Abstract
The neuropeptide oxytocin plays an important role in social cognition. One valuable tool to study social cognition in healthy and autistic humans in a neuroscientific context is the investigation of gaze toward another person. Of importance, it has been demonstrated that pronounced amygdala activation could be observed, when participants are confronted with direct gaze pictures in an fMRI setting, an effect that can be particularly observed in autistic individuals. In the present study, a combined pharmacological imaging genetics study has been conducted to further investigate the biological basis of direct gaze processing. N = 55 healthy males were invited to an oxytocin challenge study administered while watching direct vs. averted gaze pictures in an fMRI setting. In addition, the promoter region of the oxytocin receptor (OXTR) gene of the participants was investigated to search for individual differences in the recorded BOLD signal. The main result revealed that a genetic variation of the OXTR gene (rs401015) modulated the right amygdala activity for the fMRI contrast “direct > averted gaze” under the influence of the neuropeptide oxytocin. Here, carriers of the heterozygous CT variant showed higher activity compared to the TT group. The present study highlights the role of individual differences in a genetic variant of the OXTR gene for amygdala activation during processing of direct gaze pictures after intranasal oxytocin administration. In sum, the study shows the importance of combining a pharmacological challenge with genetic imaging to better understand the biological basis of social cognition.
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References
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 12:524–538
Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435:673–676
Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC (2007) Oxytocin improves “mind-reading” in humans. Biol Psychiatry 61:731–733
Schulze L, Lischke A, Greif J, Herpertz SC, Heinrichs M, Domes G (2011) Oxytocin increases recognition of masked emotional faces. Psychoneuroendocrinology 36:1378–1382
Guastella AJ, Mitchell PB, Dadds MR (2008) Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 63:3–5
Insel TR, O’Brien DJ, Leckman JF (1999) Oxytocin, vasopressin, and autism: is there a connection? Biol Psychiatry 45:145–157
Senju A, Johnson MH (2009) Atypical eye contact in autism: models, mechanisms and development. Neurosci Biobehav Rev 33:1204–1214
Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 107:4389–4394
Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, Hickie IB (2010) Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 67:692–694
Bakermans-Kranenburg MJ, van IJzendoorn MH (2013) Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry 3:e258
Ebstein RP, Knafo A, Mankuta D, Chew SH, Lai PS (2012) The contributions of oxytocin and vasopressin pathway genes to human behavior. Horm Behav 61:359–379
Kumsta R, Heinrichs M (2013) Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system. Curr Opin Neurobiol 23:11–16
Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (2009) Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc Natl Acad Sci USA 106:21437–21441
Lucht MJ, Barnow S, Sonnenfeld C, Rosenberger A, Grabe HJ, Schroeder W, Volzke H, Freyberger HJ, Herrmann FH, Kroemer H, Rosskopf D (2009) Associations between the oxytocin receptor gene (oxtr) and affect, loneliness and intelligence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 33:860–866
Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS, Weinberger DR, Meyer-Lindenberg A (2010) A common allele in the oxytocin receptor gene (oxtr) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proc Natl Acad Sci USA 107:13936–13941
Wu S, Jia M, Ruan Y, Liu J, Guo Y, Shuang M, Gong X, Zhang Y, Yang X, Zhang D (2005) Positive association of the oxytocin receptor gene (oxtr) with autism in the Chinese Han population. Biol Psychiatry 58:74–77
Wang J, Qin W, Liu B, Zhou Y, Wang D, Zhang Y, Jiang T, Yu C (2013) Neural mechanisms of oxytocin receptor gene mediating anxiety-related temperament. Brain Struct Funct. doi: 10.1007/s00429-013-0584-9
Inoue H, Yamasue H, Tochigi M, Abe O, Liu X, Kawamura Y, Takei K, Suga M, Yamada H, Rogers MA, Aoki S, Sasaki T, Kasai K (2010) Association between the oxytocin receptor gene and amygdalar volume in healthy adults. Biol Psychiatry 68:1066–1072
