Medial prefrontal pathways for the contextual regulation of extinguished fear in humans
Open accessAbstract
The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.
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New research implicates a dmPFC-hippocampus circuit that controls fear renewal by modulating amygdala output according to differing contexts.
“New research implicates vmPFC in the learning of safety memories by the inhibition of fear responses previously linked to danger signals in the Am (196) and implicates a dmPFC–hippocampus circuit that controls fear renewal by modulating Am output according to differing contexts (197).”
From The Stress Acceleration Hypothesis of Nightmares (2017) · cites this paper as [197]
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Cites
Structural Equations with Latent Variables.
Clogg, C. C., & Bollen, K. A. (1991) · Contemporary Sociology A Journal of Reviews · doi:10.2307/2072165 · Cited by 17,471 · see citing works
Maldjian, J., Laurienti, P., Kraft, R., & Burdette, J. (2003) · NeuroImage · doi:10.1016/s1053-8119(03)00169-1 · Cited by 5,453 · see citing works
Are the Dorsal and Ventral Hippocampus Functionally Distinct Structures?
Fanselow, M. S., & Dong, H.-W. (2010) · Neuron · doi:10.1016/j.neuron.2009.11.031 · Cited by 3,358 · see citing works
Fears, phobias, and preparedness: toward an evolved module of fear and fear learning
Öhman, A., & Mineka, S. (2001) · Psychological Review · doi:10.1037/0033-295x.108.3.483 · Cited by 3,147 · cited 1× · see citing works
“Fear-relevant stimuli were used because of their relevance for anxiety disorders and because they are particularly resistant to extinction learning (Ohman and Mineka, 2001).”
BackgroundThe expected value of control: an integrative theory of anterior cingulate cortex function
Shenhav, A., Botvinick, M. M., & Cohen, J. D. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.007 · Cited by 2,321 · see citing works
Structural equations with latent variables
(1989) · Choice Reviews Online · doi:10.5860/choice.27-0974 · Cited by 2,177 · see citing works
Context and Behavioral Processes in Extinction: Table 1.
Bouton, M. E. (2004) · Learning & Memory · doi:10.1101/lm.78804 · Cited by 1,808 · see citing works
Phelps, E. A., Delgado, M. R., Nearing, K. I., & LeDoux, J. E. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.042 · Cited by 1,753 · see citing works
(1995) · American Journal of Psychiatry · doi:10.1176/ajp.152.7.973 · Cited by 1,610 · see citing works
The contextual brain: implications for fear conditioning, extinction and psychopathology
Maren, S., Phan, K. L., & Liberzon, I. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3492 · Cited by 1,547 · see citing works
Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress
Milad, M. R., & Quirk, G. J. (2012) · Annual Review of Psychology · doi:10.1146/annurev.psych.121208.131631 · Cited by 1,466 · see citing works
LaBar, K. S., Gatenby, J. C., Gore, J. C., LeDoux, J. E., & Phelps, E. A. (1998) · Neuron · doi:10.1016/s0896-6273(00)80475-4 · Cited by 1,402 · see citing works
Self-citationRauch, S. L., Shin, L. M., & Phelps, E. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.004 · Cited by 1,397 · see citing works
Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder
Milad, M. R., Pitman, R. K., Ellis, C. B., Gold, A. L., Shin, L. M., Lasko, N. B., Zeidan, M. A., Handwerger, K., Orr, S. P., & Rauch, S. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.026 · Cited by 1,339 · see citing works
The Variability of Human, BOLD Hemodynamic Responses
Aguirre, G. K., Zarahn, E., & D’Esposito, M. (1998) · NeuroImage · doi:10.1006/nimg.1998.0369 · Cited by 1,224 · see citing works
Milad, M. R., Wright, C. I., Orr, S. P., Pitman, R. K., Quirk, G. J., & Rauch, S. L. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.10.011 · Cited by 1,197 · see citing works
Long-axis specialization of the human hippocampus
Poppenk, J., Evensmoen, H. R., Moscovitch, M., & Nadel, L. (2013) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2013.03.005 · Cited by 1,100 · see citing works
Ventromedial prefrontal–subcortical systems and the generation of affective meaning
Roy, M., Shohamy, D., & Wager, T. D. (2012) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2012.01.005 · Cited by 856 · see citing works
Beckmann, M., Johansen-Berg, H., & Rushworth, M. F. S. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3328-08.2009 · Cited by 789 · see citing works
Johansen-Berg, H., Gutman, D. A., Behrens, T. E. J., Matthews, P. M., Rushworth, M. F. S., Katz, E., Lozano, A. M., & Mayberg, H. S. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhm167 · Cited by 561 · see citing works
