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. 2026 Mar 11;35(2):96–108. doi: 10.5607/en25029

The Timing of Attentional Distraction Matters in Facilitating Extinction of Trace Fear Memory

Seung-Min Baek 1,†, Sung-Moo Park 2,†, Hyoung-Ro Lee 1,2, Ung-Gu Kang 3, Suk-Ho Lee 1,2,*
PMCID: PMC13106958  PMID: 41807046

Abstract

Eye movement desensitization and reprocessing (EMDR) is a popular psychotherapy used to alleviate mental distress associated with anxiety and trauma-related disorders. Although working memory taxation has been proposed as an underlying mechanism of the therapy, such claim yet remains controversial due to lack of neurobiological foundations and conflicting findings among studies. In this study, we distracted rats with flickering lights during their training of fear memory extinction. Temporal overlap of twenty-second visual stimulations with the anticipatory shock timing of trace fear conditioning effectively facilitated fear extinction in a subset of animals that showed relatively low freezing during the conditioning day, while random intermittent visual stimulations did not. Moreover, fear extinction in delay fear conditioned animals was not affected either by the same visual stimulations or the stimulations that overlapped with shock timing. These results show that attentional distraction facilitates trace fear extinction, and proper timing is a necessary condition for a sensory stimulation to effectively facilitate trace fear extinction. Implications of our findings in EMDR and potential neurobiological mechanisms are discussed.

Keywords: Trace fear conditioning, Fear extinction, Working memory taxation, Eye movement desensitization and reprocessing

INTRODUCTION

Understanding the physiology of fear and anxiety has long been a goal of neuroscientific research [1, 2]. While the knowledge on the formation of fear memory offers insights into the pathophysiology of anxiety and trauma-related disorders, investigating the mechanisms underlying fear extinction is essential to develop novel treatments and improve current clinical practices [3]. Working memory, a cognitive mechanism for temporary maintenance and manipulation of information [4], may play a role in fear extinction by supporting the formation of inhibitory memory trace that counteracts pre-existing aversive memory [5, 6]. However, it can also worsen maladaptive symptoms of aversive memory recall by increasing its vividness, which can be problematic for patients with post-traumatic stress disorder (PTSD) [7].

Eye movement desensitization and reprocessing (EMDR), a popular psychotherapy for PTSD and anxiety [8-10], is grounded on a belief that taxing working memory alleviates distressing symptoms from aversive memories. Working memory consists of multiple subsystems: the “central executive” (CE), which allocates attention between tasks and coordinates information from subsidiary slave systems, namely the “visuospatial sketchpad” (VSSP) and the “phonological loop” (PL), each responsible for processing visuospatial and verbal information [4]. Generally, due to the limited capacity of these subsystems, performing multiple tasks simultaneously can degrade task performance [11]. EMDR directs patients to attend to bilateral sensory stimulations (BLS), such as alternating visual or auditory signals, while recalling a traumatic memory [12]. Aversive memories frequently take a form of visual image, recruiting working memory during its recall [13, 14]. Due to the limited capacity of the VSSP and CE, taxing working memory by drawing dual attention toward sensory stimulation and aversive memory recall may decrease the vividness and emotionality of memory recall [15-17], which can leave a long-term effect on the aversive memory through mechanisms such as reconsolidation disruption or fear extinction [18-20]. However, this hypothesis is faced with inconsistencies among studies and a lack of biological understandings [21], necessitating further investigations into how working memory taxation contributes to the therapeutic effects of EMDR.

Classical fear conditioning can serve as a useful experimental framework to test this. Fear conditioning is a simple and evolutionarily conserved model for investigating how associative fear memory is formed, retrieved, and modified [22, 23]. Notably, a specific type of fear conditioning protocol, trace fear conditioning (TFC), can offer a unique opportunity to evaluate situations when working memory is involved in fear retrieval [24-26]. While delay fear conditioning (DFC) presents its subjects with consecutive delivery of the conditioned stimulus (CS) and unconditioned stimulus (US), TFC incorporates a temporal gap (i.e., trace interval) between the two stimuli, similar to delay periods of working memory tasks [27, 28]. This requires subjects to hold information about the CS even when it is absent. In the acquisition phase, neural representations of the CS should be maintained during the trace interval to bridge the CS and US [29-31]. During retrieval, temporal discontiguity between the CS and US creates uncertainty about the timing of the US [32, 33], drawing sustained attention toward the upcoming US even after CS offset. Notably, subjects that underwent TFC tend to anticipate US timing by showing stronger conditioned responses near the US timing than during CS presentations [34-36], suggesting that trace interval, especially around the timing of US delivery can serve as an ideal time window for evaluating the impact of working memory taxation on fear conditioning.

The present study tested whether visual sensory stimulation can enhance trace fear extinction when it distracts attention of animals during trace interval. By examining fear extinction of rats across distinct visual stimulation and fear conditioning protocols, we show that temporal overlap of visual stimulation with anticipatory shock timing was crucial in facilitating fear extinction in TFC but not in DFC.

MATERIALS AND METHODS

Subjects

All experiments described in this study were approved by the Institutional Animal Care and Use Committee of Seoul National University. Experiments were conducted in male Sprague-Dawley rats (Orient Bio, Seongnam, Korea; Koatech, Pyeongtaek, Korea) aged 6~9 weeks. The animals were housed in pairs, and acclimated to the facility for at least 1 week before the experiments (temperature: 25±2°C; humidity: 60±5%). All animals were maintained on a 12-hour light/dark cycle (8 a.m. to 8 p.m.), and provided with food and water ad libitum. In total, 105 rats were used in this study.

Behavioral apparatus

Two distinct contexts, ‘Context A’ and ‘Context B’ were used in the experiments. Each context was placed in a separate sound-attenuating chamber under a background noise of ~60 dB. Context A (Conditioning context) was composed of aluminum side walls and an electrical grid floor (30 cm width×30 cm height×25 cm depth; H10-11R-TC; Coulbourn Instruments). Context B (Extinction context) was a rectangular acrylic box (36 cm width×25 cm height×21 cm depth) composed of black floor and plexiglass walls with blue sheet papers attached at the outer side. In both chambers, a speaker was placed at the left side of the contexts. For visual stimulation, a custom-made visual stimulator was placed on the front wall of Context B. The visual stimulator was composed of two ring-shaped LED modules (3 cm diameter), each containing 8 white LEDs (~30 lux) (Adafruit Neopixel). The LED modules were installed side-by-side on the wall of the Context B with a distance of 20 cm, and about 25 cm high from the bottom (Fig. 1B). Animal behavior was recorded with CCD camera fixed over the contexts (30 FPS). Data collection and control of behavior protocols were automatically performed with Ethovision XT 13 (Noldus information technology) in Context A, and custom-designed Arduino and Bonsai software in Context B. The contexts were cleansed with 70% ethanol at the end of each experiment.

Fig. 1.

