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Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder

  • E. Via (a1), M. A. Fullana (a2), X. Goldberg (a1), D. Tinoco-González (a3), I. Martínez-Zalacaín (a4), C. Soriano-Mas (a4), C. G. Davey (a5), J. M. Menchón (a4), B. Straube (a6), T. Kircher (a6), J. Pujol (a7), N. Cardoner (a1) and B. J. Harrison (a5)...



Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.


To study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals.


In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging.


Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety–threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC.


Poor vmPFC safety–threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.

Declaration of interest



Corresponding author

Correspondence: Narcís Cardoner, MD, PhD, Department of Mental Health, Corporació Sanitaria Parc Taulí-i3PT, CIBERSAM. c/o Edifici Santa Fe, Corporació Sanitària Parc Taulí, 1 Parc Taulí, 08208 Sabadell, Spain. Email:


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1American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, DSM-5 (5th edn). APA, 2013.
2Woody, S, Rachman, S. Generalized anxiety disorder (GAD) as an unsuccessful search for safety. Clin Psychol Rev 1994; 14: 743–53.
3Lissek, S, Kaczkurkin, AN, Rabin, S, Geraci, M, Pine, DS, Grillon, C. Generalized anxiety disorder is associated with overgeneralization of classically conditioned fear. Biol Psychiatry 2014; 75: 909–15.
4Myers-Schulz, B, Koenigs, M. Functional anatomy of ventromedial prefrontal cortex implications for mood and anxiety disorders. Mol Psychiatry 2012; 17: 132–41.
5Fullana, MA, Harrison, BJ, Soriano-Mas, C, Vervliet, B, Cardoner, N, Àvila-Parcet, A, et al. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Mol Psychiatry 2016; 21: 500–8.
6Milad, MR, Wright, CI, Orr, SP, Pitman, RK, Quirk, GJ, Rauch, SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007; 62: 446–54.
7Phelps, EA, Delgado, MR, Nearing, KI, LeDoux, JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 2004; 43: 897905.
8Schiller, D, Delgado, MR. Overlapping neural systems mediating extinction, reversal and regulation of fear. Trends Cogn Sci 2010; 14: 268–76.
9Lissek, S, Bradford, DE, Alvarez, RP, Burton, P, Espensen-sturges, T, Reynolds, RC, et al. Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study. Soc Cogn Affect Neurosci 2014; 9: 1134–42.
10Lissek, S. Toward an account of clinical anxiety predicted on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for coditioned overgeneralization. Depress Anxiety 2012; 29: 257–63.
11Harrison, BJ, Fullana, MA, Via, E, Soriano-Mas, C, Vervliet, B, Martínez-Zalacaín, I, et al. Human ventromedial prefrontal cortex and the positive affective processing of safety signals. Neuroimage 2017; 152: 12–8.
12Greenberg, T, Carlson, JM, Cha, J, Hajcak, G, Mujica-Parodi, LR. Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization. Depress Anxiety 2013; 30: 242–50.
13Borkovec, T. The nature, functions, and origins of worry. In Worrying: Perspectives on Theory, Assessment, and Treatment. (eds Davey, CG and Tallis, F): 593. John Wiley, 1994.
14Ruscio, AM. Delimiting the boundaries of generalized anxiety disorder: differentiating high worriers with and without GAD. J Anxiety Disord 2002; 16: 377400.
15Bobes, J, García-Calvo, C, Prieto, R, García-García, M, Rico-Villademoros, F. Psychometric properties of the Spanish version of the screening scale for DSM-IV generalized anxiety disorder of Carroll and Davidson. Actas Españolas Psiquiatr 2006; 34: 8393.
16Sheehan, DV, Lecrubier, Y, Sheehan, KH, Amorim, P, Janavs, J, Weiller, E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 (suppl 2): 2233.
17Sandín, B, Chorot, P, Valiente, RM, Lostao, L. Validación española del cuestionario de preocupación PSWQ: estructura factorial y propiedades psicométricas. Rev Psicopatología y Psicol Clínica 2009; 14: 107–22.
18Sanz, J, Navarro, ME, Vazquez, C. Adaptación española del Inventario para la Depresión de Beck-II (BDI-II): 1. Propiedades psicométricas en estudiantes universitarios. Análisis y Modif Conduct 2003; 29: 239–88.
