Fear conditioning paradigms have been studied for over 100 years and are of great interest to the behavioral and clinical sciences given that several safety learning processes (e.g., extinction learning and recall) are thought to be fundamental to the success of exposure-based therapies for anxiety and related disorders. This chapter provides an overview of preclinical and clinical investigations that examined the effects of exercise on initial fear acquisition, fear extinction learning and consolidation, and return of fear outcomes. This chapter highlights the collective body of evidence suggesting that exercise administered after extinction learning enhances the consolidation and subsequent recall of extinction memories to a greater extent than exercise administered prior to extinction learning. This suggests that the addition of exercise after exposure therapy sessions may improve treatment outcomes for people with anxiety and related disorders. Potential mechanisms are discussed in addition to suggestions for future research to improve our understanding of the effects of exercise on fear conditioning and extinction outcomes.

Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions, further research is needed regarding the effects of glucose on fear extinction. In two experimental studies with healthy participants (Study 1: N = 68, 39 females; Study 2: N = 89, 67 females), we investigated the effects of glucose on fear extinction learning and its consolidation. Participants completed a differential fear conditioning paradigm consisting of acquisition, extinction, and return of fear tests: reinstatement, and extinction recall. US-expectancy ratings, skin conductance response (SCR), and fear potentiated startle (FPS) were collected. Participants were pseudorandomized and double-blinded to one of two groups: They received either a drink containing glucose or saccharine 20 min before (Study 1) or immediately after extinction (Study 2). The glucose group showed a significantly stronger decrease in differential FPS during extinction (Study 1) and extinction recall (Study 2). Additionally, the glucose group showed a significantly lower contextual anxiety at test of reinstatement (Study 2). Our findings provide first evidence that glucose supports the process of fear extinction, and in particular the consolidation of fear extinction memory, and thus has potential as a beneficial adjuvant to extinction-based treatments. Registered through the German Clinical Trials Registry (https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html; Study 1: DRKS00010550; Study 2: DRKS00018933).

This chapter reviews the literature on the impact of stress and exercise on fear extinction. Given that key brain regions of the fear circuitry (e.g., hippocampus, amygdala and frontal cortex) can be modulated by stress hormones, it is important to investigate how stress influences this process. Laboratory-based studies performed in healthy adults have yielded mixed results, which are most likely attributable to various methodological factors. Among these factors, inter-individual differences modulating the stress response and timing of stressor administration with respect to the task may contribute to this heterogeneity. Given that fear is a core manifestation of various psychopathologies and that exposure-based therapy relies on fear extinction principles, several studies have attempted to assess the role of stress hormones on exposure-based therapy in patients suffering from post-traumatic stress disorder or anxiety disorders. These studies tend to suggest a beneficial impact of stress hormones (through either natural endogenous variations or synthetic administration) on exposure-based therapy as assessed mostly by subjective fear measures. Similar to stress, exercise can have an impact on many physiological and biological systems in humans. Of note, exercise modulates biomarkers such as brain-derived neurotrophic factor (BDNF) and anandamide (EAE) that act on brain regions implicated in the fear circuitry, supporting the importance of studying the impact of exercise on fear extinction. Overall, the results converge and indicate that fear extinction (tested in the laboratory or via exposure-based therapy in clinical populations) can be enhanced with exercise. Further research is needed to understand the mechanisms by which stress and exercise modulate fear learning and extinction processes, as well as to maximize the applicability to clinical contexts.

Sleep has been found to play a key role in fear conditioning, extinction learning and extinction recall, and sleep disturbances are linked to many mental disorders including post-traumatic stress disorder (PTSD). Previous studies examining associations between sleep and fear or extinction processes primarily focused on objectively measured sleep architecture. Little research has so far focused on subjective sleep measures and particularly in clinical populations, which often experience subjectively poor sleep, including PTSD. Here we investigated whether subjective sleep disturbance, sleep onset latency, wake after sleep onset or sleep efficiency were related to fear conditioning, extinction learning or extinction recall in a large sample of individuals with a range of PTSD symptom severity (n = 248). Overall, we did not find that subjective sleep was associated with fear conditioning or extinction processes. However, exploratory analyses examining the moderating effect of sex found that shorter sleep onset latency and greater sleep efficiency were associated with improved extinction recall in women with higher PTSD symptom severity. This suggests that less time falling asleep and longer time asleep while in bed may be protective in highly symptomatic women against the commonly observed impaired extinction recall in PTSD. More studies are needed to explore sex-specific effects further.