Fig. 1

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Experimental design. (A) 3-Day fear conditioning and extinction paradigm. Visual stimulation was delivered on Day 2. (B) Schematic of visual stimulation during fear extinction. A custom-made visual stimulator was placed on the front wall of the extinction chamber (Context B). During stimulation, two modules of white LEDs were turned on and off in an alternating manner at 3 Hz. (C) Schematic of Post-CS visual stimulation protocol. To evaluate visual stimulation-induced changes in freezing behavior, each trial was divided into three periods (PRE/STIM/POST) depending on the onset and offset of the visual stimulation. (D) Mean freezing ratio of each experimental group during fear conditioning on Day 1 (i.e., fear reactivity). Conditioning method is denoted as Trace (trace fear conditioning) and Delay (delay fear conditioning). Mann-Whitney U-test: p=0.0543 for Trace (Post-CS, n=13; Control, n=14); p=0.1037 for Delay (n=Post-CS, n=12; Control, n=11). The median value of each experimental group is indicated as a horizontal line in the box. Throughout the experiments, animals with freezing levels above the median were classified as high-freezing (HI), while those below the median were classified as low-freezing (LO). Whiskers denote the minimum and maximum values. CS, conditioned stimulus. US, unconditioned stimulus. VS, visual stimulation.

Fear conditioning and extinction

A 3-day fear conditioning and extinction paradigm was applied throughout the experiments (Fig. 1A). On Day 1 (Fear Conditioning), animals were placed in Context A and received either TFC or DFC depending on their experimental groups. Following a 5-minute baseline period, auditory cue (conditioned stimulus; CS; 2.5 kHz pure tone, 75 dB) was presented for 20 seconds. A 1 s-footshock (unconditioned stimulus; US; 0.5 mA) was delivered 20 seconds (trace interval) after CS offset in TFC, or immediately following CS offset in DFC. The animals received a total of eight conditioning trials with random inter-trial intervals (ITIs) within a range of 210±30 seconds. On Day 2 (Extinction Training), the animals were placed in Context B and underwent 15 CS-only trials. Following a 10-minute baseline period, the CS was presented for 20 seconds with no subsequent US administration. ITIs of CS-only trials were given randomly between 100±20 seconds. On Day 3 (Extinction Retention), freezing behavior of the animals was re-evaluated in Context B. Following a 5-minute baseline period, 5 CS-only presentations were conducted with randomly selected ITIs within a range of 100±20 seconds.

Visual stimulation

Visual stimulation was delivered on Day 2 (Extinction Training). During visual stimulation, the two visual stimulator modules were switched on and off alternately at 3 Hz, similar to alternating bilateral sensory stimulations used in EMDR [12]. Three distinct stimulation protocols were applied throughout the study: ‘Post-CS’, ‘DFC-Overlap’, and ‘Random’. Post-CS and Random stimulation protocol experiments were performed together and shared the same control group (i.e., animals that did not receive visual stimulation), while DFC-Overlap stimulation protocol experiment was done separately and the experimental group was compared against its own control group. Under Post-CS protocol, visual stimulations were performed 14 seconds after CS offsets, persisting for 20 seconds. The stimulation was performed in all 15 trials. Under DFC-Overlap protocol, visual stimulations were performed 14 seconds after CS onsets, persisting for 20 seconds. Under Random protocol, visual stimulations were intermittently presented at randomly selected intervals of either 10 or 15 seconds, each lasting 6 seconds [37, 38]. The first stimulation under Random protocol initiated one minute prior to the first CS presentation (Trial 1). Animals were assigned randomly to experimental groups.

Quantification of behavior data

Behavioral index of conditioned fear was evaluated from freezing behavior, defined as the absence of movement except for breathing. This was automatically quantified from live video recordings through frame-by-frame analysis of pixel change using a python-based open-source software, ezTrack [39]. The parameters required for the analysis were set to meet the definition, and confirmed by manually comparing the freezing quantification data with live video recordings (motion cutoff, 20; freezing threshold, 20; minimum freezing duration, 1 s). For Day 2, raw freezing quantification data were reprocessed in order to remove false identification of animal motion due to visual stimulation. Frames with aberrant pixel change were automatically detected using custom-made python codes, and their pixel change values were substituted to the mean value of its neighboring frames. Whether the additional procedure minimized false identification of animal motion was confirmed by manually comparing the freezing quantification data with live video recordings.

Statistical analysis

Statistical analyses were carried out using R (version 4.4.1) and GraphPad Prism (version 9.5.1). Five animals were excluded from final analysis due to experimental error. Mean freezing ratio over first three trials on extinction training (Day 2) was used to assess fear acquisition following fear conditioning. Two animals showed lower freezing levels during the first three CS-only presentations on Day 2 than their baseline, indicating a failure in acquiring trace fear memory, and were therefore excluded from the final analysis. For the experiments using Post-CS protocol, each trial of the extinction training was divided into three periods (Fig. 1C): before stimulation (PRE, from CS onset to visual stimulation onset), during stimulation (STIM, between visual stimulation onset and offset), and after stimulation (POST, from visual stimulation offset to the end of the trial). For analytical purpose, animals of each experimental group were classified into high-freezing (HI) and low-freezing (LO) clusters based on a median split of mean freezing level during fear conditioning (Fig. 1D). For groups with odd number of animals, we matched the size of the HI and LO clusters by removing the animal with the median value. The group differences in percent freezing were assessed by two-way repeated measures ANOVA followed by Fisher’s least significant difference (LSD) post hoc test. Mann-Whitney U-test was used to compare two independent groups. Two-tailed tests were used for all analyses. All statistical data except for Fig. 1D are expressed as mean±standard error of the mean (SEM). Throughout the study, p values below 0.05 were considered statistically significant. The level of statistical significance is indicated as follows: n.s. not significant; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. Sample size (denoted as n) of each experiment is stated at corresponding figure legend. No statistical method was used to pre-determine sample size, but the sizes are similar to those applied in previous studies of the field.

RESULTS

Post-CS visual stimulation facilitated extinction of trace fear memory but not of delay fear memory

We examined whether fear extinction is affected by visual sensory stimulation. Three-day fear conditioning and extinction paradigm was applied in this study (Fig. 1A). At the first day, animals were placed in a fear conditioning context (Context A), and were subjected to trace fear conditioning (TFC), in which a 20 second interval intervened between a CS (tone) and a US (electrical shock). On the next day, the animals were trained for fear extinction (extinction training, ET) by presenting the CS without a shock in a distinct context (Context B). The extinction context was equipped with two overhead LED modules (Fig. 1B), and the animals underwent fear extinction with or without visual stimulation. During visual stimulation, the two LED modules alternately switched on and off at 3 Hz. To effectively distract animal’s attention while it anticipates US delivery, visual stimulation started 14 seconds after CS offset, and was delivered for 20 seconds to the test group animals (Post-CS group), thereby the period of visual stimulation encompassing the anticipatory US timing (‘Post-CS protocol’, Fig. 1C). On Day 3, animals were tested for extinction retention (ER) by measuring freezing ratio in response to the CS in Context B. For comparison, different groups of animals were subjected to delay fear conditioning (DFC), which presented the CS and US consecutively, and were trained for fear extinction with or without Post-CS visual stimulation. The mean freezing level during fear conditioning did not differ among animal groups (Fig. 1D).

