Fear extinction processes are central to the pathology and treatment of anxiety disorders. Emerging evidence implicates rapid eye movement (REM) sleep in the consolidation of extinction memory. Separately, converging theory and empirical work suggest that vagally mediated heart rate variability (VmHRV) serves as a peripheral index of cortico-subcortical regulatory capacity relevant to extinction circuitry. On this basis, we tested the hypothesis that VmHRV during REM sleep would be associated with the retention of extinction memory in individuals with generalized anxiety disorder (GAD). Participants underwent a validated two-day fear conditioning and extinction paradigm. Subjective extinction retention (sERI) was quantified during a recall test 24 hours after learning, and ambulatory polysomnography was recorded on the intervening night. As hypothesized, higher REM VmHRV was significantly associated with better extinction retention. This association remained robust after controlling psychotropic medication use and REM density. In contrast, VmHRV during SWS or wakefulness, as well as other REM sleep measures, were not associated with extinction retention. These findings identify REM VmHRV as a significant predictor of extinction memory retention in GAD, extending prior findings in trauma-exposed individuals. We propose that reduced vagal tone indexes compromised prefrontal inhibitory control over amygdala and noradrenergic circuits, thereby impairing REM sleep-dependent consolidation. These results position VmHRV during REM sleep as a potential transdiagnostic biomarker of extinction memory processing and suggest that interventions enhancing vagal tone could improve treatment outcomes in anxiety disorders. ### Competing Interest Statement The authors have declared no competing interest.

This study examined the role of a daytime nap in the consolidation and generalization of fear learning. 31 healthy, young adult participants (16 in the wake group and 15 in the sleep group) underwent a fear acquisition procedure in which the conditioned stimulus (CS+), a composite image consisting of a geometrical figure imposed on a background, was repeatedly paired with a mild electric shock. The safety stimulus (CS-), another geometrical figure imposed on another background, was never paired with the shock. After a delay interval containing either a 2-h nap opportunity or an equivalent amount of time spent awake, participants performed a fear memory and generalization test. Here, participants viewed four different stimuli: the CS+ and CS- seen before, as well as two novel stimuli composed of the same two geometrical figures seen before imposed on novel background images. This design allowed us to examine a) whether sleep consolidates the original fear memory and b) whether sleep affects the degree of generalization of fear learning to the original fear-eliciting geometrical figure presented on a novel background image. Results revealed no group differences for either the consolidation or generalization of fear learning in any of our outcome measures (skin conductance responses, subjective ratings of unpleasantness, retrospective shock expectancy ratings, or explicit memory performance). This study adds to the body of work showing mixed findings on the effect of sleep on consolidation and generalization of fear learning, in which there is currently limited evidence for sleep having an effect in either direction.

BACKGROUND:Posttraumatic stress disorder (PTSD) can be characterized as a disorder of fear learning and memory in which there is a failure to retain memory for the extinction of conditioned fear. Sleep has been implicated in successful extinction retention. The coupling of sleep spindles to slow oscillations (SOs) during non-rapid eye movement sleep has been shown to broadly underpin sleep's beneficial effect on memory consolidation. However, the role of this oscillatory coupling in the retention of extinction memories is unknown. METHODS:In a large sample of 124 trauma-exposed individuals, we investigated SO-spindle coupling in relation to fear extinction memory. RESULTS:We found that participants with a PTSD diagnosis, relative to trauma-exposed control participants, showed significantly altered SO-spindle timing, such that participants with PTSD exhibited spindle coupling farther away from the peak of the SO. Across participants, the amount of coupling significantly predicted extinction retention, with coupled spindles uniquely predicting successful extinction retention compared with uncoupled spindles. CONCLUSIONS:These results suggest that SO-spindle coupling is critical for successful retention of extinguished fear and that SO-spindle coupling dynamics are altered in PTSD. These alterations in the mechanics of sleep may have substantial clinical implications, meriting further investigation.

