Skip to main content Accessibility help

Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies

  • Benjamin Suarez-Jimenez (a1) (a2), Anton Albajes-Eizagirre (a3), Amit Lazarov (a1) (a2) (a4), Xi Zhu (a1) (a2), Ben J. Harrison (a5), Joaquim Radua (a3) (a6) (a7) (a8), Yuval Neria (a1) (a2) and Miquel A. Fullana (a3) (a9)...



Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers.


Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall.


Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis.


Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.


Corresponding author

Author for correspondence: Benjamin Suarez-Jimenez, E-mail: and Joaquim Radua, E-mail:


Hide All

Share senior authorship



Hide All
Alvarez, RP, Biggs, A, Chen, G, Pine, DS and Grillon, C (2008) Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 28, 62116219.
Bechara, A, Tranel, D, Damasio, H, Adolphs, R and others (1995) Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269, 1115.
Blanchard, DC and Blanchard, RJ (1972) Innate and conditioned reactions to threat in rats with amygdaloid lesions. Journal of Comparative and Physiological Psychology 81, 281290.
Bremner, JD, Vermetten, E, Schmahl, C, Vaccarino, V, Vythilingam, M, Afzal, N, Grillon, C and Charney, DS (2005) Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychological Medicine 35, 791806.
Britton, JC, Lissek, S, Grillon, C, Norcross, MA and Pine, DS (2011) Development of anxiety: the role of threat appraisal and fear learning. Depression and Anxiety 28, 517.
Buhle, JT, Silvers, JA, Wager, TD, Lopez, R, Onyemekwu, C, Kober, H, Weber, J and Ochsner, KN (2014) Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex (New York, N.Y.: 1991) 24, 29812990.
Cassel, J-C and Pereira de Vasconcelos, A (2015) Importance of the ventral midline thalamus in driving hippocampal functions. Progress in Brain Research 219, 145161.
Cholvin, T, Hok, V, Giorgi, L, Chaillan, FA and Poucet, B (2018) Ventral midline thalamus is necessary for hippocampal place field stability and cell firing modulation. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 38, 158172.
Chudasama, Y, Izquierdo, A and Murray, EA (2009) Distinct contributions of the amygdala and hippocampus to fear expression. The European Journal of Neuroscience 30, 23272337.
Corcoran, KA and Quirk, GJ (2007) Recalling safety: cooperative functions of the ventromedial prefrontal cortex and the hippocampus in extinction. CNS Spectrums 12, 200206.
Critchley, HD, Wiens, S, Rotshtein, P, Öhman, A and Dolan, RJ (2004) Neural systems supporting interoceptive awareness. Nature Neuroscience 7, 189195.
Delgado, MR, Nearing, KI, LeDoux, JE and Phelps, EA (2008) Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron 59, 829838.
Diekhof, EK, Geier, K, Falkai, P and Gruber, O (2011) Fear is only as deep as the mind allows: a coordinate-based meta-analysis of neuroimaging studies on the regulation of negative affect. NeuroImage 58, 275285.
Diener, SJ, Nees, F, Wessa, M, Wirtz, G, Frommberger, U, Penga, T, Ruttorf, M, Ruf, M, Schmahl, C and Flor, H (2016) Reduced amygdala responsivity during conditioning to trauma-related stimuli in posttraumatic stress disorder. Psychophysiology 53, 14601471.
Egger, M, Davey Smith, G, Schneider, M and Minder, C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical Research ed.) 315, 629634.
Eickhoff, SB, Laird, AR, Grefkes, C, Wang, LE, Zilles, K and Fox, PT (2009) Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Human Brain Mapping 30, 29072926.
Etkin, A and 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.
Etkin, A, Egner, T and Kalisch, R (2011) Emotional processing in anterior cingulate and medial prefrontal cortex. Trends in Cognitive Sciences 15, 8593.
Fullana, M, Harrison, B, Soriano-Mas, C, Vervliet, B, Cardoner, N, Àvila-Parcet, A and Radua, J (2016) Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Molecular Psychiatry 21, 500508.
Fullana, MA, Albajes-Eizagirre, A, Soriano-Mas, C, Vervliet, B, Cardoner, N, Benet, O, Radua, J and Harrison, BJ (2018) Fear extinction in the human brain: a meta-analysis of fMRI studies in healthy participants. Neuroscience and Biobehavioral Reviews 88, 1625.
Garfinkel, SN, Abelson, JL, King, AP, Sripada, RK, Wang, X, Gaines, LM and Liberzon, I (2014) Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 34, 1343513443.
Gottfried, JA and Dolan, RJ (2004) Human orbitofrontal cortex mediates extinction learning while accessing conditioned representations of value. Nature Neuroscience 7, 11441152.
Grillon, C, Pine, DS, Lissek, S, Rabin, S, Bonne, O and Vythilingam, M (2009) Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biological Psychiatry 66, 4753.