Thompson RJ, Parker KJ, Hallmayer JF, Waugh CE, Gotlib IH (2011) Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls. Psychoneuroendocrinology 36:144–147
Kiy A, Wilhelm O, Hildebrandt A, Reuter M, Sommer W (2013) On the genetic basis of face cognition and its relation to fluid cognitive abilities. Genes Brain Behav 12:438–445
Melchers M, Montag C, Markett S, Reuter M (in press) Relationship between oxytocin receptor genotype and recognition of facial emotion. Behav Neurosci
Montag C, Fiebach CJ, Kirsch P, Reuter M (2011) Interaction of 5-httlpr and a variation on the oxytocin receptor gene influences negative emotionality. Biol Psychiatry 69:601–603
Walter NT, Montag C, Markett S, Felten A, Voigt G, Reuter M (2012) Ignorance is no excuse: moral judgments are influenced by a genetic variation on the oxytocin receptor gene. Brain Cogn 78:268–273
Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489–11493
Bethlehem RA, van Honk J, Auyeung B, Baron-Cohen S (2013) Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 38:962–974
Domes G, Heinrichs M, Kumbier E, Grossmann A, Hauenstein K, Herpertz SC (2013) Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry 74:164–171
O’Connell G, Whalley HC, Mukherjee P, Stanfield AC, Montag C, Hall J, Reuter M (2012) Association of genetic variation in the promoter region of oxtr with differences in social affective neural processing. J Behav Brain Sci 2:60–66
Sauer C, Montag C, Reuter M, Kirsch P (2013) Imaging oxytocin x dopamine interactions: an epistasis effect of cd38 and comt gene variants influences the impact of oxytocin on amygdala activation to social stimuli. Front Neurosci 7:45
Lopatina O, Inzhutova A, Salmina AB, Higashida H (2012) The roles of oxytocin and cd38 in social or parental behaviors. Front Neurosci 6:182
Sauer C, Montag C, Worner C, Kirsch P, Reuter M (2012) Effects of a common variant in the cd38 gene on social processing in an oxytocin challenge study: possible links to autism. Neuropsychopharmacology 37:1474–1482
Itier RJ, Batty M (2009) Neural bases of eye and gaze processing: the core of social cognition. Neurosci Biobehav Rev 33:843–863
Kawashima R, Sugiura M, Kato T, Nakamura A, Hatano K, Ito K, Fukuda H, Kojima S, Nakamura K (1999) The human amygdala plays an important role in gaze monitoring. A pet study. Brain 122(Pt 4):779–783
Dalton KM, Nacewicz BM, Johnstone T, Schaefer HS, Gernsbacher MA, Goldsmith HH, Alexander AL, Davidson RJ (2005) Gaze fixation and the neural circuitry of face processing in autism. Nat Neurosci 8:519–526
Morris JS, Friston KJ, Buchel C, Frith CD, Young AW, Calder AJ, Dolan RJ (1998) A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 121(Pt 1):47–57
Adams RB Jr, Gordon HL, Baird AA, Ambady N, Kleck RE (2003) Effects of gaze on amygdala sensitivity to anger and fear faces. Science 300:1536
Kumsta R, Hummel E, Chen FS, Heinrichs M (2013) Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front Neurosci 7:83
Acknowledgments
This research was supported by a research grant from the Deutsche Forschungsgemeinschaft (German Research Association, DFG) to PK (KI 576/10-1) and MR (RE 1692/4-1). We thank Christiane Wörner, André Spachmann and Dagmar Gass for their assistance during data collection and analysis.
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The authors declare that they have no conflict of interest.
This article is part of the supplement “Bridging the gap between Neurobiology and Psychosocial Medicine.” This supplement was not sponsored by outside commercial interests. It was funded by the German Association for Psychiatry and Psychotherapy (DGPPN).
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Christian Montag and Carina Sauer have contributed equally to this study.
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Montag, C., Sauer, C., Reuter, M. et al. An interaction between oxytocin and a genetic variation of the oxytocin receptor modulates amygdala activity toward direct gaze: evidence from a pharmacological imaging genetics study. Eur Arch Psychiatry Clin Neurosci 263 (Suppl 2), 169–175 (2013). https://doi.org/10.1007/s00406-013-0452-x
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DOI: https://doi.org/10.1007/s00406-013-0452-x