We first compared extinction learning and retention between the control and Post-CS group animals that underwent TFC (Fig. 2A). Compared to the control (n=14), the Post-CS group animals (n=13) displayed faster attenuation of freezing levels during extinction training (F1,25=6.816, p=0.0151 for main effect of group; Fig. 2B). The freezing response to CS during the extinction retention test on Day 3, however, were not different between the control and Post-CS group animals (F1,25=2.568, p=0.1216 for main effect of group). To resolve the discrepancy between the faster extinction learning on Day 2 and similar extinction retention on Day 3 of the Post-CS group animals, we conducted further analysis by grouping the animals based on their fear reactivity, which was evaluated by the mean freezing levels during fear conditioning. Given the influence of fear reactivity on animal behavior during the following days of fear conditioning [40], this may potentially differentiate stimulation outcome across subjects. Animals were clustered by median split of mean freezing levels during fear conditioning (fear reactivity), resulting in two clusters: high-freezing (HI) and low-freezing (LO) (for each cluster, Post-CS, n=6; Control, n=7). We first compared fear memory retrieval of the two clusters at Day 2, measured as mean freezing level over first three trials. In the control group, fear memory retrieval was not different between the clusters (Fig. 2C, left). Furthermore, no correlation was observed between fear reactivity and fear memory retrieval on Day 2 (Fig. 2C, right), indicating that fear reactivity did not alter fear memory retrieval on Day 2. When the analysis was restricted to the HI cluster, the control and Post-CS group animals showed comparable freezing levels throughout the extinction training and the extinction retention test (Fig. 2D, left). On the contrary, the LO cluster of the Post-CS group exhibited significantly low freezing levels during extinction training (F1,11=14.64, p=0.0028 for main effect of group, Fig. 2E, left), as well as during the extinction retention test (F1,11=7.330, p=0.0204 for main effect of group). For more detailed evaluation of visual stimulation-induced changes in freezing behavior, we divided time windows of each extinction training trial into three nonoverlapping periods, before (PRE), during (STIM), and after (POST) visual stimulation (Fig. 1C). The freezing levels of first five trials (Trial 1~5 of extinction training) were averaged for each period. Comparing freezing levels of the control and Post-CS group animals showed that the LO cluster of the Post-CS group showed significantly lower freezing in both the STIM and POST periods, whereas lower freezing was limited to the STIM period in the HI cluster (Fig. 2D, E, right; for each bar, Post-CS, n=6; Control, n=7). Such sustained low freezing even after the cessation of visual stimulation suggests that fear extinction rather than visually-evoked response is responsible for the rapid attenuation of freezing levels observed in the Post-CS group of the LO cluster [41].

Fig. 2.

Fig. 2

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Post-CS stimulation protocol facilitated trace fear extinction in low-freezing animals. (A) Trace fear conditioning and extinction training under Post-CS protocol. The unconditioned stimulus (US) was delivered 20 s after the conditioned stimulus (CS). Visual stimuli (VS) were delivered 14 s after CS offset for 20 s. (B) Freezing behavior across 3 days (Post-CS, n=13, blue; Control, n=14, red). Freezing levels are presented in averaged values of two-trial bins for FC, of individual trials for ET, and of all five trials (CS trials) for ER. The first point of each day represents mean freezing during the baseline period. ET: F1,25=6.816, p=0.0151 for main effect of group; p=0.0462 for trial 3; p=0.0219 for trial 4; p=0.0208 for trial 7; p=0.0136 for trial 8; p=0.0136 for trial 9; p=0.0250 for trial 10. ER: F1,25=2.568, p=0.1216 for main effect of group. (C) Fear memory retrieval on Day 2 in the control group animals with high and low fear reactivity on Day 1. Left, fear memory retrieval of the HI and LO clusters of the control group. Fear memory retrieval was measured as the mean freezing levels during the initial three trials of the extinction training. p=0.0530. Right, fear memory retrieval on Day 2 as a function of fear reactivity on Day 1. Pearson’s correlation (r)=0.311, p=0.280. (D, E) Freezing behavior of the Post-CS and Control groups in HI and LO clusters. (D) Left, freezing behavior across 3 days in HI cluster (Post-CS, n=6; Control, n=7). ET: F1,11=0.6965, p=0.4217 for main effect of group. ER: F1,11=0.03274, p=0.8597 for main effect of group. F1,11=7.115, p=0.0219 for trial×group interaction; p=0.1686 for baseline, p=0.1002 for CS trials. Right, freezing during initial 5 trials of ET (Gray area of left). Freezing ratios on first five trials of ET were averaged over each of three phases as shown Fig. 1C (PRE/STIM/POST). PRE: p=0.1474; STIM: p=0.0309; POST: p=0.6282. (E) Same as D but for the LO cluster (Post-CS, n=6; Control, n=7). Left, ET: F1,11=14.64, p=0.0028 for main effect of group; p=0.0483 for trial 2; p=0.0165 for trial 3; p<0.0001 for trial 4; p=0.0169 for trial 9; p=0.0207 for trial 11; p=0.0498 for trial 13. ER: F1,11=7.330, p=0.0204 for main effect of group; p=0.0111 for CS trials. Right, PRE: p=0.3660; STIM: p=0.0012; POST: p=0.0047. Data for B, D, E (left) were assessed by two-way repeated measures ANOVA followed by Fisher’s LSD post hoc test. Data for C (left) and D, E (right) were assessed by Mann-Whitney U-test. FC, fear conditioning. ET, extinction training. ER, extinction retention. HI, high-freezing cluster. LO, low-freezing cluster. *p<0.05; **p<0.01.

To test whether the effect of Post-CS visual stimulation is specific for trace fear memory, we applied the same stimulation protocol to the animals that underwent DFC during extinction training (Fig. 3A, Post-CS, n=12; Control, n=13). Unlike above results, freezing levels were little affected by Post-CS protocol throughout the extinction training and the extinction retention test (Fig. 3B). We further analyzed animal behavior by splitting the control and Post-CS group animals by the median of mean freezing levels during fear conditioning (for each cluster, Post-CS, n=6; Control, n=6). The two clusters of the control group exhibited comparable fear memory retrieval at Day 2 (Fig. 3C), and visual stimulation failed to facilitate fear extinction in both clusters (Fig. 3D, E, left). Both clusters of the Post-CS group demonstrated similar freezing levels with the control group clusters during the POST periods of the initial five trials, further validating a lack of stimulation effect on fear extinction (Fig. 3D, E, right). To summarize, Post-CS protocol facilitated trace but not delay fear extinction, albeit its effect was observed only in the low fear reactivity group.

Fig. 3.