Harrison, BJ, Fullana, MA, Soriano-Mas, C, Via, E, Pujol, J, Martínez-Zalacaín, I, Tinoco-Gonzalez, D, Davey, CG, López-Solà, M, Pérez Sola, V, Menchón, JM and Cardoner, N (2015) A neural mediator of human anxiety sensitivity. Human Brain Mapping 36, 39503958.
Harrison, BJ, Fullana, MA, Via, E, Soriano-Mas, C, Vervliet, B, Martínez-Zalacaín, I, Pujol, J, Davey, CG, Kircher, T, Straube, B and Cardoner, N (2017) Human ventromedial prefrontal cortex and the positive affective processing of safety signals. NeuroImage 152, 1218.
Kaczkurkin, AN, Burton, PC, Chazin, SM, Manbeck, AB, Espensen-Sturges, T, Cooper, SE, Sponheim, SR and Lissek, S (2016) Neural substrates of overgeneralized conditioned fear in PTSD. American Journal of Psychiatry, 174, 125134.
Kalin, NH, Shelton, SE and Davidson, RJ (2004) The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 24, 55065515.
LaBar, KS, LeDoux, JE, Spencer, DD and Phelps, EA (1995) Impaired fear conditioning following unilateral temporal lobectomy in humans. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 15, 68466855.
Laird, AR, Eickhoff, SB, Kurth, F, Fox, PM, Uecker, AM, Turner, JA, Robinson, JL, Lancaster, JL and Fox, PT (2009) ALE meta-analysis workflows via the brainmap database: progress towards a probabilistic functional brain atlas. Frontiers in Neuroinformatics 3, 23.
LeDoux, JE, Iwata, J, Cicchetti, P and Reis, D (1988) Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. Journal of Neuroscience 8, 25172529.
Liberzon, I and Sripada, CS (2008) The functional neuroanatomy of PTSD: a critical review. Progress in Brain Research 167, 151169.
Liberzon, I and Abelson, JL (2016) Context processing and the neurobiology of post-traumatic stress disorder. Neuron 92, 1430.
Linnman, C, Zeidan, MA, Furtak, SC, Pitman, RK, Quirk, GJ and Milad, MR (2012) Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit. American Journal of Psychiatry 169, 415423.
Lonsdorf, TB, Menz, MM, Andreatta, M, Fullana, MA, Golkar, A, Haaker, J, Heitland, I, Hermann, A, Kuhn, M, Kruse, O, Meir Drexler, S, Meulders, A, Nees, F, Pittig, A, Richter, J, Römer, S, Shiban, Y, Schmitz, A, Straube, B, Vervliet, B, Wendt, J, Baas, JMP and Merz, CJ (2017) Don't fear ‘fear conditioning’: methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neuroscience and Biobehavioral Reviews 77, 247285.
Maldjian, JA, Laurienti, PJ, Kraft, RA and Burdette, JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19, 12331239.
Maldjian, JA, Laurienti, PJ and Burdette, JH (2004) Precentral gyrus discrepancy in electronic versions of the Talairach atlas. NeuroImage 21, 450455.
Maren, S and Holmes, A (2016) Stress and Fear Extinction. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 41, 5879.
Mechias, M-L, Etkin, A and Kalisch, R (2010) A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. NeuroImage 49, 17601768.
Milad, MR and Quirk, GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 7074.
Milad, MR, Wright, CI, Orr, SP, Pitman, RK, Quirk, GJ and Rauch, SL (2007) Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biological Psychiatry 62, 446454.
Milad, MR, Pitman, RK, Ellis, CB, Gold, AL, Shin, LM, Lasko, NB, Zeidan, MA, Handwerger, K, Orr, SP and Rauch, SL (2009) Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biological Psychiatry 66, 10751082.
Morey, RA, Dunsmoor, JE, Haswell, CC, Brown, VM, Vora, A, Weiner, J, Stjepanovic, D, Wagner, HR and LaBar, KS (2015) Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder. Translational Psychiatry 5, e700.
Morgan, MA and LeDoux, JE (1995) Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behavioral Neuroscience 109, 681688.
Müller, VI, Cieslik, EC, Laird, AR, Fox, PT, Radua, J, Mataix-Cols, D, Tench, CR, Yarkoni, T, Nichols, TE, Turkeltaub, PE, Wager, TD and Eickhoff, SB (2018) Ten simple rules for neuroimaging meta-analysis. Neuroscience and Biobehavioral Reviews 84, 151161.
Neria, Y (2019) A PTSD database on MRI modalities. Unpublished.
Niendam, TA, Laird, AR, Ray, KL, Dean, YM, Glahn, DC and Carter, CS (2012) Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions. Cognitive, Affective & Behavioral Neuroscience 12, 241268.
Ohman, A (2005) The role of the amygdala in human fear: automatic detection of threat. Psychoneuroendocrinology 30, 953958.
Phan, KL, Fitzgerald, DA, Nathan, PJ, Moore, GJ, Uhde, TW and Tancer, ME (2005) Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biological Psychiatry 57, 210219.
Phillips, RG and LeDoux, JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral Neuroscience 106, 274285.
Pitman, RK, Rasmusson, AM, Koenen, KC, Shin, LM, Orr, SP, Gilbertson, MW, Milad, MR and Liberzon, I (2012) Biological studies of post-traumatic stress disorder. Nature Reviews. Neuroscience 13, 769787.
