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Neural indicators of interpersonal anger as cause and consequence of combat training stress symptoms

Published online by Cambridge University Press:  05 January 2017

G. Gilam*
Tel Aviv Center for Brain Function, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, 64239, Israel School of Psychological Sciences, Tel Aviv University, PO Box 39040, Tel Aviv 69978, Israel
T. Lin
Tel Aviv Center for Brain Function, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, 64239, Israel School of Psychological Sciences, Tel Aviv University, PO Box 39040, Tel Aviv 69978, Israel
E. Fruchter
Division of Mental Health, Israeli Defense Force Medical Corp, Tel Hashomer, Military Mail 02149, Israel
T. Hendler*
Tel Aviv Center for Brain Function, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, 64239, Israel School of Psychological Sciences, Tel Aviv University, PO Box 39040, Tel Aviv 69978, Israel Faculty of Medicine, Tel Aviv University, PO Box 39040, Tel Aviv 69978, Israel Sagol School of Neuroscience, Tel Aviv University, PO Box 39040, Tel Aviv 69978, Israel
*Address for correspondence: T. Hendler and G. Gilam, Tel Aviv Center for Brain Function, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, 64239, Israel. (Email: [T.H.] (Email: [G.G.]
*Address for correspondence: T. Hendler and G. Gilam, Tel Aviv Center for Brain Function, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, 64239, Israel. (Email: [T.H.] (Email: [G.G.]



Angry outbursts are an important feature of various stress-related disorders, and commonly lead to aggression towards other people. Findings regarding interpersonal anger have linked the ventromedial prefrontal cortex (vmPFC) to anger regulation and the locus coeruleus (LC) to aggression. Both regions were previously associated with traumatic and chronic stress symptoms, yet it is unclear if their functionality represents a consequence of, or possibly also a cause for, stress symptoms. Here we investigated the relationship between the neural trajectory of these indicators of anger and the development and manifestation of stress symptoms.


A total of 46 males (29 soldiers, 17 civilians) participated in a prospective functional magnetic resonance imaging experiment in which they played a modified interpersonal anger-provoking Ultimatum Game (UG) at two-points. Soldiers were tested at the beginning and end of combat training, while civilians were tested at the beginning and end of civil service. We assumed that combat training would induce chronic stress and result in increased stress symptoms.


Soldiers showed an increase in stress symptoms following combat training while civilians showed no such change following civil service. All participants were angered by the modified UG irrespective of time point. Higher post-combat training stress symptoms were associated with lower pre-combat training vmPFC activation and with higher activation increase in the LC between pre- and post-combat training.


Results suggest that during anger-provoking social interactions, flawed vmPFC functionality may serve as a causal risk factor for the development of stress symptoms, and heightened reactivity of the LC possibly reflects a consequence of stress-inducing combat training. These findings provide potential neural targets for therapeutic intervention and inoculation for stress-related psychopathological manifestations of anger.

