REM Sleep Measures and REM Vagal Activity Predict Extinction Recall in Trauma-Exposed Individuals.

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 high-frequency heart rate variability; HF-HRV) in a large sample of trauma-exposed individuals (n=113). Consistent with our hypotheses, REM sleep characteristics (increased REM density and shortened REM latency) were associated with poorer physiological and explicit extinction memory. Furthermore, higher HF-HRV during REM was associated with better explicit extinction memory. These findings support the notion that disrupted 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.

Epigenetic aging and PTSD outcomes in the immediate aftermath of trauma.

BACKGROUND: Psychological trauma exposure and posttraumatic stress disorder (PTSD) have been associated with advanced epigenetic age. However, whether epigenetic aging measured at the time of trauma predicts the subsequent development of PTSD outcomes is unknown. Moreover, the neural substrates underlying posttraumatic outcomes associated with epigenetic aging are unclear. METHODS: We examined a multi-ancestry cohort of women and men (n = 289) who presented to the emergency department (ED) after trauma. Blood DNA was collected at ED presentation, and EPIC DNA methylation arrays were used to assess four widely used metrics of epigenetic aging (HorvathAge, HannumAge, PhenoAge, and GrimAge). PTSD symptoms were evaluated longitudinally at the time of ED presentation and over the ensuing 6 months. Structural and functional neuroimaging was performed 2 weeks after trauma. RESULTS: After covariate adjustment and correction for multiple comparisons, advanced ED GrimAge predicted increased risk for 6-month probable PTSD diagnosis. Secondary analyses suggested that the prediction of PTSD by GrimAge was driven by worse trajectories for intrusive memories and nightmares. Advanced ED GrimAge was also associated with reduced volume of the whole amygdala and specific amygdala subregions, including the cortico-amygdaloid transition and the cortical and accessory basal nuclei. CONCLUSIONS: Our findings shed new light on the relation between biological aging and trauma-related phenotypes, suggesting that GrimAge measured at the time of trauma predicts PTSD trajectories and is associated with relevant brain alterations. Furthering these findings has the potential to enhance early prevention and treatment of posttraumatic psychiatric sequelae.

Rapid eye movement sleep parasympathetic activity predicts wake hyperarousal symptoms following a traumatic event.

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.

Autonomic activity, posttraumatic and nontraumatic nightmares, and PTSD after trauma exposure.

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.

Associations of sleep measures with neural activations accompanying fear conditioning and extinction learning and memory in trauma-exposed individuals.

STUDY OBJECTIVES: Sleep disturbances increase risk of posttraumatic stress disorder (PTSD). Sleep effects on extinction may contribute to such risk. Neural activations to fear extinction were examined in trauma-exposed participants and associated with sleep variables. METHODS: Individuals trauma-exposed within the past 2 years (N = 126, 63 PTSD) completed 2 weeks actigraphy and sleep diaries, three nights ambulatory polysomnography and a 2-day fMRI protocol with Fear-Conditioning, Extinction-Learning and, 24 h later, Extinction-Recall phases. Activations within the anterior cerebrum and regions of interest (ROI) were examined within the total, PTSD-diagnosed and trauma-exposed control (TEC) groups. Sleep variables were used to predict activations within groups and among total participants. Family wise error was controlled at p < 0.05 using nonparametric analysis with 5,000 permutations. RESULTS: Initially, Fear Conditioning activated broad subcortical and cortical anterior-cerebral regions. Within-group analyses showed: (1) by end of Fear Conditioning activations decreased in TEC but not PTSD; (2) across Extinction Learning, TEC activated medial prefrontal areas associated with emotion regulation whereas PTSD did not; (3) beginning Extinction Recall, PTSD activated this emotion-regulatory region whereas TEC did not. However, the only between-group contrast reaching significance was greater activation of a hippocampal ROI in TEC at Extinction Recall. A greater number of sleep variables were associated with cortical activations in separate groups versus the entire sample and in PTSD versus TEC. CONCLUSIONS: PTSD nonsignificantly delayed extinction learning relative to TEC possibly increasing vulnerability to pathological anxiety. The influence of sleep integrity on brain responses to threat and extinction may be greater in more symptomatic individuals.

Neural contributors to trauma resilience: a review of longitudinal neuroimaging studies.