Gold standard treatments for anxiety- and trauma-related disorders focus on exposure therapy promoting extinction learning and extinction retention. However, its efficacy is limited. Preclinical and particularly animal research has been able to demonstrate that homozygosity for the fatty acid amide hydrolase (FAAH) C385A allele, similar to FAAH inhibition, is associated with elevated concentrations of anandamide (AEA) and facilitates extinction learning and extinction recall. However, in humans, the underlying neurobiological processes are less well understood, and further knowledge might enhance the development of more effective therapies. In this functional magnetic resonance imaging (fMRI) study, a fear conditioning, fear extinction and extinction recall paradigm was conducted with 55 healthy male adults. They were genotyped for the FAAH single-nucleotide polymorphism (SNP) rs324420 to investigate differences related to extinction recall in neural activation and State-Trait Anxiety Inventory (STAI) ratings between AC heterozygotes and CC homozygotes (FAAH C385A SNP). Differential brain activation upon an unextinguished relative to an extinguished stimulus, was greater in AC heterozygotes as compared to CC homozygotes in core neural structures previously related to extinction recall, such as the medial superior frontal gyrus, the dorsal anterior cingulate and the anterior and middle insular cortex. Furthermore, AC heterozygotes displayed higher AEA levels and lower STAI-state ratings. Our data can be interpreted in line with previous suggestions of more successful extinction recall in A-allele carriers with elevated AEA levels. Data corroborate the hypothesis that the endocannabinoid system, particularly AEA, plays a modulatory role in the extinction of aversive memory.

Sleep may contribute to the long-lasting consolidation and processing of emotional memories. Experimental fear conditioning and extinction paradigms model the development, maintenance, and treatment of anxiety disorders. The literature provides compelling evidence for the involvement of rapid eye movement (REM) sleep in the consolidation of such memories. This meta-analysis correlated polysomnographic sleep findings with psychophysiological reactivity to the danger (CS+) and safety stimuli (CS-), to clarify the specific role of sleep stages before and after fear conditioning, extinction learning and extinction recall. Overall, there was evidence that more pre-learning sleep stage two and less slow wave sleep was associated with higher psychophysiological reactivity to the safety stimulus during extinction learning. Preliminary evidence found here support the role of REM sleep during the post-extinction consolidation sleep phase in clinical populations with disrupted sleep, but not in healthy controls. Furthermore, the meta-regressions found that sex moderated the associations between sleep and psychophysiological reactivity throughout the paradigm providing evidence for diverging correlations in male and females. Specifically, increased post-extinction REM was associated with poorer extinction and safety recall in females while the opposite was found in males. These results have implications for future research in the role of sleep in emotional memory processing.

Emerging human studies demonstrate that theta oscillations in the dorsal anterior cingulate cortex are enhanced during fear recall (enhanced fear expression) and reduced during successful extinction recall (reduced fear expression). Although evidence suggests sex differences in fear recall and extinction recall, there are currently no human studies examining the oscillatory foundations of these memory processes separately in men and women.
Because previous studies suggest that estradiol partially mediates these sex differences, we examined 20 men (low estradiol and low progesterone), 20 women using oral contraceptives (low estradiol and low progesterone), and 20 free-cycling women during midcycle (high estradiol and low progesterone). We used a fear-conditioning procedure, allowing us to separately assess fear recall and extinction recall 24 hours after fear and extinction learning. Skin conductance responses and electroencephalography were recorded during fear recall and extinction recall, and prefrontal oscillations were source localized.
We found elevated fear expression during fear recall and impaired extinction recall, as indicated by increased peripheral arousal (skin conductance responses) and fronto-central theta oscillations, source localized in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex. Importantly, peripheral arousal and dorsal anterior cingulate cortex theta oscillations were stronger in men and women on oral contraceptives than in women from the midcycle group.
Our data show that neural oscillatory and peripheral correlates of heightened fear expression during fear recall and (impaired) extinction recall do not simply differ between sexes but depend on hormonal fluctuations within women.