Original Articles
Copyright © Cambridge University Press 2017 

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Admon, R, Lubin, G, Rosenblatt, JD, Stern, O, Kahn, I, Assaf, M, Hendler, T (2013 a). Imbalanced neural responsivity to risk and reward indicates stress vulnerability in humans. Cerebral Cortex 23, 2835.CrossRefGoogle ScholarPubMed
Admon, R, Milad, MR, Hendler, T (2013 b). A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities. Trends in Cognitive Sciences 17, 337347.CrossRefGoogle ScholarPubMed
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Publishing: Arlington, VA.Google Scholar
Arnsten, AFT, Raskind, MA, Taylor, FB, Connor, DF (2015). The effects of stress exposure on prefrontal cortex: translating basic research into successful treatments for post-traumatic stress disorder. Neurobiology of Stress 1, 8999.Google Scholar
Astafiev, SV, Snyder, AZ, Shulman, GL, Corbetta, M (2010). Comment on “Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI” and “Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area”. Science 328, 309.CrossRefGoogle Scholar
Aston-Jones, G, Valentino, RJ, Van Bockstaele, EJ, Meyerson, AT (1994). Locus coeruleus, stress, and PTSD: neurobiological and clinical parallels. In Catecholamine Function in Posttraumatic Stress Disorder: Emerging Concepts Progress in Psychiatry, no. 42 (ed. Murburg, MM), pp. 1762. American Psychiatric Association: Arlington, VA.Google Scholar
Baldwin, DS (2006). Serotonin noradrenaline reuptake inhibitors: a new generation of treatment for anxiety disorders. International Journal of Psychiatry in Clinical Practice 10, 1215.Google Scholar
Bardeen, JR, Kumpula, MJ, Orcutt, HK (2013). Emotion regulation difficulties as a prospective predictor of posttraumatic stress symptoms following a mass shooting. Journal of Anxiety Disorders 27, 188196.CrossRefGoogle ScholarPubMed
Beckham, JC, Feldman, ME, Kirby, AC, Hertzberg, MA, Moore, SD (1997). Interpersonal violence and its correlates in Vietnam veterans with chronic posttraumatic stress disorder. Journal of Clinical Psychology 53, 859869.3.0.CO;2-J>CrossRefGoogle ScholarPubMed
Beckham, JC, Moore, SD, Reynolds, V (2000). Interpersonal hostility and violence in Vietnam combat veterans with chronic posttraumatic stress disorder: a review of theoretical models and empirical evidence. Aggression and Violent Behavior 5, 451466.CrossRefGoogle Scholar
Bernton, E, Hoover, D, Galloway, R, Popp, K (1995). Adaptation to chronic stress in military trainees. Annals of the New York Academy of Sciences 774, 217231.Google Scholar
Berridge, CW (2008). Noradrenergic modulation of arousal. Brain Research Reviews 58, 117.CrossRefGoogle ScholarPubMed
Berridge, CW, Waterhouse, BD (2003). The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Research Reviews 42, 3384.CrossRefGoogle ScholarPubMed
Bremner, JD, Krystal, JH, Southwick, SM, Charney, DS (1996). Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23, 3951.Google Scholar
Canli, T, Lesch, K-P (2007). Long story short: the serotonin transporter in emotion regulation and social cognition. Nature Neuroscience 10, 11031109.Google Scholar
Carroll, EM, Rueger, DB, Foy, DW, Donahoe, CP (1985). Vietnam combat veterans with posttraumatic stress disorder: analysis of marital and cohabitating adjustment. Journal of Abnormal Psychology 94, 329337.Google Scholar
Chemtob, CM, Hamada, RS, Roitblat, HL, Muraoka, MY (1994). Anger, impulsivity, and anger control in combat-related posttraumatic stress disorder. Journal of Consulting and Clinical Psychology 62, 827832.Google Scholar
Chemtob, CM, Novaco, RW, Hamada, RS, Gross, DM (1997 a). Cognitive–behavioral treatment for severe anger in posttraumatic stress disorder. Journal of Consulting and Clinical Psychology 65, 184189.CrossRefGoogle ScholarPubMed