Fig. 3

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Post-CS stimulation protocol failed in facilitating delay fear extinction. (A) Delay fear conditioning and extinction training under Post-CS protocol. The US was delivered immediately after the CS. Visual stimulation (VS) was delivered 14 s after CS offset for 20 s. (B) Freezing behavior across 3 days (Post-CS, n=12, blue; Control, n=13, red). Freezing levels are presented in averaged values of two-trial bins for FC, of individual trials for ET, and of all five trials for ER. The first point of each day represents mean freezing during the baseline period. ET: F1,23=0.08940, p=0.7676 for main effect of group. ER: F1,23=0.01269, p=0.9113 for main effect of group. (C) Fear memory retrieval on Day 2 in the control group animals with high and low fear reactivity on Day 1. Left, fear memory retrieval of the HI and LO cluster of the control group. p=0.4848. Right, fear memory retrieval on Day 2 as a function of fear reactivity on Day 1. Pearson’s correlation (r)=0.009895, p=0.9757. (D, E) Freezing behavior of the Post-CS and Control groups in HI and LO clusters. (D) Left, freezing behavior across 3 days in the HI cluster (Post-CS, n=6; Control, n=6). ET: F1,10=0.3940, p=0.5443 for main effect of group. ER: F1,10=0.03903, p=0.8473 for main effect of group. Right, mean freezing levels during initial 5 trials of ET (Gray area of left) are shown for three phases. PRE: p=0.1255; STIM: p=0.3723; POST: p=0.4459. (E) Same as D but for the LO cluster (Post-CS, n=6; Control, n=6). Left, ET: F1,10=0.2142, p=0.6534 for main effect of group. ER: F1,10=0.09547, p=0.7637 for main effect of group. Right, PRE: p=0.9372; STIM: p=0.0238; POST: p=0.1255. Data for B and D, E (left) were assessed by two-way repeated measures ANOVA followed by Fisher’s LSD post hoc test. Data for C (left) and D, E (right) were assessed by Mann-Whitney U-test. HI, high-freezing cluster. LO, low-freezing cluster. *p<0.05.

Delay fear extinction was not facilitated by visual stimulations overlapping with US timing

Although we performed visual stimulation to distract animal’s attention, it can alternatively be interpreted as a safety cue indicating US omission. Dopamine neurons in the ventral tegmental area encode prediction error signal. Extinction of delay fear memory is accelerated by stimulation of dopamine neurons at the timing of US, suggesting that mesolimbic dopamine pathway is causally involved in delay fear extinction by signaling US omission through prediction error mechanism [42, 43]. If visual stimuli presented at the US timing serve as a cue amplifying this prediction error signal, it would facilitate delay fear extinction. To evaluate this possibility, we examined whether sensory stimulations presented around US timing affects extinction of fear memory formed by DFC. Twenty-second visual stimulations were given 14 seconds after CS onsets, thereby encompassing the US timing (DFC-Overlap protocol, Fig. 4A). Animals that underwent DFC were randomly assigned to visual stimulation (Overlap group, n=12) or control group (n=10). Both groups showed similar freezing levels during fear conditioning (Fig. 4B). Each group was separated into High- and Low-freezing clusters (for each cluster, Overlap, n=6; Control, n=5). Pooled data from both clusters did not reveal any significant difference in freezing level throughout extinction training and retention (Fig. 4C), nor did analyzing both freezing clusters separately (Fig. 4D). These results show that visual stimulation at US timing does not serve as a cue amplifying prediction error signal to accelerate extinction of delay fear memory. Assuming that extinction learning of trace and delay fear memory is modulated by prediction error signal to a similar extent, above results put sensory attentional distraction mechanism into a more likely scenario explaining how temporal overlap of sensory stimulation with anticipatory US timing facilitated trace fear extinction.

Fig. 4.

Fig. 4

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Delay fear extinction was not facilitated by visual stimulations overlapping with US timing. (A) Delay fear conditioning and extinction training under DFC-Overlap protocol. The US was delivered immediately after the CS. Visual stimulation (VS) was delivered 14 s after CS onset for 20 s. (B) Mean freezing ratio of each experimental group during fear conditioning on Day 1. Mann-Whitney U-test: p=0.1229 (Overlap, n=12, cyan; Control, n=10, red). (C, D) Effect of DFC-Overlap protocol on delay fear extinction. (C) Freezing behavior across 3 days. ET: F1,20=0.0002683, p=0.9871 for main effect of group. ER: F1,20=0.08457, p=0.7742 for main effect of group. (D) Left, freezing behavior across 3 days in HI cluster (Overlap, n=6; Control, n=5). ET: F1,9=0.08903, p=0.7722 for main effect of group. ER: F1,9=0.1924, p=0.6713 for main effect of group. Right, freezing behavior across 3 days in LO cluster (Overlap n=6; Control, n=5). ET: F1,9=0.1693, p=0.6904 for main effect of group; ER: F1,9=1.255, p=0.2917 for main effect of group.

Random stimulation did not facilitate fear extinction in either conditioning group

Distracting animals with intermittent visual stimulation during TFC but not DFC impairs the formation of CS-US association [37]. Unlike our Post-CS visual stimulations and US-overlapping stimulation in DFC, such intermittent stimulation may interfere with perception of CS, whose impact on trace fear extinction has not been explored. To test whether stimulation outcome depends on its timing, we adopted an intermittent visual stimulation protocol used by the previous study to distract animal’s attention (‘Random’ protocol, Fig. 5A) [37, 38]. The first visual stimulation was delivered one minute prior to the first CS presentation (Trial 1), and this was followed by intermittent stimulations at short random intervals (between 10 and 15 seconds), each lasting 6 seconds.

Fig. 5.

Fig. 5

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Random stimulation protocol did not facilitate fear extinction. (A) Extinction training under the Random protocol. Visual stimulation (VS) was delivered in random inter-stimulus intervals (ISI) between 10 or 15 s, each bout lasting for 6 s. (B) Mean freezing ratio of each experimental group during fear conditioning on Day 1. Conditioning method is denoted as Trace (trace fear conditioning) and Delay (delay fear conditioning). Mann-Whitney U-test: p=0.8300 for Trace (Random, n=13; Control, n=14); p=0.5309 for Delay (Random, n=13; Control, n=11). The median value of each experimental group is indicated as a horizontal line in the box. Animals with freezing levels above the median were classified as high-freezing (HI), while those below the median were classified as low-freezing (LO). Whiskers denote the minimum and maximum values. (C, D) Effect of the Random protocol on trace fear extinction. (C) Freezing behavior across 3 days (Random, n=13, blue; Control, n=14, red). Freezing levels are presented in averaged values of two-trial bins for FC, of individual trials for ET, and of all five trials for ER. The first point of each day represents mean freezing during the baseline period. ET: F1,25=1.719, p=0.2017 for main effect of group; p=0.0047 for trial 1. ER: F1,25=0.0002306, p=0.9880 for main effect of group. (D) Left, freezing behavior across 3 days in HI cluster (Random, n=6; Control, n=7). ET: F1,11=0.4606, p=0.5114 for main effect of group; p=0.0154 for trial 1. ER: F1,11=0.8181, p=0.3851 for main effect of group. F1,11=8.294, p=0.0150 for trial×group interaction; p=0.6939 for baseline, p=0.0538 for CS trials. Right, freezing behavior across 3 days in LO cluster (Random, n=6; Control, n=7). ET: F1,11=2.910, p=0.1161 for main effect of group; p=0.0442 for trial 1. ER: F1,11=1.712, p=0.2174 for main effect of group. (E, F) Effect of the Random protocol on delay fear extinction. (E) Freezing behavior across 3 days (Random, n=11, blue; Control, n=13, red). ET: F1,22=0.2728, p=0.6067 for main effect of group. ER: F1,22=0.02849, p=0.8675 for main effect of group. (F) Left, freezing behavior across 3 days in the HI cluster (Random, n=5; Control, n=6). ET: F1,9=0.1771, p=0.6837 for main effect of group. ER: F1,9=0.3679, p=0.5591 for main effect of group. Right, freezing behavior across 3 days in the LO cluster (Random, n=5; Control, n=6). ET: F1,9=0.01854, p=0.8947 for main effect of group. ER: F1,9=0.3137, p=0.5891 for main effect of group. Data for B were assessed by Mann-Whitney U-test. Data for C~F were assessed by two-way repeated measures ANOVA followed by Fisher’s LSD post hoc test. *p<0.05; **p<0.01.