Quirk, GJ and Mueller, D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 33, 5672.
Radua, J, Mataix-Cols, D, Phillips, ML, El-Hage, W, Kronhaus, DM, Cardoner, N and Surguladze, S (2012) A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. European Psychiatry: the Journal of the Association of European Psychiatrists 27, 605611.
Radua, J, Rubia, K, Canales-Rodríguez, EJ, Pomarol-Clotet, E, Fusar-Poli, P and Mataix-Cols, D (2014) Anisotropic kernels for coordinate-based meta-analyses of neuroimaging studies. Frontiers in Psychiatry 5, 13.
Rauch, SL, Shin, LM and Phelps, EA (2006) Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research-past, present, and future. Biological Psychiatry 60, 376382.
Reznikov, R, Binko, M, Nobrega, JN and Hamani, C (2016) Deep brain stimulation in animal models of fear, anxiety, and posttraumatic stress disorder. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 41, 28102817.
Saalmann, YB and Kastner, S (2011) Cognitive and perceptual functions of the visual thalamus. Neuron 71, 209223.
Schiller, D, Levy, I, Niv, Y, LeDoux, JE and Phelps, EA (2008) From fear to safety and back: reversal of fear in the human brain. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 28, 1151711525.
Seeley, WW, Menon, V, Schatzberg, AF, Keller, J, Glover, GH, Kenna, H, Reiss, AL and Greicius, MD (2007) Dissociable intrinsic connectivity networks for salience processing and executive control. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 27, 23492356.
Sehlmeyer, C, Schöning, S, Zwitserlood, P, Pfleiderer, B, Kircher, T, Arolt, V and Konrad, C (2009) Human fear conditioning and extinction in neuroimaging: a systematic review. PloS One 4, e5865.
Shin, LM, Lasko, NB, Macklin, ML, Karpf, RD, Milad, MR, Orr, SP, Goetz, JM, Fischman, AJ, Rauch, SL and Pitman, RK (2009) Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Archives of General Psychiatry 66, 10991107.
Shvil, E, Rusch, HL, Sullivan, GM and Neria, Y (2013) Neural, psychophysiological, and behavioral markers of fear processing in PTSD: a review of the literature. Current Psychiatry Reports 15, 358.
Shvil, E, Sullivan, GM, Schafer, S, Markowitz, JC, Campeas, M, Wager, TD, Milad, MR and Neria, Y (2014) Sex differences in extinction recall in posttraumatic stress disorder: a pilot fMRI study. Neurobiology of Learning and Memory 113, 101108.
Simmons, A, Matthews, SC, Stein, MB and Paulus, MP (2004) Anticipation of emotionally aversive visual stimuli activates right insula. Neuroreport 15, 22612265.
Sripada, RK, Garfinkel, SN and Liberzon, I (2013) Avoidant symptoms in PTSD predict fear circuit activation during multimodal fear extinction. Frontiers in Human Neuroscience 7, 672.
Steiger, F, Nees, F, Wicking, M, Lang, S and Flor, H (2015) Behavioral and central correlates of contextual fear learning and contextual modulation of cued fear in posttraumatic stress disorder. International Journal of Psychophysiology: Official Journal of the International Organization of Psychophysiology 98, 584593.
Suarez-Jimenez, B, Bisby, JA, Horner, AJ, King, JA, Pine, DS and Burgess, N (2018) Linked networks for learning and expressing location-specific threat. Proceedings of the National Academy of Sciences of the United States of America 115, E1032E1040.
Venkatraman, A, Edlow, BL and Immordino-Yang, MH (2017) The brainstem in emotion: a review. Frontiers in Neuroanatomy 11, 15.
Wager, TD, Lindquist, M and Kaplan, L (2007) Meta-analysis of functional neuroimaging data: current and future directions. Social Cognitive and Affective Neuroscience 2, 150158.
Wager, TD, Lindquist, MA, Nichols, TE, Kober, H and Van Snellenberg, JX (2009) Evaluating the consistency and specificity of neuroimaging data using meta-analysis. NeuroImage 45, S210S221.
Wicking, M, Steiger, F, Nees, F, Diener, SJ, Grimm, O, Ruttorf, M, Schad, LR, Winkelmann, T, Wirtz, G and Flor, H (2016) Deficient fear extinction memory in posttraumatic stress disorder. Neurobiology of Learning and Memory 136, 116126.
Zuj, DV and Norrholm, SD (2018) The clinical applications and practical relevance of human conditioning paradigms for posttraumatic stress disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry 88, 339351.


Related content

Powered by UNSILO
Type Description Title
Supplementary materials

Suarez-Jimenez et al. supplementary material
Suarez-Jimenez et al. supplementary material 1

 Word (55 KB)
55 KB

Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies

  • Benjamin Suarez-Jimenez (a1) (a2), Anton Albajes-Eizagirre (a3), Amit Lazarov (a1) (a2) (a4), Xi Zhu (a1) (a2), Ben J. Harrison (a5), Joaquim Radua (a3) (a6) (a7) (a8), Yuval Neria (a1) (a2) and Miquel A. Fullana (a3) (a9)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.