Posttraumatic stress disorder (PTSD) can be characterized as a disorder of fear learning and memory, in which there is a failure to retain memory for the extinction of conditioned fear. Sleep has been implicated in successful extinction retention. The coupling of sleep spindles to slow oscillations (SOs) during non-rapid eye movement sleep has been shown to broadly underpin sleep's beneficial effect on memory consolidation. However, the role of this oscillatory coupling in the retention of extinction memories is unknown. In a large sample of 124 trauma-exposed individuals, we investigated SO-spindle coupling in relation to fear extinction memory. We found that participants with a PTSD diagnosis, relative to trauma-exposed controls, showed significantly altered SO-spindle timing, such that PTSD participants exhibited spindle coupling further away from the peak of the SO. Across participants, the amount of coupling significantly predicted extinction retention, with coupled spindles uniquely predicting successful extinction retention compared to uncoupled spindles. These results suggest that SO-spindle coupling is critical for successful retention of extinguished fear, and that SO-spindle coupling dynamics are altered in PTSD. These alterations in the mechanics of sleep may have substantial clinical implications, meriting further investigation.

Background Fear extinction is an important treatment target of obsessive-compulsive disorder (OCD). In the current randomized controlled trial, we examined the therapeutic modulation of exposure and response prevention (ERP) on neural activation during fear extinction in OCD to identify mechanisms of action and response biomarkers. Methods Thirty-four patients with OCD were randomized to either 12-weeks of ERP or a waitlist. Before, during, and 12-weeks after treatment, patients were assessed using functional magnetic resonance imaging (fMRI) during a 2-day fear extinction paradigm. Neural activation was examined in disease- and construct-relevant circuits and nodes (n = 18). Results The ERP group had a significant reduction in OCD severity compared to waitlist. A voxel-wise GLM analysis of fMRI data revealed clusters of ERP > waitlist activation during fear conditioning (bilateral dorsal amygdala and right hippocampus) and extinction (right ventrolateral prefrontal cortex, located within the salience network). These changes in activation did not correlate with OCD severity changes, however. In contrast, we observed that a reduction in the activation of the left supramarginal gyrus (in the executive control network) during extinction recall correlated with OCD symptom improvement, suggesting a possible role as a response biomarker. Conclusions This study highlights the relevance of a dimensional approach (e.g., focused on fear extinction) for biomarker discovery in neuropsychiatry, provides insights into the mechanisms of action of ERP in OCD, and identifies a potential treatment target in the parietal cortex that could support the biomarker-driven development of novel therapies (e.g., brain stimulation protocols), including combination treatments with ERP. Clinicaltrials.gov identifier NCT02467374.

Sleep disturbances are common in anxiety disorders. Sleep is critical for extinction memory consolidation, a process central to exposure therapy. Here we review basic, clinical, and translational research to clarify sleep’s role in processing extinction memories, including in the context of exposure therapy. Sleep plays a significant role in extinction memory retention. Poor sleep quality predicts worse anxiety disorder treatment outcomes. Studies in specific phobia and social anxiety disorder indicate that the memory consolidation effects of sleep can be leveraged to enhance the retention of extinction memories during exposure therapy. Whether targeted memory cuing during NREM and/or REM sleep following exposure may further facilitate this enhancing effect is unclear.

Background Insomnia disorder, characterized by chronic sleep disruption, often co-occurs with maladaptive emotional memory processing. However, much remains unknown regarding the evolution of emotional memories and their neural representations over time among individuals with insomnia disorder.Method We examined the electroencephalographic (EEG) activities during emotional memory encoding, post-encoding sleep, and multiple retrieval phases - including immediate post-encoding, post-sleep, and a 7-day delayed retrieval - among 34 participants with insomnia disorder and 35 healthy control participants.Results Healthy controls exhibited adaptive dissipation of emotional memory: memory declined over time, accompanied by reduced subjective feelings toward negative memories. In contrast, participants with insomnia exhibited impaired dissipation: they retained both the emotional content and affective tone of the memories, with diminished time-dependent declines in memory and affect. Beyond behavioral performance, only participants with insomnia maintained stable neural representations of emotion over time, a pattern absent in healthy controls. Additionally, during the post-encoding sleep, slow-wave sleep (SWS), and rapid eye movement (REM) sleep durations predicted the adaptive dissipation of emotional memory over time, but only among healthy participants.Conclusion These findings highlight abnormalities in emotional memory processing among individuals with insomnia disorder and underscore the important function of SWS and REM sleep in facilitating adaptive emotional memory processing.