Animals that underwent TFC or DFC were randomly assigned to visual stimulation (Random group) or control group. Both groups showed similar freezing levels during fear conditioning (Fig. 5B). For TFC animals (Random, n=13; Control, n=14), the Random group exhibited low freezing levels at the first trial of the extinction training (p=0.0047), but no significant differences were observed in the following trials (Fig. 5C). The mean freezing level during the extinction retention test was also comparable between the two groups. Each group was separated into High- and Low-freezing clusters. Splitting the whole dataset into the HI and LO clusters (for each cluster, Random, n=6; Control, n=7) failed to find significant effect of Random stimulation on fear extinction (Fig. 5D). Likewise, for DFC animals, the control and Random groups exhibited comparable freezing levels throughout the extinction training and the extinction retention test (Random, n=11; Control, n=13), regardless of their freezing levels during fear conditioning (Fig. 5E, F, for each cluster, Random, n=5; Control, n=6). In summary, the Random protocol did not facilitate fear extinction in either trace or delay fear conditioned animals, suggesting that attentional distraction should be done at a proper timing to effectively facilitate fear extinction.

DISCUSSION

Experimental validation of the psychological model of fear extinction is essential to deepen our understandings on extinction learning and to improve current clinical practices for anxiety and trauma-related disorders. In this study, we investigated how visual attentional distraction influences the extinction of conditioned fear. Visual stimulation could facilitate trace fear extinction if the stimulation overlapped with US timing. In animals that underwent DFC, however, fear extinction was not facilitated by either the same stimulation protocol or visual stimulations temporally overlapping with the US timing, suggesting that the effects of visual stimulation in TFC animals depend on animal’s anticipation of the US delivery. Furthermore, visual attentional distraction failed to facilitate fear extinction when delivered randomly throughout the extinction training, highlighting the importance of stimulation timing. By showing that timely visual stimulations can facilitate fear extinction, our results show that visual attentional distractions can be employed to enhance extinction learning.

Unlike the vulnerability of trace fear memory formation to attentional distraction [37], how visual attentional distraction affects fear retrieval and extinction in TFC has not been explored. Acquisition and retrieval of trace fear memory is different from those of delay fear memory in that TFC depends on descriptive memory formation mediated by the medial prefrontal cortex (mPFC) [29, 30, 44-46] and hippocampus [47-50], while DFC forms an implicit fear memory, retrieval of which is independent of intention or conscious awareness. Accordingly, anticipatory awareness of upcoming US following sensation of CS would emerge in TFC animals but not in DFC animals [34-36]. Fear extinction also depends on different mechanisms, shown by a previous study that inactivation of amygdala, where implicit memory of DFC is stored, does not affect extinction of TFC memory [51]. These differences in fear retrieval and extinction mechanism would account for the reason why visual attentional distraction at the US timing affect extinction learning specifically in animals that underwent TFC but not in those that underwent DFC.

The present study does not directly demonstrate that working memory taxation underlies visual attentional distraction-induced enhancement of trace fear extinction. Nevertheless, sensory attentional distraction impairs working memory performance [52, 53], and the brain circuits of working memory are likely be recruited to anticipate US during trace interval in TFC animals [24-26]. These notions imply that our Post-CS protocol in TFC consumes limited working memory resources similar to working memory taxation. Using an explicit working memory task and testing its influence on fear extinction would provide more reliable evidence on whether working memory taxation attenuates fear memory.

Although our view that working memory taxation facilitates trace fear extinction may contrast with previous studies in which working memory taxation conversely interfered with extinction learning, it should be noted that these studies tended to present the CS in the middle of a working memory task, while performing a working memory task after CS presentation tended to facilitate fear extinction [21, 54, 55]. Similar to this, visual stimulations always preceded CS presentations in the Random protocol experiment, making the CS and visual stimuli to compete for attentional resources. Under our Post-CS protocol, visual stimulations always followed CS presentations with temporal separation, likely preserving fear retrieval when the CS is being presented. Such discrepancy indicates that perception of CS should be preserved during fear extinction for the inhibitory learning process to occur [56], and suggests further studies on working memory taxation to take its timing into consideration.

In the present study, we presumed that visual attentional distraction attenuates conditioned fear through extinction learning. We did not explicitly test whether visual stimulation exert its effect through blocking reconsolidation of fear-encoding synapses and thereby directly disrupting fear memory [57]. However, previous studies suggest that blocking reconsolidation typically requires an isolated retrieval trial before an extinction training session is required [58, 59]. Moreover, larger discrepancy between fear conditioning and retrieval trials more likely initiate new memory formation such as extinction learning rather than reconsolidation [59]. Our behavioral protocol lacks the necessary retrieval trial required to destabilize the memory trace, and the novelty of visual stimulation would increase the discrepancy between fear conditioning and retrieval trials, likely triggering an extinction-based new inhibitory learning rather than a reconsolidation-based memory update [41]. Long-term effects, such as renewal, reinstatement, and spontaneous recovery, need to be tested in future studies to specify the fear attenuation mechanism underlying the stimulation effect.

An unexpected finding was that the effectiveness of Post-CS protocol was different in HI and LO clusters. One possibility is that the working memory capacity might be lower in the LO cluster than HI cluster. Efficacy of EMDR tends to be negatively correlated with working memory capacity [60]. In line with this, animals with poorer working memory capacity might demonstrate faster attenuation of freezing under visual stimulation while showing lower freezing level during fear conditioning due to slow association formation between the CS and US [37]. Behavioral characteristics of animals, such as their tendency to exhibit avoidance rather than freezing [40, 61], or baseline trait anxiety [62], may also account for the discrepancy. Further studies are needed to elucidate how conditioning strength and/or underlying traits of animals, such as working memory capacity or anxiety, affect the outcome of attentional distraction. Such studies may help our understanding on the variations in the efficacy of EMDR among its subjects [63].

