Prefrontal cortex, amygdala, and threat processing: implications for PTSD

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Abstract

Posttraumatic stress disorder can be viewed as a disorder of fear dysregulation. An abundance of research suggests that the prefrontal cortex is central to fear processing—that is, how fears are acquired and strategies to regulate or diminish fear responses. The current review covers foundational research on threat or fear acquisition and extinction in nonhuman animals, healthy humans, and patients with posttraumatic stress disorder, through the lens of the involvement of the prefrontal cortex in these processes. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. We conclude by outlining future research directions related to the role of the prefrontal cortex in fear processing and implications for the treatment of posttraumatic stress disorder.

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Emotion Regulation: Current Status and Future Prospects

James J Gross (2015)

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Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies.

Jeffrey Binder, Rutvik Desai, William Graves … (2009)

Semantic memory refers to knowledge about people, objects, actions, relations, self, and culture acquired through experience. The neural systems that store and retrieve this information have been studied for many years, but a consensus regarding their identity has not been reached. Using strict inclusion criteria, we analyzed 120 functional neuroimaging studies focusing on semantic processing. Reliable areas of activation in these studies were identified using the activation likelihood estimate (ALE) technique. These activations formed a distinct, left-lateralized network comprised of 7 regions: posterior inferior parietal lobe, middle temporal gyrus, fusiform and parahippocampal gyri, dorsomedial prefrontal cortex, inferior frontal gyrus, ventromedial prefrontal cortex, and posterior cingulate gyrus. Secondary analyses showed specific subregions of this network associated with knowledge of actions, manipulable artifacts, abstract concepts, and concrete concepts. The cortical regions involved in semantic processing can be grouped into 3 broad categories: posterior multimodal and heteromodal association cortex, heteromodal prefrontal cortex, and medial limbic regions. The expansion of these regions in the human relative to the nonhuman primate brain may explain uniquely human capacities to use language productively, plan, solve problems, and create cultural and technological artifacts, all of which depend on the fluid and efficient retrieval and manipulation of semantic knowledge.

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Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.

Mohammed Milad, Roger K. Pitman, Cameron B. Ellis … (2009)

A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD control subjects underwent a 2-day fear conditioning and extinction protocol in a 3-T functional magnetic resonance imaging scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. The SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of functional magnetic resonance imaging data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC and greater activation in dACC were observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.

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Author and article information

Contributors

Kerry J. Ressler:

ORCID: http://orcid.org/0000-0002-5158-1103

kressler@mclean.harvard.edu

Elizabeth A. Phelps:

ORCID: http://orcid.org/0000-0002-6215-8159

phelps@fas.harvard.edu

Journal

Journal ID (nlm-ta): Neuropsychopharmacology

Journal ID (iso-abbrev): Neuropsychopharmacology

Title: Neuropsychopharmacology

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0893-133X

ISSN (Electronic): 1740-634X

Publication date (Electronic): 20 September 2021

Publication date PMC-release: 20 September 2021

Publication date (Print): January 2022

Volume: 47

Issue: 1

Pages: 247-259

Affiliations

[1 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Psychology, , Harvard University, ; Cambridge, MA USA

[2 ]GRID grid.38142.3c, ISNI 000000041936754X, Division of Depression and Anxiety, , McLean Hospital; Department of Psychiatry, Harvard Medical School, ; Cambridge, MA USA

Author information

Emma S. Laurent http://orcid.org/0000-0002-4820-8332

Kerry J. Ressler http://orcid.org/0000-0002-5158-1103

Elizabeth A. Phelps http://orcid.org/0000-0002-6215-8159

Article

Publisher ID: 1155

DOI: 10.1038/s41386-021-01155-7

PMC ID: 8617299

PubMed ID: 34545196

SO-VID: f839df4a-cfdd-4000-b988-0c2b39d1ce3f

License:

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