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Exogenous Testosterone Enhances Responsiveness to Social Threat in the Neural Circuitry of Social Aggression in Humans

      Background

      In a range of species, the androgen steroid testosterone is known to potentiate neural circuits involved in intraspecific aggression. Disorders of impulsive aggression in humans have likewise been associated with high testosterone levels, but human evidence for the link between testosterone and aggression remains correlational and inconclusive.

      Methods

      Twelve female participants underwent functional magnetic resonance imaging during three sessions while viewing stimuli differing in social threat value: angry and happy facial expressions. The first session served to establish associations between baseline hormone levels and neural activation. Participants were retested in a second and third session after placebo-controlled sublingual administration of .5 mg testosterone.

      Results

      Findings demonstrate consistent activation to angry versus happy faces in areas known to be involved in vertebrate reactive aggression, such as the amygdala and hypothalamus. Suprathreshold clusters were also found in the orbitofrontal cortex (Brodmann area 47), a region implicated in impulse control in humans. Baseline endocrine profiles of high testosterone and low cortisol were associated with stronger activation in subcortical structures. Neural responses in most activated regions were more persistent after testosterone administration than after placebo.

      Conclusions

      These data demonstrate that testosterone enhances responsiveness in neural circuits of social aggression. Based on animal literature, it is argued that actions of testosterone on subcortical reactive aggression circuits give rise to this effect. Implications for our understanding of the pathophysiology of disorders of impulsive aggression are discussed.