Trauma type moderates the impact of trauma exposure on clinical symptomatology; however, the impact of trauma type on the neural correlates of emotion regulation is not as well understood. This study examines how violent and nonviolent trauma differentially influence the neural correlates of conditioned fear and extinction. We aggregated psychophysiological and fMRI data from three studies; we categorized reported trauma as violent or nonviolent, and subdivided violent trauma as sexual or nonsexual. We examined skin conductance responses (SCR) during a fear conditioning and extinction paradigm. For fMRI data analyses, we conducted region-specific and whole-brain analyses. We examined associations between beta weights from specific brain regions and CAPS scores. The group exposed to violent trauma showed significantly higher SCR during extinction recall. Those exposed to nonviolent trauma showed significantly higher functional activation during late extinction learning. The group exposed to violent trauma showed higher functional connectivity within the default mode network (DMN) and between the DMN and frontoparietal control network. For secondary analyses of sexual vs nonsexual trauma, we did not observe any between-group differences in SCR. During late extinction learning, the group exposed to sexual trauma showed significantly higher activation in the prefrontal cortex and precuneus. During extinction recall, the group exposed to nonsexual trauma showed significantly higher activation in the insular cortex. Violent trauma significantly impacts functional brain activations and connectivity in brain areas important for perception and attention with no significant impact on brain areas that modulate emotion regulation. Sexual trauma impacts brain areas important for internal perception.

Accumulating evidence suggests that rapid eye movement sleep (REM) supports the consolidation of extinction memory. REM is disrupted in PTSD, and REM abnormalities after traumatic events increase the risk of developing PTSD. Therefore, it was hypothesized that abnormal REM in trauma-exposed individuals may pave the way for PTSD by interfering with the processing of extinction memory. In addition, PTSD patients display reduced vagal activity. Vagal activity contributes to the strengthening of memories, including fear extinction memory, and recent studies show that the role of vagus in memory processing extends to memory consolidation during sleep. Therefore, it is plausible that reduced vagal activity during sleep in trauma-exposed individuals may be an additional mechanism that impairs extinction memory consolidation. However, to date, the contribution of sleep vagal activity to the consolidation of extinction memory or any emotional memory has not been investigated. To test these hypotheses, we examined the association of extinction memory with REM characteristics and REM vagal activity (indexed as heart rate variability) in a large sample of trauma-exposed individuals (n=113). Consistent with our hypotheses, REM disruption was associated with poorer physiological and explicit extinction memory. Furthermore, higher vagal activity during REM was associated with better explicit extinction memory, and physiological extinction memory in males. These findings support the notion that abnormal REM may contribute to PTSD by impairing the consolidation of extinction memory and indicate the potential utility of interventions that target REM sleep characteristics and REM vagal activity in fear-related disorders.