Chemtob, CM, Novaco, RW, Hamada, RS, Gross, DM, Smith, G (1997 b). Anger regulation deficits in combat-related posttraumatic stress disorder. Journal of Traumatic Stress 10, 1736.Google Scholar
Corbetta, M, Patel, G, Shulman, GL (2008). The reorienting system of the human brain: from environment to theory of mind. Neuron 58, 306324.Google Scholar
Crockett, MJ, Clark, L, Tabibnia, G, Lieberman, MD, Robbins, TW (2008). Serotonin modulates behavioral reactions to unfairness. Science 320, 17391739.Google Scholar
Cukor, J, Wyka, K, Jayasinghe, N, Difede, J (2010). The nature and course of subthreshold PTSD. Journal of Anxiety Disorders 24, 918923.Google Scholar
Davidson, RJ, Putnam, KM, Larson, CL (2000). Dysfunction in the neural circuitry of emotion regulation – a possible prelude to violence. Science 289, 591594.Google Scholar
Day, AL, Livingstone, HA (2001). Chronic and acute stressors among military personnel: do coping styles buffer their negative impact on health? Journal of Occupational Health Psychology 6, 348360.Google Scholar
Emanuele, E, Brondino, N, Bertona, M, Re, S, Geroldi, D (2008). Relationship between platelet serotonin content and rejections of unfair offers in the Ultimatum Game. Neuroscience Letters 437, 158161.Google Scholar
Etkin, A, Egner, T, Kalisch, R (2011). Emotional processing in anterior cingulate and medial prefrontal cortex. Trends in Cognitive Sciences 15, 8593.Google Scholar
Etkin, A, Wager, TD (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. American Journal of Psychiatry 164, 14761488.Google Scholar
Foa, EB, Cashman, L, Jaycox, L, Perry, K (1997). The validation of a self-report measure of posttraumatic stress disorder: the Posttraumatic Diagnostic Scale. Psychological Assessment 9, 445451.CrossRefGoogle Scholar
Forbes, D, Creamer, M, Biddle, D (2001). The validity of the PTSD Checklist as a measure of symptomatic change in combat-related PTSD. Behaviour Research and Therapy 39, 977986.CrossRefGoogle ScholarPubMed
Forbes, D, Parslow, R, Creamer, M, Allen, N, McHugh, T, Hopwood, M (2008). Mechanisms of anger and treatment outcome in combat veterans with posttraumatic stress disorder. Journal of Traumatic Stress 21, 142149.CrossRefGoogle ScholarPubMed
Frewen, PA, Lanius, RA (2006). Toward a psychobiology of posttraumatic self-dysregulation: reexperiencing, hyperarousal, dissociation, and emotional numbing. Annals of the New York Academy of Sciences 1071, 110124.Google Scholar
George, SA, Knox, D, Curtis, AL, Aldridge, JW, Valentino, RJ, Liberzon, I (2013). Altered locus coeruleus–norepinephrine function following single prolonged stress. European Journal of Neuroscience 37, 901909.Google Scholar
Gilam, G, Hendler, T (2015). Deconstructing anger in the human brain. In Social Behavior from Rodents to Humans: Neural Foundations and Clinical Implications. Current Topics in Behavioral Neurosciences (ed. Wöhr, M and Krach, S), pp. 117. Springer: Berlin Heidelberg.Google Scholar
Gilam, G, Hendler, T (2016). With love, from me to you: embedding social interactions in affective neuroscience. Neuroscience and Biobehavioral Reviews 68, 590601.Google Scholar
Gilam, G, Lin, T, Raz, G, Azrielant, S, Fruchter, E, Ariely, D, Hendler, T (2015). Neural substrates underlying the tendency to accept anger-infused ultimatum offers during dynamic social interactions. NeuroImage 120, 400411.Google Scholar
Grubaugh, AL, Magruder, KM, Waldrop, AE, Elhai, JD, Knapp, RG, Frueh, BC (2005). Subthreshold PTSD in primary care: prevalence, psychiatric disorders, healthcare use, and functional status. Journal of Nervous and Mental Disease 193, 658664.Google Scholar
Haden, SC, Scarpa, A (2007). The noradrenergic system and its involvement in aggressive behaviors. Aggression and Violent Behavior 12, 115.Google Scholar
Haller, J, Makara, GB, Kruk, MR (1997). Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems. Neuroscience and Biobehavioral Reviews 22, 8597.Google Scholar
