Abstract
Background
Overgeneralization of fear is a pathogenic marker of anxiety and stress-related disorders
and has been linked with perceptual discrimination deficits, reduced fear inhibition,
and prefrontal hyporeactivity to safety-signaling stimuli. We aimed to examine whether
behavioral and neural patterns of fear generalization are influenced by the fear-inhibiting
ventromedial prefrontal cortex (vmPFC).
Methods
Three groups of healthy participants received excitatory (n = 27), inhibitory (n = 26), or sham (n = 26) transcranial direct current stimulation of the vmPFC after a fear conditioning
phase and before a fear generalization phase. We obtained, as dependent variables,
fear ratings and unconditioned stimulus–expectancy ratings, perceptual aspects of
fear generalization (perceptual discrimination), pupil dilations, and source estimations
of event-related fields elicited by conditioned and generalization stimuli.
Results
After inhibitory (compared with excitatory and sham) vmPFC stimulation, we observed
reduced performance in perceptual discrimination and less negative inhibitory gradients
in frontal structures at midlatency and late time intervals. Fear and unconditioned
stimulus–expectancy ratings as well as pupil dilation remained unaffected by stimulation.
Conclusions
These findings reveal a causal contribution of vmPFC reactivity to generalization
patterns and suggest that vmPFC hyporeactivity consequent on inhibitory vmPFC stimulation
may serve as a model for pathological processes of fear generalization (reduced discrimination,
impaired fear inhibition via frontal brain structures). This encourages further basic
and clinical research on the potential of targeted brain stimulation to modulate fear
generalization and overgeneralization.
Keywords
To read this article in full you will need to make a payment
Subscribe to Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Fear generalization in humans: Systematic review and implications for anxiety disorder research.Behav Ther. 2015; 46: 561-582
- Neural substrates of overgeneralized conditioned fear in PTSD.Am J Psychiatry. 2017; 174: 125-134
- The spread of fear: Symbolic generalization mediates graded threat-avoidance in specific phobia.Q J Exp Psychol (Hove). 2014; 67: 247-259
- Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization.Depress Anxiety. 2013; 30: 242-250
- Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults.Dev Psychobiol. 2016; 58: 471-481
- Individual differences in human fear generalization-Pattern identification and implications for anxiety disorders.Transl Psychiatry. 2019; 9: 307
- Neural substrates of classically conditioned fear-generalization in humans: A parametric fMRI study.Soc Cogn Affect Neurosci. 2014; 9: 1134-1142
- Overgeneralization of conditioned fear as a pathogenic marker of panic disorder.Am J Psychiatry. 2010; 167: 47-55
- The neuronal basis of fear generalization in humans.Nat Neurosci. 2015; 18: 1811-1818
- Top-down facilitation of visual recognition.Proc Natl Acad Sci U S A. 2006; 103: 449-454
- Fear extinction as a model for translational neuroscience: Ten years of progress.Annu Rev Psychol. 2012; 63: 129-151
- Fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants.Neurosci Biobehav Rev. 2018; 88: 16-25
- Changing fear: The neurocircuitry of emotion regulation.Neuropsychopharmacology. 2010; 35: 136-146
- Fear generalization of implicit conditioned facial features - Behavioral and magnetoencephalographic correlates.Neuroimage. 2020; 205: 116302
- A network-based neurobiological model of PTSD: Evidence from structural and functional neuroimaging studies.Curr Psychiatry Rep. 2017; 19: 81
- Can transcranial direct current stimulation augment extinction of conditioned fear?.Brain Stimul. 2016; 9: 529-536
- A systematic review on the effect of transcranial direct current and magnetic stimulation on fear memory and extinction.Front Hum Neurosci. 2021; 15: 655947
- Noninvasive stimulation of the ventromedial prefrontal cortex modulates emotional face processing.Neuroimage. 2018; 175: 388-401
- Noninvasive stimulation of the ventromedial prefrontal cortex enhances pleasant scene processing.Cereb Cortex. 2017; 27: 3449-3456
- Noninvasive stimulation of the ventromedial prefrontal cortex indicates valence ambiguity in sad compared to happy and fearful face processing.Front Behav Neurosci. 2019; 13: 83