Human Fear Conditioning and Extinction in Neuroimaging: A Systematic Review
Sehlmeyer, C., Schöning, S., Zwitserlood, P., Pfleiderer, B., Kircher, T., Arolt, V., & Konrad, C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005865 · Cited by 543 · see citing works
Kalisch, R., Korenfeld, E., Stephan, K. E., Weiskopf, N., Seymour, B., & Dolan, R. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2021-06.2006 · Cited by 493 · see citing works
A Role for the Human Dorsal Anterior Cingulate Cortex in Fear Expression
Milad, M. R., Quirk, G. J., Pitman, R. K., Orr, S. P., Fischl, B., & Rauch, S. L. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.04.032 · Cited by 485 · see citing works
Generalized Anxiety Disorder Is Associated With Overgeneralization of Classically Conditioned Fear
Lissek, S. M., Kaczkurkin, A. N., Rabin, S. J., Geraci, M. F., Pine, D. S., & Grillon, C. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.025 · Cited by 462 · see citing works
Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction.Preprint
Sotres-Bayon, F., Bush, D. E. A., & LeDoux, J. E. (2004) · Learning & memory (Cold Spring Harbor, N.Y.) · doi:10.1101/lm.79504 · Cited by 437 · see citing works
From Fear to Safety and Back: Reversal of Fear in the Human Brain
Schiller, D., Levy, I., Niv, Y., LeDoux, J. E., & Phelps, E. A. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2265-08.2008 · Cited by 429 · see citing works
Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory
Milad, M. R., Quinn, B. T., Pitman, R. K., Orr, S. P., Fischl, B., & Rauch, S. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502441102 · Cited by 412 · see citing works
The Study of Fear Extinction: Implications for Anxiety Disorders
Graham, B. M., & Milad, M. R. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.11040557 · Cited by 387 · see citing works
Garfinkel, S. N., Abelson, J. L., King, A. P. J., Sripada, R. K., Wang, X., Gaines, L. M., & Liberzon, I. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4287-13.2014 · Cited by 361 · see citing works
Baronchelli, A., Ferrer‐i‐Cancho, R., Pastor‐Satorras, R., Chater, N., & Christiansen, M. H. (2013) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2013.04.010 · Cited by 344 · see citing works
Amygdala Volume Changes in Posttraumatic Stress Disorder in a Large Case-Controlled Veterans Group
Morey, R. A., Gold, A. L., LaBar, K. S., Beall, S. K., Brown, V. M., Haswell, C. C., Nasser, J. D., Wagner, H. R., McCarthy, G., & Mid-Atlantic MIRECC Workgroup, F. T. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2012.50 · Cited by 289 · see citing works
Self-citationSeeking a Spotless Mind: Extinction, Deconsolidation, and Erasure of Fear Memory
Maren, S. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.023 · Cited by 259 · cited 9× · see citing works
“The choice of ROIs followed the model proposed by Maren (Maren, 2011) and included bilateral amygdalae and dorsal (posterior) hippocampi, as well as the vmPFC and the dmPFC (Fig.”
BackgroundMethodInfluentialGeneralization of conditioned fear along a dimension of increasing fear intensityPreprint
Dunsmoor, J. E., Mitroff, S. R., & LaBar, K. S. (2009) · Learning & Memory · doi:10.1101/lm.1431609 · Cited by 203 · see citing works
Self-citationNeurobehavioral mechanisms of human fear generalization
Dunsmoor, J. E., Prince, S. E., Murty, V. P., Kragel, P. A., & LaBar, K. S. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.01.041 · Cited by 197 · see citing works
Self-citationExtinction, generalization, and return of fear: A critical review of renewal research in humans
Vervliet, B., Baeyens, F., Van den Bergh, O., & Hermans, D. (2013) · Biological Psychology · doi:10.1016/j.biopsycho.2012.01.006 · Cited by 178 · see citing works
Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.Preprint
Ji, J.-Z., & Maren, S. (2005) · Learning & memory (Cold Spring Harbor, N.Y.) · doi:10.1101/lm.91705 · Cited by 174 · see citing works
Fear potentiation and fear inhibition in a human fear-potentiated startle paradigm
Jovanovic, T., Keyes, M., Fiallos, A., Myers, K. M., Davis, M., & Duncan, E. J. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.02.025 · Cited by 150 · see citing works
Hartley, C. A., Fischl, B., & Phelps, E. A. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhq253 · Cited by 143 · see citing works
Failure of Neural Responses to Safety Cues in Schizophrenia
Holt, D. J., Coombs, G., Zeidan, M. A., Goff, D. C., & Milad, M. R. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.2310 · Cited by 121 · see citing works