Background: Current noninvasive brain stimulation methods are incapable of directly modulating subcortical brain regions critically involved in psychiatric disorders. Transcranial Focused Ultrasound (tFUS) is a newer form of noninvasive stimulation that could modulate the amygdala, a subcortical region implicated in fear. Objective: We investigated the effects of active and sham tFUS of the amygdala on fear circuit activation, skin conductance responses (SCR), and self-reported anxiety during a fear-inducing task. We also investigated amygdala tFUS’ effects on amygdala-fear circuit resting-state functional connectivity. Methods: Thirty healthy individuals were randomized in this double-blinded study to active or sham tFUS of the left amygdala. We collected fMRI scans, SCR, and self-reported anxiety during a fear-inducing task (participants viewed red or green circles which indicated the risk of receiving an aversive stimulus), as well as resting-state scans, before and after tFUS. Results: Compared to sham tFUS, active tFUS was associated with decreased (pre to post tFUS) blood-oxygen-level-dependent fMRI activation in the amygdala (F(1,25) = 4.86, p = 0.04, η2 = 0.16) during the fear task, and lower hippocampal (F(1,27) = 4.41, p = 0.05, η2 = 0.14), and dorsal anterior cingulate cortex (F(1,27) = 6.26, p = 0.02; η2 = 0.19) activation during the post tFUS fear task. The decrease in amygdala activation was correlated with decreased subjective anxiety (r = 0.62, p = 0.03). There was no group effect in SCR changes from pre to post tFUS (F(1,23) = 0.85, p = 0.37). The active tFUS group also showed decreased amygdala-insula (F(1,28) = 4.98, p = 0.03) and amygdala-hippocampal (F(1,28) = 7.14, p = 0.01) rsFC, and increased amygdala-ventromedial prefrontal cortex (F(1,28) = 3.52, p = 0.05) resting-state functional connectivity. Conclusions: tFUS can change functional connectivity and brain region activation associated with decreased anxiety. Future studies should investigate tFUS’ therapeutic potential for individuals with clinical levels of anxiety.

Study Objectives:Trauma-related nightmares (TRNs) are a hallmark symptom of PTSD and are highly correlated with PTSD severity and poor sleep quality. Given the salience and arousal associated with TRNs, they might be an effective target for imaginal exposures during Prolonged Exposure (PE) therapy. As a first step in this line of research, the current study compared participants' emotional reactivity during recollection of TRNs to their recollection of the index traumatic event. Methods:Seventeen trauma-exposed participants with clinical or sub-clinical PTSD who reported frequent TRNs engaged in script-driven imagery using scripts depicting their index trauma and their most trauma-like TRN. Heart rate (HRR), skin conductance (SCR), corrugator EMG (EMGR) responses, and emotional ratings were recorded. Results:HRR, SCR, and EMGR did not differ significantly between trauma-related and TRN scripts. Bayesian analyses confirmed support for the null hypothesis, indicating no differences. With the exception of "Sadness," for which TRNs elicited significantly lower ratings than trauma scripts, individual emotion ratings showed no significant differences, suggesting likely parity between the emotionality of trauma-related and TRN recollections. Conclusions:Together, TRN content elicited psychophysiological reactivity similar to that of the index trauma in this pilot study. Upon replication, studies testing TRNs as potential targets for imaginal exposures during PE may be warranted.

Detecting and responding to threat engages several neural nodes including the amygdala, hippocampus, insular cortex, and medial prefrontal cortices. Recent propositions call for the integration of more distributed neural nodes that process sensory and cognitive facets related to threat. Integrative, sensitive, and reproducible distributed neural decoders for the detection and response to threat and safety have yet to be established. We combine functional MRI data across varying threat conditioning and negative affect paradigms from 1465 participants with multivariate pattern analysis to investigate distributed neural representations of threat and safety. The trained decoders sensitively and specifically distinguish between threat and safety cues across multiple datasets. We further show that many neural nodes dynamically shift representations between threat and safety. Our results establish reproducible decoders that integrate neural circuits, merging the well-characterized ‘threat circuit’ with sensory and cognitive nodes, discriminating threat from safety regardless of experimental designs or data acquisition parameters.