The neurobiological mechanism how sensory distraction attenuates fear has largely been unknown. Recent findings raise a possibility that sensory distraction facilitates fear extinction by modulating activities of the mediodorsal thalamus (MD) and prelimbic cortex. The MD thalamus regulates fear memory bidirectionally depending on its firing modes: tonic firings support fear extinction, whereas burst firings impede it [64]. Sensory stimulation during fear extinction increases MD tonic firings [41], serving as a plausible explanation on how sensory distraction facilitates fear extinction. Furthermore, sensory distraction can disrupt top-down fear expression mechanism in the prelimbic cortex [65-67]. Development of 4 Hz local field potential (LFP) oscillation in the prelimbic cortex is causally related with freezing expression [68, 69], and its phase-locking to MD burst firings suggests that the 4 Hz oscillation may allow the prelimbic cortex to impede fear extinction during its expression [70]. Interestingly, freezing behavior-specific respiratory rhythm drives the 4 Hz oscillation in the prelimbic cortex [71], and sensory distraction would reduce fear expression and facilitate extinction if it is able to alter the respiratory rhythm during freezing. Together, these modulations of MD thalamic firing and prelimbic cortical rhythms are feasible targets to investigate how sensory distraction attenuates fear.

To summarize, the present study shows that sensory attentional distraction can be used to attenuate fear and highlights the importance of stimulation timing in facilitating trace fear extinction. Our results support the notion that working memory taxation underlies the therapeutic effect of EMDR and may help resolve inconsistencies regarding the influence of working memory taxation on fear memory. Explicit neurobiological mechanism underlying EMDR should be identified in future studies.

ACKNOWLEDGEMENTS

This work was supported by National Research Foundation of Korea (grant/award number, RS-2024-00333669 to SHL), a stipend from Seoul National University College of Medicine (to SMB) and the BK21 stipend (to SMP).

Footnotes

AUTHOR CONTRIBUTIONS

Conceptualization: SMB, HRL, SHL. Methodology: SMB, HRL, SMP. Investigation: SMB, SMP. Visualization: SMB. Supervision: HRL, UGK, SHL. Writing—original draft: SMB, SHL. Writing—review & editing: SMB, SMP, HRL, SHL.

CONFLICT OF INTEREST

The authors do not have any conflicts of interest to declare.