      Key Words

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      References

        • Nelson R.J.
        • Chiavegatto S.
        Molecular basis of aggression.
        Trends Neurosci. 2001; 24: 713-719
        • Öhman A.
        Face the beast and fear the face: Animal and social fears as prototypes for evolutionary analyses of emotion.
        Psychophysiology. 1986; 23: 123-145
        • Blair R.J.
        Facial expressions, their communicatory functions and neuro-cognitive substrates.
        Philos Trans R Soc Lond B Biol Sci. 2003; 358: 561-572
        • Lee R.
        • Coccaro E.
        The neuropsychopharmacology of criminality and aggression.
        Can J Psychiatry. 2001; 46: 35-44
        • Giammanco M.
        • Tabacchi G.
        • Giammanco S.
        • Di Majo D.
        • La Guardia M.
        Testosterone and aggressiveness.
        Med Sci Monit. 2005; 11: RA136-RA145
        • Lumia A.R.
        • Thorner K.M.
        • McGinnis M.Y.
        Effects of chronically high doses of the anabolic androgenic steroid, testosterone, on intermale aggression and sexual behavior in male rats.
        Physiol Behav. 1994; 55: 331-335
        • Melloni Jr, R.H.
        • Connor D.F.
        • Hang P.T.
        • Harrison R.J.
        • Ferris C.F.
        Anabolic-androgenic steroid exposure during adolescence and aggressive behavior in golden hamsters.
        Physiol Behav. 1997; 61: 359-364
        • Rejeski W.J.
        • Brubaker P.H.
        • Herb R.A.
        • Kaplan J.R.
        • Koritnik D.
        Anabolic steroids and aggressive behavior in cynomolgus monkeys.
        J Behav Med. 1988; 11: 95-105
        • Archer J.
        Testosterone and human aggression: An evaluation of the challenge hypothesis.
        Neurosci Biobehav Rev. 2006; 30: 273-436
        • Virkkunen M.
        • Rawlings R.
        • Tokola R.
        • Poland R.E.
        • Guidotti A.
        • Nemeroff C.
        • et al.
        CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers.
        Arch Gen Psychiatry. 1994; 51: 20-27
        • Stalenheim E.G.
        • Eriksson E.
        • von Knorring L.
        • Wide L.
        Testosterone as a biological marker in psychopathy and alcoholism.
        Psychiatry Res. 1998; 77: 79-88
        • Aromäki A.S.
        • Lindman R.E.
        • Eriksson C.J.
        Testosterone, sexuality and antisocial personality in rapists and child molesters: A pilot study.
        Psychiatry Res. 2002; 110: 239-247
        • Rasanen P.
        • Hakko H.
        • Visuri S.
        • Paanila J.
        • Kapanen P.
        • Suomela T.
        • Tiihonen J.
        Serum testosterone levels, mental disorders and criminal behaviour.
        Acta Psychiatr Scand. 1999; 99: 348-352
        • Ferris C.F.
        • Delville Y.
        Vasopressin and serotonin interactions in the control of agonistic behavior.
        Psychoneuroendocrinology. 1994; 19: 593-601
        • de Vries G.J.
        • Miller M.A.
        Anatomy and function of extrahypothalamic vasopressin systems in the brain.
        Prog Brain Res. 1998; 119: 3-20
        • Delville Y.
        • Mansour K.M.
        • Ferris C.F.
        Testosterone facilitates aggression by modulating vasopressin receptors in the hypothalamus.
        Physiol Behav. 1996; 60: 25-29
        • Viau V.
        Functional cross-talk between the hypothalamic–pituitary–gonadal and –adrenal axes.
        J Neuroendocrinol. 2002; 14: 506-513
        • Sapolsky R.M.
        Adrenocortical function, social rank, and personality among wild baboons.
        Biol Psychiatry. 1990; 28: 862-878
        • Kalin N.H.
        Primate models to understand human aggression.
        J Clin Psychiatry. 1999; 60: 29-32
        • Popma A.
        • Vermeiren R.
        • Geluk C.A.
        • Rinne T.
        • van den Brink W.
        • Knol D.L.
        • et al.
        Cortisol moderates the relationship between testosterone and aggression in delinquent male adolescents.
        Biol Psychiatry. 2006; 61: 405-411
        • Blair R.J.
        • Cipolotti L.
        Impaired social response reversal.
        Brain. 2000; 123: 1122-1141
        • Eslinger P.J.
        • Damasio A.R.
        Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR.
        Neurology. 1985; 35: 1731-1741
        • Goyer P.F.
        • Andreason P.J.
        • Semple W.E.
        • Clayton A.H.
        • King A.C.
        • Compton-Toth B.A.
        • et al.
        Positron-emission tomography and personality disorders.
        Neuropsychopharmacology. 1994; 10: 21-28
        • New A.S.