- Repeated noninvasive stimulation of the ventromedial prefrontal cortex reveals cumulative amplification of pleasant compared to unpleasant scene processing: A single subject pilot study.PLoS One. 2020; 15e0222057
- Behavioral and magnetoencephalographic correlates of fear generalization are associated with responses to later virtual reality exposure therapy in spider phobia [published online ahead of print Jul 26].Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;
- The Karolinska Directed Emotional Faces - KDEF, CD ROM from Department of Clinical Neuroscience.Karolinska Institutet, Solna1998: 630
- International Affective Digitized Sounds (IADS): Stimuli, Instruction Manual and Affective Ratings (Tech. Rep. No. B-2).The Center for Research in Psychophysiology, University of Florida, Gainesville1999
- Investigation of tDCS volume conduction effects in a highly realistic head model.J Neural Eng. 2014; 11016002
- Stimulus timing-dependent plasticity in high-level vision.Curr Biol. 2012; 22: 332-337
- Statistical control of artifacts in dense array EEG/MEG studies.Psychophysiology. 2000; 37: 523-532
- Interpreting magnetic fields of the brain: Minimum norm estimates.Med Biol Eng Comput. 1994; 32: 35-42
- ElectroMagnetoEncephalography software: Overview and integration with other EEG/MEG toolboxes.Comput Intell Neurosci. 2011; 2011: 861705
- Nonparametric statistical testing of EEG- and MEG-data.J Neurosci Methods. 2007; 164: 177-190
- Behavioral and neural mechanisms of overgeneralization in anxiety.Curr Biol. 2016; 26: 713-722
- Orbital versus dorsolateral prefrontal cortex: Anatomical insights into content versus process differentiation models of the prefrontal cortex.Ann N Y Acad Sci. 2007; 1121: 395-406
- Emotion regulation and trait anxiety are predicted by the microstructure of fibers between amygdala and prefrontal cortex.J Neurosci. 2015; 35: 6020-6027
- The causal role of prefrontal hemispheric asymmetry in valence processing of words - Insights from a combined cTBS-MEG study.Neuroimage. 2019; 191: 367-379
- How the dorsolateral prefrontal cortex controls affective processing in absence of visual awareness - Insights from a combined EEG-rTMS study.Front Hum Neurosci. 2018; 12: 412
- Effect of threat on right dlPFC activity during behavioral pattern separation.J Neurosci. 2017; 37: 9160-9171
- Modulating emotion perception: Opposing effects of inhibitory and excitatory prefrontal cortex stimulation.Biol Psychiatry Cogn Neurosci Neuroimaging. 2018; 3: 329-336
- Optimizing inhibitory learning during exposure therapy.Behav Res Ther. 2008; 46: 5-27
- Maximizing exposure therapy: An inhibitory learning approach.Behav Res Ther. 2014; 58: 10-23
- Prefrontal oscillations during recall of conditioned and extinguished fear in humans.J Neurosci. 2014; 34: 7059-7066
- The relationship of perceptual discrimination to neural mechanisms of fear generalization.Neuroimage. 2019; 188: 445-455
- Modulation of fear extinction processes using transcranial electrical stimulation.Transl Psychiatry. 2016; 6: e913
- Cost of focality in TDCS: Interindividual variability in electric fields.Brain Stimul. 2020; 13: 117-124
- Die Bedeutung von unsicherheitsintoleranz für die Generalisierte Angststörung Modellüberlegungen und Entwicklung einer deutschen Version der Unsicherheitsintoleranz-Skala.Z Klin Psychol Psychother. 2008; 37: 190-199
- The CES-D scale: A self-report depression scale for research in the general population.Appl Psychol Meas. 1977; 1: 385-401
- A new scale of social desirability independent of psychopathology.J Consult Psychol. 1960; 24: 349-354
- An empirically derived inventory to measure social fears and anxiety: The social phobia and anxiety inventory.Psychol Assess. 1989; 1: 35-40
- Social phobia.Mod Probl Pharmacopsychiatry. 1987; 22: 141-173
- Spielberger state-trait anxiety inventory.in: Michalos A.C. Encyclopedia of Quality of Life and Well-Being Research. Springer, Dordrecht2014: 6261-6264
- Development and validation of brief measures of positive and negative affect: The PANAS scales.J Pers Soc Psychol. 1988; 54: 1063-1070
Article Info
Publication History
Published online: August 14, 2021
Accepted:
August 2,
2021
Received in revised form:
July 15,
2021
Received:
May 10,
2021
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2021 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