References

  • 1.Maren S, Quirk GJ (2004) Neuronal signalling of fear memory. Nat Rev Neurosci 5:844-852. 10.1038/nrn1535 [DOI] [PubMed]
  • 2.Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667-687. 10.1038/nrd4075 [DOI] [PMC free article] [PubMed]
  • 3.Milad MR, Rosenbaum BL, Simon NM (2014) Neuroscience of fear extinction: implications for assessment and treatment of fear-based and anxiety related disorders. Behav Res Ther 62:17-23. 10.1016/j.brat.2014.08.006 [DOI] [PubMed]
  • 4.Baddeley A (1992) Working memory. Science 255:556-559. 10.1126/science.1736359 [DOI] [PubMed]
  • 5.Brewin CR, Smart L (2005) Working memory capacity and suppression of intrusive thoughts. J Behav Ther Exp Psychiatry 36:61-68. 10.1016/j.jbtep.2004.11.006 [DOI] [PubMed]
  • 6.Stout DM, Acheson DT, Moore TM, Gur RC, Baker DG, Geyer MA, Risbrough VB (2018) Individual variation in working memory is associated with fear extinction performance. Behav Res Ther 102:52-59. 10.1016/j.brat.2018.01.002 [DOI] [PMC free article] [PubMed]
  • 7.Baddeley AD, Andrade J (2000) Working memory and the vividness of imagery. J Exp Psychol Gen 129:126-145. 10.1037/0096-3445.129.1.126 [DOI] [PubMed]
  • 8.Sharpley CF, Montgomery IM, Scalzo LA (1996) Comparative efficacy of EMDR and alternative procedures in reducing the vividness of mental images. Scand J Behav Ther 25:37-42. 10.1080/16506079609456006 [DOI]
  • 9.Seidler GH, Wagner FE (2006) Comparing the efficacy of EMDR and trauma-focused cognitive-behavioral therapy in the treatment of PTSD: a meta-analytic study. Psychol Med 36:1515-1522. 10.1017/S0033291706007963 [DOI] [PubMed]
  • 10.Wurtz H, El-Khoury-Malhame M, Wilhelm FH, Michael T, Beetz EM, Roques J, Reynaud E, Courtin J, Khalfa S, Herry C (2016) Preventing long-lasting fear recovery using bilateral alternating sensory stimulation: a translational study. Neuroscience 321:222-235. 10.1016/j.neuroscience.2015.06.012 [DOI] [PubMed]
  • 11.Cowan N (2017) The many faces of working memory and short-term storage. Psychon Bull Rev 24:1158-1170. 10.3758/s13423-016-1191-6 [DOI] [PubMed]
  • 12.Shapiro F (2001) Eye movement desensitization and reprocessing: basic principles, protocols, and procedures. 2nd ed. Guilford Press, New York.
  • 13.Arntz A, De Groot C, Kindt M (2005) Emotional memory is perceptual. J Behav Ther Exp Psychiatry 36:19-34. 10.1016/j.jbtep.2004.11.003 [DOI] [PubMed]
  • 14.Holmes EA, Bourne C (2008) Inducing and modulating intrusive emotional memories: a review of the trauma film paradigm. Acta Psychol (Amst) 127:553-566. 10.1016/j.actpsy.2007.11.002 [DOI] [PubMed]
  • 15.Schubert SJ, Lee CW, Drummond PD (2011) The efficacy and psychophysiological correlates of dual-attention tasks in eye movement desensitization and reprocessing (EMDR). J Anxiety Disord 25:1-11. 10.1016/j.janxdis.2010.06.024 [DOI] [PubMed]
  • 16.Van Den Hout MA, Engelhard IM, Rijkeboer MM, Koekebakker J, Hornsveld H, Leer A, Toffolo MB, Akse N (2011) EMDR: eye movements superior to beeps in taxing working memory and reducing vividness of recollections. Behav Res Ther 49:92-98. 10.1016/j.brat.2010.11.003 [DOI] [PubMed]
  • 17.Wadji DL, Martin-Soelch C, Camos V (2022) Can working memory account for EMDR efficacy in PTSD? BMC Psychol 10:245. 10.1186/s40359-022-00951-0 [DOI] [PMC free article] [PubMed]
  • 18.Leer A, Engelhard IM, Van Den Hout MA (2014) How eye movements in EMDR work: changes in memory vividness and emotionality. J Behav Ther Exp Psychiatry 45:396-401. 10.1016/j.jbtep.2014.04.004 [DOI] [PubMed]
  • 19.Van Den Hout MA, Engelhard IM (2012) How does EMDR work? J Exp Psychopathol 3:724-738. 10.5127/jep.028212 [DOI]
  • 20.Maxfield L, Melnyk WT, Hayman GCA (2008) A working memory explanation for the effects of eye movements in EMDR. J EMDR Pract Res 2:247-261. 10.1891/1933-3196.2.4.247 [DOI]
  • 21.Cheng Y, Jackson TB, MacNamara A (2022) Modulation of threat extinction by working memory load: an event-related potential study. Behav Res Ther 150:104031. 10.1016/j.brat.2022.104031 [DOI] [PMC free article] [PubMed]
  • 22.LeDoux JE (2014) Coming to terms with fear. Proc Natl Acad Sci U S A 111:2871-2878. 10.1073/pnas.1400335111 [DOI] [PMC free article] [PubMed]
  • 23.Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61-71. 10.1016/j.biopsycho.2006.01.008 [DOI] [PubMed]
  • 24.Carter RM, Hofstotter C, Tsuchiya N, Koch C (2003) Working memory and fear conditioning. Proc Natl Acad Sci U S A 100:1399-1404. 10.1073/pnas.0334049100 [DOI] [PMC free article] [PubMed]
  • 25.Sehlmeyer C, Schöning S, Zwitserlood P, Pfleiderer B, Kircher T, Arolt V, Konrad C (2009) Human fear conditioning and extinction in neuroimaging: a systematic review. PLoS One 4:e5865. 10.1371/journal.pone.0005865 [DOI] [PMC free article] [PubMed]
  • 26.Connor DA, Gould TJ (2016) The role of working memory and declarative memory in trace conditioning. Neurobiol Learn Mem 134(Pt B):193-209. 10.1016/j.nlm.2016.07.009 [DOI] [PMC free article] [PubMed]
  • 27.Liu D, Gu X, Zhu J, Zhang X, Han Z, Yan W, Cheng Q, Hao J, Fan H, Hou R, Chen Z, Chen Y, Li CT (2014) Medial prefrontal activity during delay period contributes to learning of a working memory task. Science 346:458-463. 10.1126/science.1256573 [DOI] [PubMed]
  • 28.Sobotka S, Diltz MD, Ringo JL (2005) Can delay-period activity explain working memory? J Neurophysiol 93:128-136. 10.1152/jn.01002.2003 [DOI] [PubMed]
  • 29.Baeg EH, Kim YB, Jang J, Kim HT, Mook-Jung I, Jung MW (2001) Fast spiking and regular spiking neural correlates of fear conditioning in the medial prefrontal cortex of the rat. Cereb Cortex 11:441-451. 10.1093/cercor/11.5.441 [DOI] [PubMed]
  • 30.Gilmartin MR, McEchron MD (2005) Single neurons in the medial prefrontal cortex of the rat exhibit tonic and phasic coding during trace fear conditioning. Behav Neurosci 119:1496-1510. 10.1037/0735-7044.119.6.1496 [DOI] [PubMed]
  • 31.Pilkiw M, Takehara-Nishiuchi K (2018) Neural representations of time-linked memory. Neurobiol Learn Mem 153:57-70. 10.1016/j.nlm.2018.03.024 [DOI] [PubMed]
  • 32.Kobayashi S, Schultz W (2008) Influence of reward delays on responses of dopamine neurons. J Neurosci 28:7837-7846. 10.1523/JNEUROSCI.1600-08.2008 [DOI] [PMC free article] [PubMed]
  • 33.Grabenhorst M, Maloney LT, Poeppel D, Michalareas G (2021) Two sources of uncertainty independently modulate temporal expectancy. Proc Natl Acad Sci U S A 118:e2019342118. 10.1073/pnas.2019342118 [DOI] [PMC free article] [PubMed]
  • 34.Raybuck JD, Lattal KM (2014) Bridging the interval: theory and neurobiology of trace conditioning. Behav Processes 101:103-111. 10.1016/j.beproc.2013.08.016 [DOI] [PMC free article] [PubMed]
  • 35.Burman MA, Gewirtz JC (2004) Timing of fear expression in trace and delay conditioning measured by fear-potentiated startle in rats. Learn Mem 11:205-212. 10.1101/lm.66004 [DOI] [PMC free article] [PubMed]
  • 36.Nobre AC, Van Ede F (2018) Anticipated moments: temporal structure in attention. Nat Rev Neurosci 19:34-48. 10.1038/nrn.2017.141 [DOI] [PubMed]
  • 37.Han CJ, O'Tuathaigh CM, Van Trigt L, Quinn JJ, Fanselow MS, Mongeau R, Koch C, Anderson DJ (2003) Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc Natl Acad Sci U S A 100:13087-13092. 10.1073/pnas.2132313100 [DOI] [PMC free article] [PubMed]
