Pre-trauma memory contextualization as predictor for PTSD-like behavior in male rats.

While many people experience potentially threatening events during their life, only a minority develops posttraumatic stress disorder (PTSD). The identification of individuals at risk among those exposed to trauma is crucial for PTSD prevention in the future. Since re-experiencing trauma elements outside of the original trauma-context is a core feature of PTSD, we investigate if the ability to bind memories to their original encoding context (i.e. memory contextualization) predicts PTSD vulnerability. We hypothesize that pre-trauma neutral memory contextualization (under stress) negatively relates to PTSD-like behavior, in a prospective design using the cut-off behavioral criteria rat model for PTSD. 72 male Sprague Dawley rats were divided in two experimental groups to assess the predictive value of 1) memory contextualization without acute stress (NS-group) and 2) memory contextualization during the recovery phase of the acute stress-response (S-group) for susceptibility to PTSD-like behavior. A powerful extension to regression analysis -path analysis-was used to test this specific hypothesis, together with secondary research questions. Following traumatic predator scent stress, 19.4% of the rats displayed PTSD-like behavior. Results showed a negative relation between pre-trauma memory contextualization and PTSD-like behavior, but only in the NS-group. Pre-trauma memory contextualization was positively related to fear association in the trauma environment, again only in the NS group. If the predictive value of pre-trauma contextualization of neutral information under non-stressful conditions for PTSD susceptibility is replicated in prospective studies in humans, this factor would supplement already known vulnerability factors for PTSD and improve the identification of individuals at risk among the trauma exposed, especially those at high trauma risk such as soldiers deployed on a mission.

Impaired learning, memory, and extinction in posttraumatic stress disorder: translational meta-analysis of clinical and preclinical studies.

Current evidence-based treatments for post-traumatic stress disorder (PTSD) are efficacious in only part of PTSD patients. Therefore, novel neurobiologically informed approaches are urgently needed. Clinical and translational neuroscience point to altered learning and memory processes as key in (models of) PTSD psychopathology. We extended this notion by clarifying at a meta-level (i) the role of information valence, i.e. neutral versus emotional/fearful, and (ii) comparability, as far as applicable, between clinical and preclinical phenotypes. We hypothesized that cross-species, neutral versus emotional/fearful information processing is, respectively, impaired and enhanced in PTSD. This preregistered meta-analysis involved a literature search on PTSD+Learning/Memory+Behavior, performed in PubMed. First, the effect of information valence was estimated with a random-effects meta-regression. The sources of variation were explored with a random forest-based analysis. The analyses included 92 clinical (N = 6732 humans) and 182 preclinical (N = 6834 animals) studies. A general impairment of learning, memory and extinction processes was observed in PTSD patients, regardless of information valence. Impaired neutral learning/memory and fear extinction were also present in animal models of PTSD. Yet, PTSD models enhanced fear/trauma memory in preclinical studies and PTSD impaired emotional memory in patients. Clinical data on fear/trauma memory was limited. Mnemonic phase and valence explained most variation in rodents but not humans. Impaired neutral learning/memory and fear extinction show stable cross-species PTSD phenotypes. These could be targeted for novel PTSD treatments, using information gained from neurobiological animal studies. We argue that apparent cross-species discrepancies in emotional/fearful memory deserve further in-depth study; until then, animal models targeting this phenotype should be applied with utmost care.

Individual differences in the encoding of contextual details following acute stress: An explorative study.

Information processing under stressful circumstances depends on many experimental conditions, like the information valence or the point in time at which brain function is probed. This also holds true for memorizing contextual details (or 'memory contextualization'). Moreover, large interindividual differences appear to exist in (context-dependent) memory formation after stress, but it is mostly unknown which individual characteristics are essential. Various characteristics were explored from a theory-driven and data-driven perspective, in 120 healthy men. In the theory-driven model, we postulated that life adversity and trait anxiety shape the stress response, which impacts memory contextualization following acute stress. This was indeed largely supported by linear regression analyses, showing significant interactions depending on valence and time point after stress. Thus, during the acute phase of the stress response, reduced neutral memory contextualization was related to salivary cortisol level; moreover, certain individual characteristics correlated with memory contextualization of negatively valenced material: (a) life adversity, (b) α-amylase reactivity in those with low life adversity and (c) cortisol reactivity in those with low trait anxiety. Better neutral memory contextualization during the recovery phase of the stress response was associated with (a) cortisol in individuals with low life adversity and (b) α-amylase in individuals with high life adversity. The data-driven Random Forest-based variable selection also pointed to (early) life adversity-during the acute phase-and (moderate) α-amylase reactivity-during the recovery phase-as individual characteristics related to better memory contextualization. Newly identified characteristics sparked novel hypotheses about non-anxious personality traits, age, mood and states during retrieval of context-related information.

The rodent object-in-context task: A systematic review and meta-analysis of important variables.

Environmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as 'context') and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and-for those who design a new experiment or carry out pilot experiments-the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations on sex, strain, prior arousal, context (size, walls, shape, etc.) and timing (habituation, learning, and memory phase) to create more consensus in the set-up, procedure, and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.

The relation between anxious personality traits and fear generalization in healthy subjects: A systematic review and meta-analysis.

BACKGROUND: Anxious personality characteristics form a risk factor for anxiety disorders. A proposed mechanistic pathway is that anxious personality could lead to greater vulnerability by increasing fear generalization. Here, we investigate if there is evidence for this relationship before the onset of pathological anxiety, with a meta-analysis in healthy subjects. METHODS: Our search (anxious personality & fear generalization) was performed in PubMed, PsychInfo, and Embase and via snowballing. RESULTS: In total, 4892 studies were screened and 19 studies (1348 participants) were included in the current review (meta-analysis: 18 studies, 1310 participants). The meta-analysis showed a significant, small, positive relationship between anxious personality and fear generalization (r = .19, 95%CI [.126, .260], p <.001). No moderators of the relationship were identified. CONCLUSIONS: The identified robust relation suggests that people who score high on anxious personality have a somewhat stronger tendency to generalize fear to safe or novel situations. This might explain their vulnerability to anxiety disorders mechanistically, yet future (prospective) studies are warranted to confirm the hypothesized directionality of this effect.

Time-dependent effects of psychosocial stress on the contextualization of neutral memories.

Memories about stressful experiences need to be both specific and generalizable to adequately guide future behavior. Memory strength is influenced by emotional significance, and contextualization (i.e., encoding experiences with their contextual details) enables selective context-dependent retrieval and protects against overgeneralization. The current randomized-controlled study investigated how the early and late phase of the endogenous stress response affects the contextualization of neutral and negative information. One hundred healthy male participants were randomly divided into three experimental groups that performed encoding either 1) without stress (control), 2) immediately after acute stress (early) or 3) two hours after acute stress (late). Stress was induced via the Trier Social Stress Test and salivary alpha-amylase and cortisol levels were measured throughout the experiment. In the Memory Contextualization Task, neutral and angry faces (items) were depicted against unique context pictures during encoding. During testing 24 h later, context-dependent recognition memory of the items was assessed by presenting these in either congruent or incongruent contexts (relative to encoding). Multilevel analyses revealed that neutral information was more contextualized when encoding took place two hours after psychosocial stress, than immediately after the stressor. Results suggest that the late effects in the unique, time-dependent sequence of a healthy endogenous stress response, could complement reduced contextualization immediately after stress. The contextualization of negative information was not influenced by psychosocial stress, as opposed to earlier reported effects of exogenous hydrocortisone administration. An imbalance between the early and late effects of the endogenous stress response could increase vulnerability for stress-related psychopathology.

No Time-Dependent Effects of Psychosocial Stress on Fear Contextualization and Generalization: A Randomized-Controlled Study With Healthy Participants.

The formation of context-dependent fear memories (fear contextualization) can aid the recognition of danger in new, similar, situations. Overgeneralization of fear is often seen as hallmark of anxiety and trauma-related disorders. In this randomized-controlled study, we investigated whether exposure to a psychosocial stressor influences retention of fear contextualization and generalization in a time-dependent manner. The Trier Social Stress Test was used to induce psychosocial stress. Healthy male participants (n = 117) were randomly divided into three experimental groups that were subjected to the acquisition phase of the Fear Generalization Task: (1) without stress, (2) immediately after acute stress, or (3) 2 h after acute stress. In this task, a male with neutral facial expression (conditioned stimuli) was depicted in two different contexts that modulated the conditioned stimuli-unconditioned stimuli (=shock) association (threat, safe). Salivary alpha-amylase and cortisol levels were measured throughout the experiment. After a 24-h delay, context-dependency of fear memory was investigated with an unannounced memory test consisting of the threat and safe contexts alternated with a novel context (the generalization context). Multilevel analyses revealed that participants showed increased fear-potentiated startle responses to the conditioned stimuli in the threat compared to the safe context, at the end of the acquisition phase, indicating adequate fear contextualization. Directly after acquisition, there were no time-dependent effects of psychosocial stress on fear contextualization. Context-dependency of fear memories was retained 24 h later, as fear-potentiated startle responding was modulated by context (threat > safe or novel). At that time, the context-dependency of fear memories was also not influenced by the early or late effects of the endogenous stress response during acquisition. These results with experimental stress deviate in some aspects from those earlier obtained with exogenous hydrocortisone administration, suggesting a distinct role for stress mediators other than cortisol.

Trait anxiety mediates the effect of stress exposure on post-traumatic stress disorder and depression risk in cardiac surgery patients.