Resilience in the face of major life stressors is changeable over time and with experience. Accordingly, differing sets of neurobiological factors may contribute to an adaptive stress response before, during, and after the stressor. Longitudinal studies are therefore particularly effective in answering questions about the determinants of resilience. Here we provide an overview of the rapidly-growing body of longitudinal neuroimaging research on stress resilience. Despite lingering gaps and limitations, these studies are beginning to reveal individual differences in neural circuit structure and function that appear protective against the emergence of future psychopathology following a major life stressor. Here we outline a neural circuit model of resilience to trauma. Specifically, pre-trauma biomarkers of resilience show that an ability to modulate activity within threat and salience networks predicts fewer stress-related symptoms. In contrast, early post-trauma biomarkers of subsequent resilience or recovery show a more complex pattern, spanning a number of major circuits including attention and cognitive control networks as well as primary sensory cortices. This novel synthesis suggests stress resilience may be scaffolded by stable individual differences in the processing of threat cues, and further buttressed by post-trauma adaptations to the stressor that encompass multiple mechanisms and circuits. More attention and resources supporting this work will inform the targets and timing of mechanistic resilience-boosting interventions.

Emotional and feature-based modulation of the early posterior negativity.

The early posterior negativity (EPN) has been shown to be enhanced by emotional relative to neutral scene perception. A subset of studies has also reported a bias in the EPN toward pleasant relative to unpleasant scenes. Functional MRI research has also identified a region in lateral occipital cortex that shows a sensitivity to the visual perception of body parts, which may contribute to the EPN. Here, we assess the roles of rated scene pleasantness and the depiction of body parts on modulation of the EPN in two studies, using scenes that are chosen to be of equivalent perceptual complexity. In Study 1, we presented two distinct highly pleasant and arousing scene contents (erotic couples and moments of jubilant victory) as well as neutral people, threat, and mutilation scenes. As in prior research, the EPN was enhanced by emotionally arousing scenes, with the greatest modulation evoked by erotic scenes, although victory scenes elicited stronger ratings of pleasantness and equivalent ratings of arousal. This result suggests that the EPN may be sensitive to distinct features found in erotic scenes. To determine the extent to which body part perception modulates the EPN, Study 2 compared EPN modulation evoked by erotic scenes with nonerotic nudist scenes. Ratings of pleasantness and arousal were reduced, yet nudist scenes led to stronger modulation of the EPN compared to erotic scenes. These data indicate that, in addition to the emotional intensity of scenes, modulation of the EPN may in part reflect the discrimination of unclothed body parts.

In Trauma-Exposed Individuals, Self-reported Hyperarousal and Sleep Architecture Predict Resting-State Functional Connectivity in Frontocortical and Paralimbic Regions.

BACKGROUND: Symptoms of posttraumatic stress disorder (PTSD) reflect abnormalities in large-scale brain networks. In individuals with recent trauma exposure, we examined associations of seed-based resting-state functional connectivity (rs-FC) with posttraumatic symptoms and sleep. We hypothesized that more severe PTSD symptoms and poorer sleep quality would predict 1) greater rs-FC between fear-related seeds and other fear-related regions and 2) lesser rs-FC between fear-related seeds and emotion-regulatory regions. METHODS: Seventy-four participants who had experienced a DSM-5 criterion A stressor within the past 2 years and ranged from asymptomatic to fully meeting criteria for PTSD diagnosis underwent 14 days of actigraphy and sleep diaries, a night of ambulatory polysomnography, and a functional magnetic resonance imaging resting-state scan at 3T. rs-FC measures of 5 fear-related seeds and 1 emotion regulatory seed with regions of the anterior cerebrum were correlated with PTSD symptoms, objective and subjective habitual sleep quality, and sleep architecture. RESULTS: Longer objective habitual sleep onset latency was associated with greater connectivity between fear-related seeds and other regions of the salience network. Greater PTSD symptoms were associated with less connectivity between fear-related seeds and anterior emotion regulatory regions, whereas greater percent slow wave sleep was associated with more connectivity between these regions. However, other objective and subjective measures reflecting better habitual sleep quality were associated with less rs-FC between these regions. CONCLUSIONS: Longer sleep onset latency predicted greater rs-FC among fear-related areas. More severe PTSD symptoms predicted less rs-FC between fear and fear regulatory regions reflecting putatively reduced top-down fear regulation. Some (e.g., percent slow wave sleep), but not all sleep indices predicted greater top-down fear regulation.