Human Fear Conditioning and Extinction in Neuroimaging: A Systematic Review

Department of Psychiatry, University of Muenster, Muenster, Germany.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(6):e5865. DOI: 10.1371/journal.pone.0005865
Source: PubMed

ABSTRACT Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm.
A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas.
Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.

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    • "This response is not surprising due to previous findings showing that the ACC plays a crucial role within a general neural fear circuit (Hariri et al, 2003) as well as within the framework of Pavlovian fear conditioning (see reviews by Milad et al, 2007; Sehlmeyer et al, 2009). Furthermore, OXT has been found to moderate ACC activity (Gorka et al, 2015; Scheele et al, 2014a), and the ACC is characterized by a high OXT receptor density (Boccia et al, 2013). "
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    ABSTRACT: In human evolution, social group living and Pavlovian fear conditioning have evolved as adaptive mechanisms promoting survival and reproductive success. The evolutionarily conserved hypothalamic peptide oxytocin is a key modulator of human sociality, but its effects on fear conditioning are still elusive. In the present randomized controlled study involving 97 healthy male subjects, we therefore employed functional magnetic resonance imaging and simultaneous skin conductance response (SCR) measures to characterize the modulatory influence of intranasal oxytocin (24 IU) on Pavlovian fear conditioning. We found that the peptide strengthened conditioning on both the behavioral and neural levels. Specifically, subjects exhibited faster task-related responses and enhanced SCRs to fear-associated stimuli in the late phase of conditioning, which was paralleled by heightened activity in cingulate cortex subregions in the absence of changes in amygdala function. This speaks against amygdalocentric views of oxytocin having pure anxiolytic-like effects. Instead, it suggests that the peptide enables extremely rapid and flexible adaptation to fear signals in social contexts, which may confer clear evolutionary advantages but could also elevate vulnerability for the pathological sequelae of interpersonal trauma.Neuropsychopharmacology accepted article preview online, 14 August 2015. doi:10.1038/npp.2015.245.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2015; DOI:10.1038/npp.2015.245 · 7.05 Impact Factor
    • "The amygdala is commonly considered to be the region most implicated in fear conditioning. However, BOLD modulations have also been observed in a wider set of subcortical structures such as thalamus, hippocampus and anterior cingulate cortex [B€ uchel and Dolan, 2000; Knight et al., 2004; Sehlmeyer et al., 2009]. Crucially, the thalamic nuclei play a major role in mediating auditory fear conditioning in rats [Apergis- Schoute et al., 2005; Quirk et al., 1997]. "
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    ABSTRACT: Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 08/2015; DOI:10.1002/hbm.22940 · 5.97 Impact Factor
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    • "The function of the dmPFC in fear memory has been previously linked to fear expression during extinction recall as a marker of retention failure (Graham and Milad, 2011; Milad et al., 2007a). The dmPFC also signals fear cues during initial learning, a robust finding in the fear conditioning literature (Sehlmeyer et al., 2009). Here we add to this literature the novel finding that the dmPFC correlates with the difference in the conditioned response to the fear vs. safe cue in the Fear Renewal (but not the Extinction Recall) context, such that an increased response in the dmPFC was associated with increased autonomic fear expression. "
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    ABSTRACT: The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 07/2015; 122. DOI:10.1016/j.neuroimage.2015.07.051 · 6.36 Impact Factor
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