        • Buchsbaum M.S.
        • Hazlett E.A.
        • Goodman M.
        • Koenigsberg H.W.
        • Lo J.
        • et al.
        Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression.
        Psychopharmacology (Berl). 2004; 176: 451-458
        • Blair R.J.
        • Morris J.S.
        • Frith C.D.
        • Perrett D.I.
        • Dolan R.J.
        Dissociable neural responses to facial expressions of sadness and anger.
        Brain. 1999; 122: 883-893
        • Whalen P.J.
        • Shin L.M.
        • McInerney S.C.
        • Fischer H.
        • Wright C.I.
        • Rauch S.L.
        A functional MRI study of human amygdala responses to facial expressions of fear versus anger.
        Emotion. 2001; 1: 70-83
        • Fischer H.
        • Sandblom J.
        • Gavazzeni J.
        • Fransson P.
        • Wright C.I.
        • Backman L.
        Age-differential patterns of brain activation during perception of angry faces.
        Neurosci Lett. 2005; 386: 99-104
        • Hariri A.R.
        • Tessitore A.
        • Mattay V.S.
        • Fera F.
        • Weinberger D.R.
        The amygdala response to emotional stimuli: a comparison of faces and scenes.
        Neuroimage. 2002; 17: 317-323
        • Sprengelmeyer R.
        • Rausch M.
        • Eysel U.T.
        • Przuntek H.
        Neural structures associated with recognition of facial expressions of basic emotions.
        Proc Biol Sci. 1998; 265: 1927-1931
        • Van Honk J.
        • Tuiten A.
        • Verbaten R.
        • van den Hout M.
        • Koppeschaar H.
        • Thijssen J.
        • de Haan E.
        Correlations among salivary testosterone, mood, and selective attention to threat in humans.
        Horm Behav. 1999; 36: 17-24
        • Wirth M.M.
        • Schultheiss O.C.
        Basal testosterone moderates responses to anger faces in humans.
        Physiol Behav. 2007; 90: 496-505
        • Van Honk J.
        • Tuiten A.
        • van den Hout M.
        • Koppeschaar H.
        • Thijssen J.
        • de Haan E.
        • Verbaten R.
        Baseline salivary cortisol levels and preconscious selective attention for threat.
        Psychoneuroendocrinology. 1998; 23: 741-747
        • Van Honk J.
        • Tuiten A.
        • Hermans E.
        • Putman P.
        • Koppeschaar H.
        • Thijssen J.
        • et al.
        A single administration of testosterone induces cardiac accelerative responses to angry faces in healthy young women.
        Behav Neurosci. 2001; 115: 238-242
        • Blair R.J.
        The roles of orbital frontal cortex in the modulation of antisocial behavior.
        Brain Cogn. 2004; 55: 198-208
        • Lundqvist D.
        • Flykt A.
        • Öhman A.
        The Karolinska Directed Emotional Faces.
        Karolinska Institute, Stockholm1998
        • Ekman P.
        • Friesen W.V.
        Pictures of Facial Affect.
        Consulting Psychologists Press, Palo Alto, CA1976
        • Tuiten A.
        • Van Honk J.
        • Koppeschaar H.
        • Bernaards C.
        • Thijssen J.
        • Verbaten R.
        Time course of effects of testosterone administration on sexual arousal in women.
        Arch Gen Psychiatry. 2000; 57: 149-153
        • Hermans E.J.
        • Putman P.
        • Baas J.M.P.
        • Koppeschaar H.
        • Van Honk J.
        A single administration of testosterone reduces fear potentiated startle in humans.
        Biological Psychiatry. 2006; 59: 872-874
        • van Gelderen P.
        • Ramsey N.F.
        • Liu G.
        • Duyn J.H.
        • Frank J.A.
        • Weinberger D.R.
        • Moonen C.T.
        Three-dimensional functional magnetic resonance imaging of human brain on a clinical 1.5-T scanner.
        Proc Natl Acad Sci U S A. 1995; 92: 6906-6910
        • Ramsey N.F.
        • Tallent K.
        • Van Gelderen P.
        • Frank J.A.
        • Moonen C.T.W.
        • Weinberger D.R.
        Reproducibility of human 3D fMRI brain maps acquired during a motor task.
        Hum Brain Mapp. 1996; 4: 113-121
        • Dabbs Jr., J.M.
        Salivary testosterone measurements: Reliability across hours, days, and weeks.
        Physiol Behav. 1990; 48: 83-86
        • Kirschbaum C.
        • Hellhammer D.H.
        Salivary cortisol in psychoneuroendocrine research: recent developments and applications.
        Psychoneuroendocrinology. 1994; 19: 313-333
        • Kling A.S.
        • Brothers L.A.
        The amygdala and social behavior.
        in: Aggleton J.P. The Amygdala. Wiley-Liss, New York1992: 353-377
        • Mayr E.