BACKGROUND: Post-traumatic stress disorder (PTSD) and depression are common after cardiac surgery. Lifetime stress exposure and personality traits may influence the development of these psychiatric conditions. METHODS: Self-reported rates of PTSD and depression and potential determinants (i.e., trait anxiety and stress exposure) were established 1.5 to 4 years after cardiac surgery. Data was available for 1125 out of 1244 (90.4%) participants. Multivariable linear regressions were conducted to investigate mediating and/or moderating effects of trait anxiety on the relationship between stress exposure, and PTSD and depression. Pre-planned subgroup analyses were performed for both sexes. RESULTS: PTSD and depression symptoms were present in 10.2% and 13.1% of the participants, respectively. Trait anxiety was a full mediator of the association between stress exposure and depression in both the total cohort and female and male subgroups. Moreover, trait anxiety partially mediated the relationship between stress exposure and PTSD in the full cohort and the male subgroup, whereas trait anxiety fully mediated this relationship in female patients. Trait anxiety did not play a moderating role in the total patient sample, nor after stratification on gender. LIMITATIONS: The unequal distribution of male (78%) and female patients (22%) might limit the generalizability of our findings. Furthermore, risk factors were investigated retrospectively and with variable follow-up time. CONCLUSIONS: In cardiac surgery patients, trait anxiety was found to be an important mediator of postoperative PTSD and depression. Prospective research is necessary to verify whether these factors are reliable screening measures of individuals' vulnerability for psychopathology development after cardiac surgery.

The Effect of Dexamethasone on Symptoms of Posttraumatic Stress Disorder and Depression After Cardiac Surgery and Intensive Care Admission: Longitudinal Follow-Up of a Randomized Controlled Trial.

OBJECTIVE: Cardiac surgery and postoperative admission to the ICU may lead to posttraumatic stress disorder and depression. Perioperatively administered corticosteroids potentially alter the risk of development of these psychiatric conditions, by affecting the hypothalamic-pituitary-adrenal axis. However, findings of previous studies are inconsistent. We aimed to assess the effect of a single dose of dexamethasone compared with placebo on symptoms of posttraumatic stress disorder and depression and health-related quality of life after cardiac surgery and ICU admission. DESIGN: Follow-up study of a randomized clinical trial. SETTING: Five Dutch heart centers. PATIENTS: Cardiac surgery patients (n = 1,244) who participated in the Dexamethasone for Cardiac Surgery trial. INTERVENTIONS: A single intraoperative IV dose of dexamethasone or placebo was administered in a randomized, double-blind way. MEASUREMENTS AND MAIN RESULTS: Symptoms of posttraumatic stress disorder, depression, and health-related quality of life were assessed with validated questionnaires 1.5 years after randomization. Data were available for 1,125 patients (90.4%); of which 561 patients received dexamethasone and 564 patients received placebo. Overall, the prevalence of psychopathology was not influenced by dexamethasone. Posttraumatic stress disorder and depression were present in, respectively, 52 patients (9.3%) and 69 patients (12.3%) who received dexamethasone and in 66 patients (11.7%) and 78 patients (13.8%) who received placebo (posttraumatic stress disorder: odds ratio, 0.82; 95% CI, 0.55-1.20; p = 0.30; depression: odds ratio, 0.92; 95% CI, 0.64-1.31; p = 0.63). Subgroup analysis revealed a lower prevalence of posttraumatic stress disorder (odds ratio, 0.23; 95% CI, 0.07-0.72; p < 0.01) and depression (odds ratio, 0.29; 95% CI, 0.11-0.77; p < 0.01) in female patients after dexamethasone administration. Health-related quality of life did not differ between groups and was not associated with psychopathology. CONCLUSIONS: Overall, our findings suggest that exogenous administration of the glucocorticoid receptor agonist dexamethasone-compared with placebo-during cardiac surgery does not positively or negatively affect the prevalence of posttraumatic stress disorder and depression. However, in female patients, beneficial effects on the occurrence of posttraumatic stress disorder and depression may be present.

The power of clinicians' affective communication: how reassurance about non-abandonment can reduce patients' physiological arousal and increase information recall in bad news consultations. An experimental study using analogue patients.

OBJECTIVE: The diagnosis of incurable cancer may evoke physiological arousal in patients. Physiological arousal can negatively impact patients' recall of information provided in the medical consultation. We aim to investigate whether clinicians' affective communication during a bad news consultation will decrease patients' physiological arousal and will improve recall. METHODS: Healthy women (N=50), acting as analogue patients, were randomly assigned to watch one out of the two versions of a scripted video-vignette of a bad news consultation in which clinician's communication differed: standard vs. affective communication. Participants' skin conductance levels were obtained during video-watching, and afterwards their recall was assessed. RESULTS: While the diagnosis increased skin conductance levels in all analogue patients, skin conductance levels during the remainder of the consultation decreased more in the affective communication condition than in the standard condition. Analogue patients' recall was significantly higher in the affective condition. CONCLUSION: Breaking bad news evokes physiological arousal. Affective communication can decrease this evoked physiological arousal and might be partly responsible for analogue patients' enhanced information recall. PRACTICE IMPLICATIONS: Although our findings need to be translated to clinical patients, they suggest that clinicians need to deal with patients' emotions before providing additional medical information.