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Early life stress and the anxious brain: evidence for a neural mechanism linking childhood emotional maltreatment to anxiety in adulthood

Published online by Cambridge University Press:  16 December 2015

G. A. Fonzo*
Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA
H. J. Ramsawh
Department of Clinical Effectiveness Research, Patient-Centered Outcomes Research Institute, Washington, DC, USA
T. M. Flagan
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
A. N. Simmons
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA VA San Diego Healthcare System, San Diego, CA, USA Center of Excellence in Stress and Mental Health, San Diego, CA, USA
S. G. Sullivan
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
C. B. Allard
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA VA San Diego Healthcare System, San Diego, CA, USA Center of Excellence in Stress and Mental Health, San Diego, CA, USA
M. P. Paulus
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA VA San Diego Healthcare System, San Diego, CA, USA Laureate Institute for Brain Research, Tulsa, OK, USA
M. B. Stein
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA VA San Diego Healthcare System, San Diego, CA, USA Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
*Address for correspondence: G. A. Fonzo, Ph.D., Department of Psychiatry & Behavioral Sciences, Stanford University, 401 Quarry Road, MC 4797, Stanford, CA 94305, USA. (Email:



Childhood emotional maltreatment (CEM) increases the likelihood of developing an anxiety disorder in adulthood, but the neural processes underlying conferment of this risk have not been established. Here, we test the potential for neuroimaging the adult brain to inform understanding of the mechanism linking CEM to adult anxiety symptoms.


One hundred eighty-two adults (148 females, 34 males) with a normal-to-clinical range of anxiety symptoms underwent structural and functional magnetic resonance imaging while completing an emotion-processing paradigm with facial expressions of fear, anger, and happiness. Participants completed self-report measures of CEM and current anxiety symptoms. Voxelwise mediation analyses on gray-matter volumes and activation to each emotion condition were used to identify candidate brain mechanisms relating CEM to anxiety in adulthood.


During processing of fear and anger faces, greater amygdala and less right dorsolateral prefrontal (dlPFC) activation partially mediated the positive relationship between CEM and anxiety symptoms. Greater right posterior insula activation to fear also partially mediated this relationship, as did greater ventral anterior cingulate (ACC) and less dorsal ACC activation to anger. Responses to happy faces in these regions did not mediate the CEM-anxiety relationship. Smaller right dlPFC gray-matter volumes also partially mediated the CEM-anxiety relationship.


Activation patterns of the adult brain demonstrate the potential to inform mechanistic accounts of the CEM conferment of anxiety symptoms. Results support the hypothesis that exaggerated limbic activation to negative valence facial emotions links CEM to anxiety symptoms, which may be consequent to a breakdown of cortical regulatory processes.

Original Articles
Copyright © Cambridge University Press 2015 

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