J. Neurosci. 25, 11489–1149310.1523/JNEUROSCI.3984-05.2005
    1. Kuo M., Mohler B., Raudenbush S. L., Earls F. J. (2000). Assessing exposure to violence using multiple informants: application of hierarchical linear model. J. Child. Psychol. Psychiatry 41, 1049–105610.1111/1469-7610.00692
    1. Marsh A. A., Yu H. H., Pine D. S., Blair R. J. (2010). Oxytocin improves specific recognition of positive facial expressions. Psychopharmacology (Berl) 209, 225–23210.1007/s00213-010-1780-4
    1. Mayberg H. S., Liotti M., Brannan S. K., McGinnis S., Mahurin R. K., Jerabek P. A., Silva J. A., Tekell J. L., Martin C. C., Lancaster J. L., Fox P. T. (1999). Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J Psychiatry 156, 675–682
    1. Mayer J. D., Salovey P., Caruso D. R., Sitarenios G. (2003). Measuring emotional intelligence with the MSCEIT V2.0. Emotion 3, 97–10510.1037/1528-3542.3.1.97
    1. McGuigan W. M., Katzev A. R., Pratt C. C. (2003). Multi-level determinants of retention in a home-visiting child abuse prevention program. Child Abuse Negl. 27, 363–38010.1016/S0145-2134(03)00024-3
    1. Meins E., Fernyhough C., Wainwright R., Das Gupta M., Fradley E., Tuckey M. (2002). Maternal mind-mindedness and attachment security as predictors of theory of mind understanding. Child Dev. 73, 1715–172610.1111/1467-8624.00501
    1. Nelson E. E., Panksepp J. (1998). Brain substrates of infant-mother attachment: contributions of opioids, oxytocin, and norepinephrine. Neurosci. Biobehav. Rev. 22, 437–45210.1016/S0149-7634(97)00052-3
    1. Nezlek J. B., Zyzniewski L. E. (1998). Using hierarchical linear modeling to analyze grouped data. Grouped Dyn. 2, 313–32010.1037/1089-2699.2.4.313
    1. Northoff G. (2007). Psychopathology and pathophysiology of the self in depression – neuropsychiatric hypothesis. J. Affect. Disord. 104, 1–1410.1016/j.jad.2007.02.012
    1. Ozonoff S., Pennington B. F., Rogers S. J. (1991). Executive function deficits in high-functioning autistic individuals: relationship to theory of mind. J. Child Psychol. Psychiatry 32, 1081–110510.1111/j.1469-7610.1991.tb00351.x
    1. Panksepp J. (2005). Affective consciousness: core emotional feelings in animals and humans. Conscious. Cogn. 14, 30–8010.1016/j.concog.2004.10.004
    1. Petrides M., Pandya D. (2007). Efferent association pathways from the rostral prefrontal cortex in the macaque monkey. J. Neurosci. 27, 11573–1158610.1523/JNEUROSCI.2419-07.2007
    1. Pilowsky T., Yirmiya N., Arbelle S., Mozes T. (2000). Theory of mind abilities of children with schizophrenia, children with autism, and normally developing children. Schizophr. Res. 42, 145–15510.1016/S0920-9964(99)00101-2
    1. Pontiroli A. E. (1998). Peptide hormones: review of current and emerging uses by nasal delivery. Adv. Drug Deliv. Rev. 29, 81–8710.1016/S0169-409X(97)00062-8
    1. Price J. L., Drevets W. C. (2009). Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–21610.1038/npp.2009.104
    1. Raudenbush S. W., Chan W. S. (1993). Application of a hierarchical linear model to the study of adolescent deviance in an overlapping cohort design. J. Consult. Clin. Psychol. 61, 941–95110.1037/0022-006X.61.6.941
    1. Rizzolatti G., Fabbri-Destro M. (2008). The mirror system and its role in social cognition. Curr. Opin. Neurobiol. 18, 179–18410.1016/j.conb.2008.08.001
    1. Sliwinski M. J., Hall C. B. (1998). Constraints on general slowing: a meta-analysis using hierarchical linear models with random coefficients. Psychol. Aging 13, 164–17510.1037/0882-7974.13.1.164
    1. Smith S. M. (2002). Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143–15510.1002/hbm.10062
    1. Stuss D. T., Gallup G. G. Jr., Alexander M. P. (2001). The frontal lobes are necessary for ‘theory of mind’. Brain 124, 279–28610.1093/brain/124.2.279
    1. Uekermann J., Channon S., Lehmkamper C., Abdel-Hamid M., Vollmoeller W., Daum I. (2008). Executive function, mentalizing and humor in major depression. J. Int. Neuropsychol. Soc. 14, 55–6210.1017/S1355617708080016
    1. Uvnas-Moberg K. (1998). Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 23, 819–83510.1016/S0306-4530(98)00056-0
    1. Vogeley K., Bussfeld P., Newen A., Herrmann S., Happe F., Falkai P., Maier W., Shah N. J., Fink G. R., Zilles K. (2001a). Mind reading: neural mechanisms of theory of mind and self-perspective. Neuroimage 14, 170–18110.1006/nimg.2001.0789
    1. Vogeley K., Bussfeld P., Newen A., Herrmann S., Happe F., Falkai P., Maier W., Shah N. J., Fink G. R., Zilles K. (2001b). Mind reading: neural mechanisms of theory of mind and self-perspective. Neuroimage 14, 170–18110.1006/nimg.2001.0789
    1. Williams J. G., Allison C., Scott F. J., Bolton P. F., Baron-Cohen S., Matthews F. E., Brayne C. (2008). The Childhood Autism Spectrum Test (CAST): sex differences. J. Autism Dev. Disord. 38, 1731–173910.1007/s10803-008-0558-6
    1. Winslow J. T., Insel T. R. (2004). Neuroendocrine basis of social recognition. Curr. Opin. Neurobiol. 14, 248–25310.1016/j.conb.2004.03.009
    1. Woolrich M. W., Ripley B. D., Brady M., Smith S. M. (2001). Temporal autocorrelation in univariate linear modeling of FMRI data. Neuroimage 14, 1370–138610.1006/nimg.2001.0931
    1. Worsley K. J. (2001). “Statistical analysis of activation images,” in Functional MRI: An Introduction to Methods, Jezzard P., Matthews P. H., Smith S. M. (Oxford: Oxford University Press; ), 251–270
    1. Zak P. J., Kurzban R., Matzner W. T. (2005). Oxytocin is associated with human trustworthiness. Horm. Behav. 48, 522–52710.1016/j.yhbeh.2005.07.009

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