Medial prefrontal pathways for the contextual regulation of extinguished fear in humans

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.

Dynamic causal modeling in PTSD and its dissociative subtype: Bottom–up versus top–down processing within fear and emotion regulation circuitry

“…Broadly, the vmPFC is involved heavily in implicit regulation of fear and emotions [Etkin et al, ]. Given this role, the amygdala may serve as an emotion processing region resulting from the integration of top–down emotion regulation from the vmPFC (cognitive circuit) and bottom–up defense/fear generation from the PAG/midbrain (defensive survival circuit) [Åhs et al, ; Etkin et al, ; Ledoux, ; Panksepp, ; Panksepp et al, ]. Interestingly, recent studies have shown more emotional dysregulation and numbing, as well as self‐blame, detachment, and an inability to feel positive emotions among PTSD + DS patients [Bennett et al, ; Hansen et al, ].…”

Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions

“…Modeling variability in signaling pathways using functional genetic polymorphisms does not provide direct evidence for these interactions in humans; establishing functional correlates of our target polymorphisms through assays of circulating cortisol or AEA concentrations would underscore the accuracy of our model (43). The amygdala habituation phenotype we examined may be associated with fear extinction; for instance, during early extinction trials the amygdala is activated by stimuli previously conditioned to aversive outcomes, while in late extinction trials it is not (20, 21). However, our task did not condition individuals to specific stimuli.…”

“…Custom Illumina BeadChip arrays were used to provide genome-wide data from which the following single nucleotide polymorphisms (SNPs) were extracted: FAAH rs324420 and CRHR1 rs110402. SNPs were coded according to minor allele carrier status due to low numbers of minor allele homozygotes in cells: CRHR1 G carriers ( n =415; CRHR1 heterozygotes ( n =277) and CRHR1 G homozygotes ( n =138)), and CRHR1 A homozygotes ( n =246) and FAAH A carriers ( n =249; FAAH heterozygotes ( n =229) and FAAH A homozygotes (20)) and FAAH C homozygotes ( n =412). The genotyping rate of rs110402 was 99.9% and HWE criteria was met (all ps>.22) within each self-reported ethnicity subsample (Supplementary Table S2).…”

“…Further, we examined if individual differences in amygdala habituation indirectly link this genetic background to the presence of an anxiety disorder. We focused on amygdala habituation, as opposed to activity, in light of evidence that reductions in amygdala activation are associated with successful fear extinction (20, 21), and that decreased amygdala habituation is associated with psychopathology characterized by anxiety and excessive fear (22–25). A focus on habituation is further consistent with knockout and pharmacologic manipulation studies in rodents suggesting that eCB signaling is critical for fear extinction, but not conditioning (1, 4, 26), and prior evidence that genetic variation in the eCB system is associated with amygdala habituation in humans (1, 27).…”

The effect of cathodal tDCS on fear extinction: a cross-measures study

“…One hypothesis derived from the abovementioned studies is that by means of a reduced participation of the PFC in emotional regulation, cathodal tDCS may allow for a long-lasting fear memory update by disrupting reconsolidation processes (38,39). If this is true, then cathodal stimulation to the rDLPFC in tandem with a typical fear extinction procedure may lead to the extinction of autonomic fear responses, along with other resilient components of fear, such as avoidance tendencies.…”