19Lobo, A, Chamorro, L, Luque, A, Dal-Ré, R, Badia, X, Baró, E, et al. Validation of the Spanish versions of the Montgomery-Asberg Depression and Hamilton Anxiety Rating scales [in Italian]. Med Clínica 2002; 118: 493–9.
20Spielberger, CD, Gorsuch, RL, Lushene, R. Escala de Ansiedad Estado/Rasgo (STAI). Original title: State-Trait Anxiety Inventory. TEA Ediciones, 1982.
21Harrison, BJ, Fullana, MA, Soriano-Mas, C, Via, E, Pujol, J, Martínez-Zalacaín, I, et al. A neural mediator of human anxiety sensitivity. Hum Brain Mapp 2015; 36:3950–8.
22Reinhardt, I, Jansen, A, Kellermann, T, Schüppen, A, Kohn, N, Gerlach, AL, et al. Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders. Eur Arch Psychiatry Clin Neurosci 2010; 260: 443–53.
23Kircher, T, Arolt, V, Jansen, A, Pyka, M, Reinhardt, I, Kellermann, T, et al. Effect of cognitive-behavioral therapy on neural correlates of fear conditioning in panic disorder. Biol Psychiatry 2013; 73: 93101.
24Schiller, D, Levy, I, Niv, Y, LeDoux, JE, Phelps, EA. From fear to safety and back: reversal of fear in the human brain. J Neurosci 2008; 28: 11517–25.
25Cognitive and Affective Neuroscience Lab - Tor D. Wager PD. Core Brain Masks. Cognitive and Affective Neuroscience Lab, 2016 (
26Seeley, SH, Mennin, DS, Aldao, A, McLaughlin, KA, Rottenberg, J, Fresco, DM. Impact of comorbid depressive disorders on subjective and physiological responses to emotion in generalized anxiety disorder. Cognit Ther Res 2016; 40: 290303.
27Paulesu, E, Sambugaro, E, Torti, T, Danelli, L, Ferri, F, Scialfa, G, et al. Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study. Psychol Med 2010; 40: 117–24.
28Mohlman, J, Eldreth, DA, Price, RB, Staples, AM, Hanson, C. Prefrontal-limbic connectivity during worry in older adults with generalized anxiety disorder. Aging Ment Health 2015; 21: 113.
29Cuthbert, BN, Kozak, MJ. Constructing constructs for psychopathology: the NIMH research domain criteria. J Abnorm Psychol 2013; 122: 928–37.
30Harrison, BJ, Soriano-Mas, C, Pujol, J, Ortiz, H, López-Solà, M, Hernández-Ribas, R, et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch Gen Psychiatry 2009; 66: 1189–200.
31Etkin, A, Wagner, TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007; 164: 1476–88.
32Lueken, U, Straube, B, Konrad, C, Wittchen, H-U, Ströhle, A, Wittmann, A, et al. Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia. Am J Psychiatry 2013; 170: 1345–55.
33Tinoco-González, D, Fullana, MA, Torrents-Rodas, D, Bonillo, A, Vervliet, B, Blasco, MJ, et al. Conditioned fear acquisition and generalization in generalized anxiety disorder. Behav Ther 2014; 46: 627–39.
34Rescorla, RA. Establishment of a positive reinforcer through contrast with shock. J Comp Physiol Psychol 1969; 67: 260–3.
35Christianson, JP, Fernando, ABP, Kazama, AM, Jovanovic, T, Ostroff, LE, Sangha, S. Inhibition of fear by learned safety signals: a mini-symposium review. J Neurosci 2012; 32: 14118–24.
36Wager, TD, Davidson, ML, Hughes, BL, Lindquist, MA, Ochsner, KN. Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron 2008; 59: 1037–50.
37Hefner, KR, Verona, E, Curtin, JJ. Emotion regulation during threat: parsing the time course and consequences of safety signal processing. Psychophysiology 2016; 53: 1193–202.
38Hartley, CA, Gorun, A, Reddan, MC, Ramirez, F, Phelps, EA. Stressor controllability modulates fear extinction in humans. Neurobiol Learn Mem 2014; 113: 149–56.
39Bystritsky, A, Kaplan, JT, Feusner, JD, Kerwin, LE, Wadekar, M, Burock, M, et al. A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder. J Clin Psychiatry 2008; 69: 1092–8.
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Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder

  • E. Via (a1), M. A. Fullana (a2), X. Goldberg (a1), D. Tinoco-González (a3), I. Martínez-Zalacaín (a4), C. Soriano-Mas (a4), C. G. Davey (a5), J. M. Menchón (a4), B. Straube (a6), T. Kircher (a6), J. Pujol (a7), N. Cardoner (a1) and B. J. Harrison (a5)...
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