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Cited by 21Schizophrenia research and treatmentFunctional Brain Connectivity StudiesMental Health and Psychiatry

Amygdala hyperconnectivity in the paranoid state: A transdiagnostic study

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Fan, Linlin, Klein, Hans, Bass, Emily, Springfield, Cassi, Pinkham, Amy·2021·Journal of Psychiatric Research
DOI 10.1016/j.jpsychires.2021.03.049PMC PMC8192453
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Abstract

Background Paranoia significantly contributes to social impairments across clinical diagnoses, and amygdala dysfunction has been identified as a neurobiological marker of paranoia among individuals with schizophrenia. Therefore, we aimed to investigate amygdala functional connectivity (FC) in paranoia across diagnoses. Methods Forty-five patients with recent history of clinically significant paranoid ideation and a current DSM-5 diagnosis of any disorder underwent resting-state functional magnetic resonance imaging either in a paranoid (N = 23) or non-paranoid (N = 22) state. Amygdala FC were compared between paranoid and non-paranoid patients. Supplemental correlation analyses between amygdala FC and paranoia score were performed separately in patients and a non-equivalent healthy control (HC; N = 60) group. Results Increased FC was found between right amygdala and the prefrontal cortex (PFC) [bilateral medial superior frontal gyrus, anterior cingulate, medial frontal gyrus, the triangular part and the opercular part of the inferior frontal gyrus (IFG); right orbital part of IFG], the frontal cortex (bilateral median cingulate, left precentral gyrus), and subcortical areas (right insula) in the paranoid group compared with the non-paranoid group. No significant between-group differences were observed in left amygdala FC. FC between right amygdala and PFC and frontal cortex was positively correlated with paranoia in patient and HC groups. Conclusion Paranoia is associated with right amygdala hyperconnectivity with PFC, frontal cortex, and insula. This hyperconnectivity was evident regardless of diagnosis and therefore identify a likely transdiagnostic neural mechanism, which may help to identify treatment targets that could potentially improve the social functioning of individuals with clinical diagnoses.

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  • Overactivation and hyperconnectivity of the amygdala - reflecting amplified detection of salience and threat and insufficient top-down regulation - have been repeatedly linked to paranoia.

    “At a neurobiological level of explanation, overactivation and hyperconnectivity of the amygdala – reflecting amplified detection of salience and threat and insufficient top-down regulation – have been repeatedly linked to paranoia (Pinkham et al., 2015; Fan et al., 2021; Pinkham et al., 2022; Walther et al., 2022).”

    From A counterweight model for understanding and treating persecutory delusions. (2025) · cites this paper as Fan et al., 2021

    The Discussion reports increased amygdala–PFC connectivity in paranoid patients and discusses prior evidence suggesting increased baseline amygdala activity. It presents amplified threat signaling and insufficient top-down control as a possible interpretation, not an established explanation; the Introduction also notes reduced amygdala activation during social-threat tasks. Thus the claim is supported for hyperconnectivity but overstates the evidence for overactivation and its proposed mechanism. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Fan, L., Klein, H., Bass, E., Springfield, C., & Pinkham, A.
Affiliations
The University of Texas at Dallas (US)
Corresponding author
Pinkham, Amy
ORCID
Venue
Journal of Psychiatric Research
Publisher
Elsevier BV
Published
2021-06
Volume
138
Pages
117-124
ISSN
0022-3956 (ISSN-L)
DOI
10.1016/j.jpsychires.2021.03.049
PMC
PMC8192453
OpenAlex
W3142046575
Cited by
21
References
7
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 1 · 2022: 3
FWCI
1.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Psychiatric Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (R21 MH112930)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
Keywords
paranoia, amygdala, functional connectivity, hyperconnectivity, paranoid ideation, transdiagnostic mechanisms, prefrontal cortex, insula, schizophrenia, social dysfunction, resting-state functional connectivity
MeSH terms
Amygdala, Cerebral Cortex, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Paranoid Disorders

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