In Posttraumatic Stress Disorder (PTSD), fear and anxiety become dysregulated following psychologically traumatic events. Regulation of fear and anxiety involves both high-level cognitive processes such as cognitive reattribution and low-level, partially automatic memory processes such as fear extinction, safety learning and habituation. These latter processes are believed to be deficient in PTSD. While insomnia and nightmares are characteristic symptoms of existing PTSD, abundant recent evidence suggests that sleep disruption prior to and acute sleep disturbance following traumatic events both can predispose an individual to develop PTSD. Sleep promotes consolidation in multiple memory systems and is believed to also do so for low-level emotion-regulatory memory processes. Consequently sleep disruption may contribute to the etiology of PTSD by interfering with consolidation in low-level emotion-regulatory memory systems. During the first weeks following a traumatic event, when in the course of everyday life resilient individuals begin to acquire and consolidate these low-level emotion-regulatory memories, those who will develop PTSD symptoms may fail to do so. This deficit may, in part, result from alterations of sleep that interfere with their consolidation, such as REM fragmentation, that have also been found to presage later PTSD symptoms. Here, sleep disruption in PTSD as well as fear extinction, safety learning and habituation and their known alterations in PTSD are first briefly reviewed. Then neural processes that occur during the early post-trauma period that might impede low-level emotion regulatory processes through alterations of sleep quality and physiology will be considered. Lastly, recent neuroimaging evidence from a fear conditioning and extinction paradigm in patient groups and their controls will be considered along with one possible neural process that may contribute to a vulnerability to PTSD following trauma.

Background Nightmares are a hallmark symptom of posttraumatic stress disorder (PTSD). This strong association may reflect a shared pathophysiology in the form of altered autonomic activity and increased reactivity. Using an acoustic startle paradigm, we investigated the interrelationships of psychophysiological measures during wakefulness and PTSD diagnosis, posttraumatic nightmares, and nontraumatic nightmares. Methods A community sample of 122 trauma survivors were presented with a series of brief loud tones, while heart rate (HRR), skin conductance (SCR), and orbicularis oculi electromyogram (EMGR) responses were measured. Prior to the tone presentations, resting heart rate variability (HRV) was assessed. Nightmares were measured using nightmare logs. Three dichotomous groupings of participants were compared: (1) current PTSD diagnosis (n = 59), no PTSD diagnosis (n = 63), (2) those with (n = 26) or without (n = 96) frequent posttraumatic nightmares, and (3) those with (n = 22) or without (n = 100) frequent nontraumatic nightmares. Results PTSD diagnosis was associated with posttraumatic but not with nontraumatic nightmares. Both PTSD and posttraumatic nightmares were associated with a larger mean HRR to loud tones, whereas nontraumatic nightmare frequency was associated with a larger SCR. EMGR and resting HRV were not associated with PTSD diagnosis or nightmares. Conclusions Our findings suggest a shared pathophysiology between PTSD and posttraumatic nightmares in the form of increased HR reactivity to startling tones, which might reflect reduced parasympathetic tone. This shared pathophysiology could explain why PTSD is more strongly related to posttraumatic than nontraumatic nightmares, which could have important clinical implications.

Persistent fear is a cardinal feature of posttraumatic stress disorder (PTSD), and deficient fear extinction retention is a proposed illness mechanism and target of exposure-based therapy. However, evidence for deficient fear extinction in PTSD has been mixed using laboratory paradigms, which may relate to underidentified methodological variation across studies. We reviewed the literature to identify parameters that differ across studies of fear extinction retention in PTSD. We then performed Multiverse Analysis in a new sample, to quantify the impact of those methodological parameters on statistical findings. In 25 PTSD patients (15 female) and 36 trauma-exposed non-PTSD controls (TENC) (20 female), we recorded skin conductance response (SCR) during fear acquisition and extinction learning (day 1) and extinction recall (day 2). A first Multiverse Analysis examined the effects of methodological parameters identified by the literature review on comparisons of SCR-based fear extinction retention in PTSD versus TENC. A second Multiverse Analysis examined the effects of those methodological parameters on comparisons of SCR to a danger cue (CS+) versus safety cue (CS-) during fear acquisition. Both the literature review and the Multiverse Analysis yielded inconsistent findings for fear extinction retention in PTSD versus TENC, and most analyses found no statistically significant group difference. By contrast, significantly elevated SCR to CS+ versus CS- was consistently found across all analyses in the literature review and the Multiverse Analysis of new data. We discuss methodological parameters that may most contribute to inconsistent findings of fear extinction retention deficit in PTSD and implications for future clinical research.

