Failure of Neural Responses to Safety Cues in Schizophrenia
Open accessAbstract
CONTEXT Abnormalities in associative memory processes, such as Pavlovian fear conditioning and extinction, have been observed in schizophrenia. The retrieval of fear extinction memories (safety signals) may be particularly affected; although schizophrenic patients can extinguish conditioned fear, they show a deficit in retrieving fear extinction memories after a delay. The neurobiological basis of this abnormality is unknown, but clues have emerged from studies in rodents and humans demonstrating that the ventromedial prefrontal cortex (vmPFC) is a key mediator of extinction memory retrieval. OBJECTIVE To measure autonomic and neural responses during the acquisition and extinction of conditioned fear and the delayed recall of fear and extinction memories in patients with schizophrenia and healthy control participants. DESIGN Cross-sectional case control, functional magnetic resonance imaging study. SETTING Academic medical center. PARTICIPANTS Twenty schizophrenic patients and 17 healthy control participants demographically matched to the patient group. MAIN OUTCOME MEASURES Skin conductance and blood oxygen level-dependent responses. RESULTS During fear conditioning, schizophrenic patients showed blunted autonomic responses and abnormal blood oxygen level-dependent responses, relative to control participants, within the posterior cingulate gyrus, hippocampus, and other regions. Several of these abnormalities were linked to negative symptoms. During extinction learning, patients with schizophrenia and control participants showed comparable autonomic and neural responses. Twenty-four hours after the learning phases, the control subjects exhibited decreased fear and increased vmPFC responses in the extinction (safe) context as expected, indicating successful retention of the extinction memory. In contrast, the schizophrenic patients showed inappropriately elevated fear and poor vmPFC responses in the safe context. CONCLUSION Failure of extinction memory retrieval in schizophrenia is associated with vmPFC dysfunction. In future studies, abnormalities in fear learning and extinction recall may serve as quantitative phenotypes that can be linked to genetic, symptom, or outcome profiles in schizophrenia and those at risk for the disorder.
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Our findings suggest that PNN abnormalities may impact on emotion processing and plasticity in major psychoses, potentially contributing to a disruption of fear learning reported in subjects with SZ.
“Our findings suggest that PNN abnormalities may impact on emotion processing and plasticity in major psychoses, potentially contributing to a disruption of fear learning reported in subjects with SZ.94”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [94]
Altered fear learning and related activity of the prefrontal cortex and amygdala have been reported in subjects with schizophrenia.
“Consistent with this possibility, altered fear learning, and related activity of the PFC and amygdala, has been reported in subjects with SZ (Holt et al., 2012; Holt et al., 2009).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Holt et al., 2012
Both the PCC/retrosplenial cortex and hippocampus are well-known components of an extended episodic memory network, and it has been proposed that coengagement of these areas may specifically encode episodic memory traces of the CS/US association.
“Both regions are well-known components of an extended episodic memory network and it has been proposed recently that the coengagement of these areas may specifically encode episodic memory traces of the CS/US association.46”
From Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies (2016) · cites this paper as [46]
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- Authors
- Holt, D. J., Coombs, G., Zeidan, M. A., Goff, D. C., & Milad, M. R.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-09-01
- Volume
- 69
- Issue
- 9
- Pages
- 893
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3767036
- OpenAlex
- W2144242982
- Cited by
- 121
- References
- 105
- Citations by year
- 2026: 9 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 6 · 2021: 18 · 2020: 5 · 2019: 15 · 2018: 8 · 2017: 12 · 2016: 4 · 2015: 13 · 2014: 6 · 2013: 6 · 2012: 2
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01mh081975-05)
- National Institute of Mental Health (R01-MH081975, K23MH076054, R01MH095904)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- schizophrenia, fear extinction, ventromedial prefrontal cortex, fear conditioning, safety signals, negative symptoms, posterior cingulate cortex, hippocampus, autonomic responses, skin conductance, fear memory
- MeSH terms
- Amygdala, Arousal, Autonomic Nervous System, Brain, Brain Mapping, Conditioning, Classical, Cross-Sectional Studies, Cues, Dominance, Cerebral, Extinction, Psychological, Fear, Galvanic Skin Response, Gyrus Cinguli, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Oxygen, Mental Recall, Retention, Psychology, Safety, Schizophrenia, Schizophrenic Psychology, Case-Control Studies, Prefrontal Cortex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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