Heinrichs, M, Wagner, D, Schoch, W, Soravia, LM, Hellhammer, DH, Ehlert, U (2005). Predicting posttraumatic stress symptoms from pretraumatic risk factors: a 2-year prospective follow-up study in firefighters. American Journal of Psychiatry 162, 22762286.Google Scholar
Jakupcak, M, Conybeare, D, Phelps, L, Hunt, S, Holmes, HA, Felker, B, Klevens, M, McFall, ME (2007). Anger, hostility, and aggression among Iraq and Afghanistan war veterans reporting PTSD and subthreshold PTSD. Journal of Traumatic Stress 20, 945954.CrossRefGoogle ScholarPubMed
Jakupcak, M, Tull, MT (2005). Effects of trauma exposure on anger, aggression, and violence in a nonclinical sample of men. Violence and Victims 20, 589598.Google Scholar
Jordan, BK, Marmar, CR, Fairbank, JA, Schlenger, WE (1992). Problems in families of male Vietnam veterans with posttraumatic stress disorder. Journal of Consulting and Clinical Psychology 60, 916926.Google Scholar
Keren, NI, Lozar, CT, Harris, KC, Morgan, PS, Eckert, MA (2009). In vivo mapping of the human locus coeruleus. NeuroImage 47, 12611267.Google Scholar
Keynan, JN, Meir-Hasson, Y, Gilam, G, Cohen, A, Jackont, G, Kinreich, S, Ikar, L, Or-Borichev, A, Etkin, A, Gyurak, A, Klovatch, I, Intrator, N, Hendler, T (2016). Limbic activity modulation guided by functional magnetic resonance imaging-inspired electroencephalography improves implicit emotion regulation. Biological Psychiatry 80, 490496.CrossRefGoogle ScholarPubMed
Kumpula, MJ, Orcutt, HK, Bardeen, JR, Varkovitzky, RL (2011). Peritraumatic dissociation and experiential avoidance as prospective predictors of posttraumatic stress symptoms. Journal of Abnormal Psychology 120, 617627.Google Scholar
Liddell, BJ, Brown, KJ, Kemp, AH, Barton, MJ, Das, P, Peduto, A, Gordon, E, Williams, LM (2005). A direct brainstem–amygdala–cortical ‘alarm’ system for subliminal signals of fear. NeuroImage 24, 235243.Google Scholar
Lin, T, Vaisvaser, S, Fruchter, E, Admon, R, Wald, I, Pine, DS, Bar-Haim, Y, Hendler, T (2015). A neurobehavioral account for individual differences in resilience to chronic military stress. Psychological Medicine 45, 10111023.Google Scholar
Lommen, MJJ, Engelhard, IM, van de Schoot, R, van den Hout, MA (2014). Anger: cause or consequence of posttraumatic stress? A prospective study of Dutch soldiers. Journal of Traumatic Stress 27, 200207.Google Scholar
MacManus, D, Rona, R, Dickson, H, Somaini, G, Fear, N, Wessely, S (2015). Aggressive and violent behavior among military personnel deployed to Iraq and Afghanistan: prevalence and link with deployment and combat exposure. Epidemiologic Reviews 37, 196212.CrossRefGoogle ScholarPubMed
McFall, M, Fontana, A, Raskind, M, Rosenheck, R (1999). Analysis of violent behavior in Vietnam combat veteran psychiatric inpatients with posttraumatic stress disorder. Journal of Traumatic Stress 12, 501517.Google Scholar
McHugh, T, Forbes, D, Bates, G, Hopwood, M, Creamer, M (2012). Anger in PTSD: is there a need for a concept of PTSD-related posttraumatic anger? Clinical Psychology Review 32, 93104.CrossRefGoogle Scholar
Meffert, SM, Metzler, TJ, Henn-Haase, C, McCaslin, S, Inslicht, S, Chemtob, C, Neylan, T, Marmar, CR (2008). A prospective study of trait anger and PTSD symptoms in police. Journal of Traumatic Stress 21, 410416.Google Scholar
Milad, MR, Pitman, RK, Ellis, CB, Gold, AL, Shin, LM, Lasko, NB, Zeidan, MA, Handwerger, K, Orr, SP, Rauch, SL (2009). Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biological Psychiatry 66, 10751082.CrossRefGoogle ScholarPubMed
Miles, SR, Menefee, DS, Wanner, J, Teten Tharp, A, Kent, TA (2016). The relationship between emotion dysregulation and impulsive aggression in veterans with posttraumatic stress disorder symptoms. Journal of Interpersonal Violence 31, 17951816.CrossRefGoogle ScholarPubMed