Over the last decades, the interdisciplinary field of the affective sciences has seen proliferation rather than integration of theoretical perspectives. This is due to differences in metaphysical and mechanistic assumptions about human affective phenomena (what they are and how they work) which, shaped by academic motivations and values, have determined the affective constructs and operationalizations. An assumption on the purpose of affective phenomenacan be used as a teleological principle to guide the construction of a common set of metaphysical and mechanistic assumptions—a framework for human affective research. In this capstone paper for the special issue “Towards an Integrated Understanding of the Human Affectome”, we gather the tiered purpose of human affective phenomena to synthesize assumptions that account for human affective phenomenacollectively. This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

Summary Heart rate variability (HRV) can be used to assess changes in output of the parasympathetic nervous system (PNS). Considering that patients with post‐traumatic stress disorder (PTSD) often experience disturbances in sleep, arousal, and autonomic functioning, we sought to explore the association of PNS activity during sleep with hyperarousal symptoms of PTSD. Because a broad literature supports the importance of rapid eye movement (REM) sleep in PTSD, REM‐sleep features were specifically examined as predictors of PTSD symptom severity. A total of 90 participants, primarily civilian and female, aged 18–40 years who had experienced a traumatic event in the last 2 years, underwent an ambulatory polysomnography (PSG) acclimation night followed by a second PSG night from which sleep physiological measures were computed. Participants underwent an ambulatory polysomnography (PSG) acclimation night followed by a second PSG night from which sleep physiological measures were computed. PTSD severity was measured using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (PCL‐5). Dependent variables were total PCL‐5 score as well as its hyperarousal symptom subscore. Predictors included REM latency, percentage, density, segment length, and an index of parasympathetic tone (root mean square of the successive differences in the R–R interval or RMSSD). Hierarchical regression models were conducted to analyse the association of REM features with PCL‐5 total and hyperarousal subscales. Using hierarchical regression, REM‐sleep RMSSD accounted for a significant proportion of the variation in outcome variables, even when accounting for other REM‐sleep features. The present findings support hypothesised relationships between PTSD symptomatology and REM‐sleep physiology and, specifically, that lowered parasympathetic tone in REM may be an important associate of the hyperarousal symptom cluster in PTSD.

Sleep plays a crucial role in the consolidation of memories, including those for fear acquisition and extinction training. This chapter reviews findings from studies testing this relationship in laboratory, naturalistic, and clinical settings. While evidence is mixed, several studies in humans have linked fear and extinction recall/retention to both rapid eye-movement and slow wave sleep. Sleep appears to further aid in the processing of both simulated and actual trauma and improves psychotherapeutic treatment outcomes in those with anxiety and trauma- and stressor-related disorders. This chapter concludes with a discussion of the current challenges facing sleep and emotional memory research in addition to suggestions for improving future research.

Sleep disturbances such as trouble falling and staying asleep and recurrent trauma nightmares are common symptoms of posttraumatic stress disorder (PTSD). Although initially considered only to be a symptom of PTSD; evidence that sleep disturbance plays a critical role in the development and persistence of this disorder is accruing. In the present chapter, key literature on sleep in PTSD, methodological factors that need to be considered when planning sleep studies with PTSD populations, and psychophysiological variables closely associated with sleep in PTSD are reviewed. This is followed by a description of both traditional and novel methods for assessing sleep and sleep-associated phenomena (e.g., traditional and quantitative polysomnography, actigraphy, subjective sleep and dream measures, fear conditioning and extinction, and brain imaging during sleep) as well as a discussion of the unique methodological challenges associated with studying sleep in PTSD.