  • 38.Wu GY, Zheng XX, Zhao SL, Wang Y, Jiang S, Wang YS, Yi YL, Yao J, Wen HZ, Liu J, Li HL, Sui JF (2022) The prelimbic cortex regulates itch processing by controlling attentional bias. iScience 26:105829. 10.1016/j.isci.2022.105829 [DOI] [PMC free article] [PubMed]
  • 39.Pennington ZT, Dong Z, Feng Y, Vetere LM, Page-Harley L, Shuman T, Cai DJ (2019) ezTrack: an open-source video analysis pipeline for the investigation of animal behavior. Sci Rep 9:19979. 10.1038/s41598-019-56408-9 [DOI] [PMC free article] [PubMed]
  • 40.Bush DE, Sotres-Bayon F, LeDoux JE (2007) Individual differences in fear: isolating fear reactivity and fear recovery phenotypes. J Trauma Stress 20:413-422. 10.1002/jts.20261 [DOI] [PubMed]
  • 41.Baek J, Lee S, Cho T, Kim SW, Kim M, Yoon Y, Kim KK, Byun J, Kim SJ, Jeong J, Shin HS (2019) Neural circuits underlying a psychotherapeutic regimen for fear disorders. Nature 566:339-343. 10.1038/s41586-019-0931-y [DOI] [PubMed]
  • 42.Cai LX, Pizano K, Gundersen GW, Hayes CL, Fleming WT, Holt S, Cox JM, Witten IB (2020) Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times. Elife 9:e54936. 10.7554/eLife.54936.sa2 [DOI] [PMC free article] [PubMed]
  • 43.Salinas-Hernández XI, Vogel P, Betz S, Kalisch R, Sigurdsson T, Duvarci S (2018) Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes. Elife 7:e38818. 10.7554/eLife.38818.024 [DOI] [PMC free article] [PubMed]
  • 44.Siegel JJ, Mauk MD (2013) Persistent activity in prefrontal cortex during trace eyelid conditioning: dissociating responses that reflect cerebellar output from those that do not. J Neurosci 33:15272-15284. 10.1523/JNEUROSCI.1238-13.2013 [DOI] [PMC free article] [PubMed]
  • 45.Lee HR, Choi SH, Kim Y, Ko S, Kang H, Lee I, Park AJ, Lee SH (2024) Prelimbic corticopontine neurons gate extinction learning. bioRxiv. doi: 10.1101/2024.08.14.607871. 10.1101/2024.08.14.607871 [DOI]
  • 46.Gilmartin MR, Miyawaki H, Helmstetter FJ, Diba K (2013) Prefrontal activity links nonoverlapping events in memory. J Neurosci 33:10910-10914. 10.1523/JNEUROSCI.0144-13.2013 [DOI] [PMC free article] [PubMed]
  • 47.Kitamura T, Macdonald CJ, Tonegawa S (2015) Entorhinal-hippocampal neuronal circuits bridge temporally discontiguous events. Learn Mem 22:438-443. 10.1101/lm.038687.115 [DOI] [PMC free article] [PubMed]
  • 48.Jeneson A, Squire LR (2012) Working memory, long-term memory, and medial temporal lobe function. Learn Mem 19:15-25. 10.1101/lm.024018.111 [DOI] [PMC free article] [PubMed]
  • 49.Bai T, Zhan L, Zhang N, Lin F, Saur D, Xu C (2023) Learning-prolonged maintenance of stimulus information in CA1 and subiculum during trace fear conditioning. Cell Rep 42:112853. 10.1016/j.celrep.2023.112853 [DOI] [PubMed]
  • 50.Ahmed MS, Priestley JB, Castro A, Stefanini F, Solis Canales AS, Balough EM, Lavoie E, Mazzucato L, Fusi S, Losonczy A (2020) Hippocampal network reorganization underlies the formation of a temporal association memory. Neuron 107:283-291. 10.1016/j.neuron.2020.04.013 [DOI] [PMC free article] [PubMed]
  • 51.Kwapis JL, Jarome TJ, Lee JL, Gilmartin MR, Helmstetter FJ (2014) Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala. Neurobiol Learn Mem 113:41-54. 10.1016/j.nlm.2013.09.007 [DOI] [PMC free article] [PubMed]
  • 52.Dolcos F, McCarthy G (2006) Brain systems mediating cognitive interference by emotional distraction. J Neurosci 26:2072-2079. 10.1523/JNEUROSCI.5042-05.2006 [DOI] [PMC free article] [PubMed]
  • 53.McNab F, Zeidman P, Rutledge RB, Smittenaar P, Brown HR, Adams RA, Dolan RJ (2015) Age-related changes in working memory and the ability to ignore distraction. Proc Natl Acad Sci U S A 112:6515-6518. 10.1073/pnas.1504162112 [DOI] [PMC free article] [PubMed]
  • 54.de Voogd LD, Phelps EA (2020) A cognitively demanding working-memory intervention enhances extinction research article. Sci Rep 10:7020. 10.1038/s41598-020-63811-0 [DOI] [PMC free article] [PubMed]
  • 55.Raes AK, De Raedt R, Verschuere B, De Houwer J (2009) Failure to loose fear: the impact of cognitive load and trait anxiety on extinction. Behav Res Ther 47:1096-1101. 10.1016/j.brat.2009.08.002 [DOI] [PubMed]
  • 56.Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120-150. 10.1038/sj.mp.4001939 [DOI] [PubMed]
  • 57.Crestani AP, Zacouteguy Boos F, Haubrich J, Ordoñez Sierra R, Santana F, Molina JM, Cassini Lde F, Alvares Lde O, Quillfeldt JA (2015) Memory reconsolidation may be disrupted by a distractor stimulus presented during reactivation. Sci Rep 5:13633. 10.1038/srep13633 [DOI] [PMC free article] [PubMed]
  • 58.Monfils MH, Cowansage KK, Klann E, LeDoux JE (2009) Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324:951-955. 10.1126/science.1167975 [DOI] [PMC free article] [PubMed]
  • 59.Sevenster D, Beckers T, Kindt M (2013) Prediction error governs pharmacologically induced amnesia for learned fear. Science 339:830-833. 10.1126/science.1231357 [DOI] [PubMed]
  • 60.Gunter RW, Bodner GE (2008) How eye movements affect unpleasant memories: support for a working-memory account. Behav Res Ther 46:913-931. 10.1016/j.brat.2008.04.006 [DOI] [PubMed]
  • 61.Misslin R (2003) The defense system of fear: behavior and neurocircuitry. Neurophysiol Clin 33:55-66. 10.1016/S0987-7053(03)00009-1 [DOI] [PubMed]
  • 62.Macêdo-Souza C, Maisonnette SS, Filgueiras CC, Landeira-Fernandez J, Krahe TE (2020) Cued fear conditioning in carioca high- and low-conditioned freezing rats. Front Behav Neurosci 13:285. 10.3389/fnbeh.2019.00285 [DOI] [PMC free article] [PubMed]
  • 63.Silberschatz G (2017) Improving the yield of psychotherapy research. Psychother Res 27:1-13. 10.1080/10503307.2015.1076202 [DOI] [PubMed]
  • 64.Lee S, Ahmed T, Lee S, Kim H, Choi S, Kim DS, Kim SJ, Cho J, Shin HS (2011) Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice. Nat Neurosci 15:308-314. 10.1038/nn.2999 [DOI] [PubMed]
  • 65.Corcoran KA, Quirk GJ (2007) Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J Neurosci 27:840-844. 10.1523/JNEUROSCI.5327-06.2007 [DOI] [PMC free article] [PubMed]
  • 66.Burgos-Robles A, Vidal-Gonzalez I, Quirk GJ (2009) Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. J Neurosci 29:8474-8482. 10.1523/JNEUROSCI.0378-09.2009 [DOI] [PMC free article] [PubMed]
  • 67.Mukherjee A, Caroni P (2018) Infralimbic cortex is required for learning alternatives to prelimbic promoted associations through reciprocal connectivity. Nat Commun 9:2727. 10.1038/s41467-018-05318-x [DOI] [PMC free article] [PubMed]
  • 68.Karalis N, Dejean C, Chaudun F, Khoder S, Rozeske RR, Wurtz H, Bagur S, Benchenane K, Sirota A, Courtin J, Herry C (2016) 4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior. Nat Neurosci 19:605-612. 10.1038/nn.4251 [DOI] [PMC free article] [PubMed]
  • 69.Dejean C, Courtin J, Karalis N, Chaudun F, Wurtz H, Bienvenu TC, Herry C (2016) Prefrontal neuronal assemblies temporally control fear behaviour. Nature 535:420-424. 10.1038/nature18630 [DOI] [PubMed]
  • 70.Frontera JL, Sala RW, Georgescu IA, Baba Aissa H, d'Almeida MN, Popa D, Léna C (2023) The cerebellum regulates fear extinction through thalamo-prefrontal cortex interactions in male mice. Nat Commun 14:1508. 10.1038/s41467-023-36943-w [DOI] [PMC free article] [PubMed]
  • 71.Bagur S, Lefort JM, Lacroix MM, De Lavilléon G, Herry C, Chouvaeff M, Billand C, Geoffroy H, Benchenane K (2021) Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation. Nat Commun 12:2605. 10.1038/s41467-021-22798-6 [DOI] [PMC free article] [PubMed]

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