Icenhour, A., Langhorst, J., Benson, S., Schlamann, M. U., Hampel, S., Engler, H., Forsting, M., & Elsenbruch, S. (2014) · Neurogastroenterology & Motility · doi:10.1111/nmo.12489 · Cited by 109 · see citing works
Aversive Learning Modulates Cortical Representations of Object Categories
Dunsmoor, J. E., Kragel, P. A., Martin, A. D., & LaBar, K. S. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht138 · Cited by 109 · see citing works
Self-citationLinnman, C., Zeidan, M. A., Furtak, S. C., Pitman, R. K., Quirk, G. J., & Milad, M. R. (2012) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10121780 · Cited by 101 · see citing works
Extinction in multiple virtual reality contexts diminishes fear reinstatement in humans
Dunsmoor, J. E., Ahs, F., Zielinski, D. J., & LaBar, K. S. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.02.010 · Cited by 93 · see citing works
Spatial proximity amplifies valence in emotional memory and defensive approach-avoidance
Åhs, F., Dunsmoor, J. E., Zielinski, D. J., & LaBar, K. S. (2014) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2014.12.018 · Cited by 58 · see citing works
Self-citationTemporal factors control hippocampal contributions to fear renewal after extinction
Zelikowsky, M., Pham, D. L., & Fanselow, M. (2011) · Hippocampus · doi:10.1002/hipo.20954 · Cited by 57 · see citing works
Revealing Context-Specific Conditioned Fear Memories with Full Immersion Virtual Reality
Huff, N. C., Hernandez, J. A., Fecteau, M. E., Zielinski, D. J., Brady, R. B., & LaBar, K. S. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00075 · Cited by 45 · see citing works
Self-citationExtinction resistant changes in the human auditory association cortex following threat learning
Apergis-Schoute, A. M., Schiller, D., LeDoux, J. E., & Phelps, E. A. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.01.016 · Cited by 32 · see citing works
Human Fear Conditioning Conducted in Full Immersion 3-Dimensional Virtual Reality
Huff, N. C., Zeilinski, D. J., Fecteau, M. E., Brady, R. B., & LaBar, K. S. (2010) · Journal of Visualized Experiments · doi:10.3791/1993 · Cited by 25 · see citing works
Self-citationHuman Fear Conditioning Conducted in Full Immersion 3-Dimensional Virtual Reality
Huff, N. C., Zielinski, D. J., Fecteau, M. E., Brady, R. B., & LaBar, K. S. (2010) · Journal of Visualized Experiments · doi:10.3791/1993-v · Cited by 12 · see citing works
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Fullana, M. A., Albajes-Eizagirre, A., Soriano-Mas, C., Vervliet, B., Cardoner, N., Benet, O., Radua, J., & Harrison, B. J. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.002 · Cited by 308 · see citing works
Nicholson, A. A., Friston, K. J., Zeidman, P., Harricharan, S., McKinnon, M. C., Densmore, M., Neufeld, R. W. J., Théberge, J., Corrigan, F., Jetly, R., et al. (2017) · Human Brain Mapping · doi:10.1002/hbm.23748 · Cited by 159 · see citing works
The Stress Acceleration Hypothesis of Nightmares
Nielsen, T. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00201 · Cited by 63 · see citing works
“New research implicates vmPFC in the learning of safety memories by the inhibition of fear responses previously linked to danger signals in the Am (196) and implicates a dmPFC–hippocampus circuit that controls fear renewal by modulating Am output according to differing contexts (197).”
Background
- Authors
- Åhs, F., Kragel, P. A., Zielinski, D. J., Brady, R., & LaBar, K. S.
- Affiliations
- Uppsala University (SE)
- Duke University (US)
- Corresponding author
- LaBar, Kevin S.
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 122
- Pages
- 262-271
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC4618170
- OpenAlex
- W987539735
- Cited by
- 75
- References
- 49
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 2 · 2022: 6 · 2021: 4 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 12 · 2016: 3 · 2015: 1
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R01DA027802)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- fear extinction, fear renewal, medial prefrontal cortex, dorsomedial prefrontal cortex, ventromedial prefrontal cortex, hippocampus, amygdala, memory extinction, anxiety disorders, fear conditioning, skin conductance response, extinction recall
- MeSH terms
- Adult, Amygdala, Anxiety, Brain Mapping, Conditioning, Psychological, Environment, Extinction, Psychological, Fear, Female, Galvanic Skin Response, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Psychophysiology, Mental Recall, User-Computer Interface, Prefrontal Cortex
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