Minzenberg, MJ, Watrous, AJ, Yoon, JH, La, C, Ursu, S, Carter, CS (2010). Response to comment on “Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI”. Science 328, 309.Google Scholar
Novaco, RW, Chemtob, CM (2002). Anger and combat-related posttraumatic stress disorder. Journal of Traumatic Stress 15, 123132.Google Scholar
Olatunji, BO, Ciesielski, BG, Tolin, DF (2010). Fear and loathing: a meta-analytic review of the specificity of anger in PTSD. Behavior Therapy 41, 93105.Google Scholar
Phillips, ML, Ladouceur, CD, Drevets, WC (2008). A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Molecular Psychiatry 13, 833857.Google Scholar
Pitman, RK, Rasmusson, AM, Koenen, KC, Shin, LM, Orr, SP, Gilbertson, MW, Milad, MR, Liberzon, I (2012). Biological studies of post-traumatic stress disorder. Nature Reviews Neuroscience 13, 769787.Google Scholar
Quirk, GJ, Beer, JS (2006). Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Current Opinion in Neurobiology 16, 723727.Google Scholar
Sanfey, AG, Rilling, JK, Aronson, JA, Nystrom, LE, Cohen, JD (2003). The neural basis of economic decision-making in the Ultimatum Game. Science 300, 17551758.Google Scholar
Sara, SJ, Bouret, S (2012). Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron 76, 130141.Google Scholar
Scherer, KR (2005). What are emotions? And how can they be measured? Social Science Information 44, 695729.CrossRefGoogle Scholar
Schmidt, C, Peigneux, P, Maquet, P, Phillips, C (2010). Response to comment on “Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area”. Science 328, 309.Google Scholar
Seligowski, AV, Lee, DJ, Bardeen, JR, Orcutt, HK (2015). Emotion regulation and posttraumatic stress symptoms: a meta-analysis. Cognitive Behaviour Therapy 44, 87102.Google Scholar
Siever, LJ (2008). Neurobiology of aggression and violence. American Journal of Psychiatry 165, 429442.Google Scholar
Southwick, SM, Bremner, JD, Rasmusson, A, Morgan, CA III, Arnsten, A, Charney, DS (1999). Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biological Psychiatry 46, 11921204.Google Scholar
Stemmler, G (2010). Somatovisceral activation during anger. In International Handbook of Anger (ed. Potegal, M, Stemmler, G and Spielberger, C), pp. 103121. Springer: New York.Google Scholar
Taylor, MK, Sausen, KP, Potterat, EG, Mujica-Parodi, LR, Reis, JP, Markham, AE, Padilla, GA, Taylor, DL (2007). Stressful military training: endocrine reactivity, performance, and psychological impact. Aviation, Space, and Environmental Medicine 78, 11431149.Google Scholar
Valentino, RJ, Van Bockstaele, E (2008). Convergent regulation of locus coeruleus activity as an adaptive response to stress. European Journal of Pharmacology 583, 194203.CrossRefGoogle ScholarPubMed
van Zuiden, M, Kavelaars, A, Rademaker, AR, Vermetten, E, Heijnen, CJ, Geuze, E (2011). A prospective study on personality and the cortisol awakening response to predict posttraumatic stress symptoms in response to military deployment. Journal of Psychiatric Research 45, 713719.Google Scholar
Vedantham, K, Brunet, A, Neylan, TC, Weiss, DS, Mannar, CR (2000). Neurobiological findings in posttraumatic stress disorder: a review. Dialogues in Clinical Neuroscience 2, 2329.Google Scholar
Weathers, F, Huska, J, Keane, T (1991). The PTSD Checklist Military Version (PCL-M). National Center for PTSD: Boston, MA.Google Scholar
Yoon, H-K, Lee, H-J, Kim, L, Lee, M-S, Ham, B-J (2012). Impact of tryptophan hydroxylase 2 G-703 T polymorphism on anger-related personality traits and orbitofrontal cortex. Behavioural Brain Research 231, 105110.Google Scholar
Young, SN, Leyton, M (2002). The role of serotonin in human mood and social interaction: insight from altered tryptophan levels. Pharmacology Biochemistry and Behavior 71, 857865.Google Scholar
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