This paper reviews the recent literature on menstrual cycle phase effects on outcomes relevant to anxiety and PTSD, discusses potential neurobiological mechanisms underlying these effects, and highlights methodological limitations impeding scientific advancement.
The menstrual cycle and its underlying hormones impact symptom expression among women with anxiety and PTSD, as well as psychophysiological and biological processes relevant to anxiety and PTSD. The most consistent findings are retrospective self-report of premenstrual exacerbation of anxiety symptoms and the protective effect of estradiol on recall of extinction learning among healthy women. Lack of rigorous methodology for assessing menstrual cycle phase and inconsistent menstrual cycle phase definitions likely contribute to other conflicting results. Further investigations that address these limitations and integrate complex interactions between menstrual cycle phase-related hormones, genetics, and psychological vulnerabilities are needed to inform personalized prevention and intervention efforts for women.

Exposure to childhood trauma is extremely common (>60 %) and is a leading risk factor for fear-based disorders, including anxiety and posttraumatic stress disorder. These disorders are characterized by deficits in fear extinction and dysfunction in underlying neural circuitry. Given the strong and pervasive link between childhood trauma and the development of psychopathology, fear extinction may be a key mechanism. The present study tests the impact of childhood trauma exposure on fear extinction and underlying neural circuitry. Children (N = 44, 45 % trauma-exposed; 6-11 yrs) completed a novel two-day virtual reality fear extinction experiment. On day one, participants underwent fear conditioning and extinction. Twenty-four hours later, participants completed a test of extinction recall during fMRI. Conditioned fear was measured throughout the experiment using skin conductance and fear-related behavior, and activation in fear-related brain regions was estimated during recall. There were no group differences in conditioned fear during fear conditioning or extinction learning. During extinction recall, however, trauma-exposed children kept more distance from both the previously extinguished and the safety cue, suggesting poor differentiation between threat and safety cues. Trauma-exposed youth also failed to approach the previously extinguished cue over the course of extinction recall. The effects on fear-related behavior during extinction recall were accompanied by higher activation to the previously extinguished cue in fear-relevant brain regions, including the dorsal anterior cingulate cortex and anterior insula, in trauma-exposed relative to control children. Alterations in fear-related brain regions and fear-related behavior may be a core mechanism through which childhood trauma confers heightened vulnerability to psychopathology.

Social Reticence (SR) is a temperament construct identified in early childhood that is expressed as shy, anxiously avoidant behavior and, particularly when stable, robustly associated with risk for anxiety disorders. Threat circuit function may develop differently for children high on SR than low on SR. We compared brain function and behavior during extinction recall in a sample of 11-to-15-year-old children characterized in early childhood on a continuum of SR. Three weeks after undergoing fear conditioning and extinction, participants completed a functional magnetic resonance imaging extinction recall task assessing memory and threat differentiation for conditioned stimuli. Whereas self-report and psychophysiological measures of differential conditioning, extinction, and extinction recall were largely similar across participants, SR-related differences in brain function emerged during extinction recall. Specifically, childhood SR was associated with a distinct pattern of hemodynamic-autonomic covariation in the brain when recalling extinguished threat and safety cues. SR and attention focus impacted associations between trial-by-trial variation in autonomic responding and in brain activation. These interactions occurred in three main brain areas: the anterior insular cortex (AIC), the anterior subdivision of the medial cingulate cortex (aMCC), and the dorsolateral prefrontal cortex (dlPFC). This pattern of SCR-BOLD coupling may reflect selective difficulty tracking safety in a temperamentally at-risk population.