Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC

Abstract

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study, we compared counterconditioning (a form of rewarded-extinction) to standard extinction, at recent (24 hours) and remote (~1 month) retrieval tests. Relative to standard extinction, counterconditioning diminished 24-hour relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standardextinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One-month later, the retrieval of both standard-and rewardedextinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-hour and 1-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans. Significance StatementPrevalent treatments for pathological fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multi-day fMRI paradigm in humans to compare the short-and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning, a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the vmPFC, for at least one month after learning..

Memory Trace for Fear Extinction: Fragile yet Reinforceable

“…Indeed, rewarded extinction, exemplified as counterconditioning in rats enhanced recruitment of an amygdala-striatal pathway and led to reduced fear relapse in the spontaneous recovery test [ 144 ], but exhibited greater levels of fear renewal [ 145 ]. Consistent with these observations in rodents, replacing shock with reward, rather than merely omitting it, generated a more stable and enduring memory trace of extinguished fear in humans [ 146 ]. As a promising pharmacological approach to enhance reward processing [ 147 ], 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has long-lasting therapeutic effects on traumatic memories for PTSD [ 148 ].…”

Event segmentation promotes the reorganization of emotional memory

“…Conversely, memories from safety learning are precise and distinct, engaged by stimuli that closely match the original safe event, emphasizing the potential difficulty for fear extinction memories to generalize compared to established fear memories (Bouton, 1993(Bouton, , 1994(Bouton, , 2002Bouton & Moody, 2004;Vervliet et al, 2013). Considering that fear extinction is often gauged via physiological responses in human studies, the integration of episodic memory paradigms could provide richer insights into mnemonic precision, including how safety memories might be augmented to better compete with maladaptive fear (Esser et al, 2021;Gerlicher et al, 2018;Haaker et al, 2013;Kalisch et al, 2019;Keller et al, , 2022Papalini et al, 2020).…”

“…This resulted in final samples of N=34 (Exp.1: 62% female, mean age = 20.27 ± 3.36, range = 18-34) and N=26 (Exp.2: 76.9% female, mean age = 20.88 ± 3.82, range = 18-34). Sample sizes were determined based on prior studies using the same experimental designs, ranging between 25-35 participants (Dunsmoor et al, , 2018Dunsmoor & Murphy, 2014;Hennings et al, 2020Hennings et al, , 2021Keller et al, 2022;Laing & Dunsmoor, 2023;Patil et al, 2017;Starita et al, 2019). This study was approved by the University of Texas at Austin Institutional Review Board (IRB: 2020020157-MOD08).…”

Resetting the Hippocampal Buffer: A Neurocognitive Account of Psychedelic Therapy for Anxiety-Related Psychopathology

“…One model suggests that the SN is engaged under stressful conditions, which is followed by engagement of the ECN to control emotional responses (Hermans et al, 2014). Finally, the vmPFC of the DMN is thought to control the amygdala's responses (Motzkin et al, 2015), including retention of fear extinction memories (Fullana et al, 2018;Keller et al, 2022), and vmPFC-amygdala connectivity is attenuated or inappropriately engaged in anxiety-related psychopathology (Fonzo & Etkin, 2017;MacNamara et al, 2016). Together, these findings suggest that anxiety-related psychopathology manifests hyperreactive SN function to perceived threat that in turn results in ECN deployment geared towards exercising top-down control to adaptively respond to environmental demands.…”