        Behavior programs and evolutionary strategies.
        Am Sci. 1974; 62: 650-659
        • Fridlund A.J.
        Evolution and facial action in reflex, social motive, and paralanguage.
        Biol Psychol. 1991; 32: 3-100
        • Putman P.
        • Hermans E.J.
        • Van Honk J.
        Emotional Stroop performance for masked angry faces: It’s BAS, not BIS.
        Emotion. 2004; 4: 305-311
        • Summers C.H.
        • Watt M.J.
        • Ling T.L.
        • Forster G.L.
        • Carpenter R.E.
        • Korzan W.J.
        • et al.
        Glucocorticoid interaction with aggression in non-mammalian vertebrates: Reciprocal action.
        Eur J Pharmacol. 2005; 526: 21-35
        • Blanchard D.C.
        • Sakai R.R.
        • McEwen B.
        • Weiss S.M.
        • Blanchard R.J.
        Subordination stress: Behavioral, brain, and neuroendocrine correlates.
        Behav Brain Res. 1993; 58: 113-121
        • Van Honk J.
        • Tuiten A.
        • de Haan E.
        • van den Hout M.
        • Stam H.
        Attentional biases for angry faces: Relationships to trait anger and anxiety.
        Cogn Emotion. 2001; 15: 279-297
        • Aikey J.L.
        • Nyby J.G.
        • Anmuth D.M.
        • James P.J.
        Testosterone rapidly reduces anxiety in male house mice (Mus musculus).
        Horm Behav. 2002; 42: 448-460
        • Van Honk J.
        • Peper J.S.
        • Schutter D.J.L.G.
        Testosterone reduces unconscious fear but not consciously experienced anxiety: Implications for the disorders of fear and anxiety.
        Biol Psychiatry. 2005; 58: 218-225
        • Koolhaas J.M.
        • Van den Brink T.H.
        • Roozendaal B.
        • Boorsma F.
        Medial amygdala and aggressive behavior: Interaction between testosterone and vasopressin.
        Aggressive Behav. 1990; 16: 223-229
        • Fischer H.
        • Wright C.I.
        • Whalen P.J.
        • McInerney S.C.
        • Shin L.M.
        • Rauch S.L.
        Brain habituation during repeated exposure to fearful and neutral faces: A functional MRI study.
        Brain Res Bull. 2003; 59: 387-392
        • Dias R.
        • Robbins T.W.
        • Roberts A.C.
        Dissociation in prefrontal cortex of affective and attentional shifts.
        Nature. 1996; 380: 69-72
        • Damasio H.
        • Grabowski T.
        • Frank R.
        • Galaburda A.M.
        • Damasio A.R.
        The return of Phineas Gage: Clues about the brain from the skull of a famous patient.
        Science. 1994; 264: 1102-1105
        • De La Fuente J.M.
        • Goldman S.
        • Stanus E.
        • Vizuete C.
        • Morlan I.
        • Bobes J.
        • Mendlewicz J.
        Brain glucose metabolism in borderline personality disorder.
        J Psychiatr Res. 1997; 31: 531-541
        • Soloff P.H.
        • Meltzer C.C.
        • Becker C.
        • Greer P.J.
        • Kelly T.M.
        • Constantine D.
        Impulsivity and prefrontal hypometabolism in borderline personality disorder.
        Psychiatry Res. 2003; 123: 153-163
        • Herpertz S.C.
        • Dietrich T.M.
        • Wenning B.
        • Krings T.
        • Erberich S.G.
        • Willmes K.
        • et al.
        Evidence of abnormal amygdala functioning in borderline personality disorder: A functional MRI study.
        Biol Psychiatry. 2001; 50: 292-298
        • Schmahl C.G.
        • Vermetten E.
        • Elzinga B.M.
        • Bremner J.D.
        A positron emission tomography study of memories of childhood abuse in borderline personality disorder.
        Biol Psychiatry. 2004; 55: 759-765
        • Coccaro E.F.
        • Kavoussi R.J.
        Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.
        Arch Gen Psychiatry. 1997; 54: 1081-1088
        • Sundblad C.
        • Eriksson E.
        Reduced extracellular levels of serotonin in the amygdala of androgenized female rats.
        Eur Neuropsychopharmacol. 1997; 7: 253-259
        • Martinez-Conde E.
        • Leret M.L.
        • Diaz S.
        The influence of testosterone in the brain of the male rat on levels of serotonin (5-HT) and hydroxyindole-acetic acid (5-HIAA).
        Comp Biochem Physiol C. 1985; 80: 411-414
        • van de Kar L.
        • Levine J.
        • Van Orden 3rd, L.S.
        Serotonin in hypothalamic nuclei: increased content after castration of male rats.
        Neuroendocrinology. 1978; 27: 186-192
        • Schutter D.J.L.G.
        • Van Honk J.
        Decoupling of midfrontal delta-beta oscillations after testosterone administration.
        Int J Psychophysiol. 2004; 53: 71-73