Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Laughter yoga reduces the cortisol response to acute stress in healthy individuals.

Stress is one of the foremost contributors to the development of psychiatric diseases. Since the prevalence of stress-related complaints is increasing, we are in need for affordable and effective treatment alternatives. Laughter yoga (LY), a popular method encouraging participants to simulate laughter and participate in yogic breathing exercises, is hypothesized to buffer negative effects of stress. Although widely practiced, empirical evidence for beneficial effects of LY is scarce. We investigated the acute effects of a single 30-min LY session on the autonomic, endocrine and psychological response to a standardized psychosocial stressor. Thirty-five healthy subjects (51% female) were randomly assigned to experience either a LY (n = 11), a relaxation breathing (n = 12) or a (non-intervention) control (n = 12) session prior to their exposure to the Trier Social Stress Test for Groups (TSST-G). Salivary cortisol, salivary alpha amylase, and subjective stress were assessed repeatedly throughout the experiment. We expected that LY and relaxation breathing group each show a downregulation of stress response indices compared to the control group. Further, we expected that LY has beneficial effects compared to relaxation breathing. The groups did not differ in salivary cortisol, alpha amylase or subjective stress reactivity during the 30-min intervention. However, in response to the TSST-G, the LY, but neither the relaxation breathing, nor the control condition, showed an attenuated cortisol stress response. These findings highlight the potential of LY to buffer the endocrine stress response. Therefore, LY could be used as a cheap and easily-to-implement add-on to more traditional stress interventions. LAY SUMMARY In recent years, more and more people have reported to feel stressed. Although our body is well equipped to deal with acute stress, chronic stress can tire our system and contribute to illness in the long run. Therefore, we need affordable and effective measures to reduce stress. In this study we have investigated whether a single laughter yoga session can help us to deal with acute stress. Although laughter yoga did not change how stressful a situation was perceived, it reduced the amount of stress hormones that were released in response to the situation. As such, laughter yoga might be a cheap and easily-to-implement add-on to more traditional stress reduction interventions.

Prioritized attentional processing: Acute stress, memory and stimulus emotionality facilitate attentional disengagement.

Rapid attentional orienting toward relevant stimuli and efficient disengagement from irrelevant stimuli are critical for survival. Here, we examined the roles of memory processes, emotional arousal and acute stress in attentional disengagement. To this end, 64 healthy participants encoded negative and neutral facial expressions and, after being exposed to a stress or control manipulation, performed an attention task in which they had to disengage from these previously encoded as well as novel face stimuli. During the attention task, electroencephalography (EEG) and pupillometry data were recorded. Our results showed overall faster reaction times after acute stress and when participants had to disengage from emotionally negative or old facial expressions. Further, pupil dilations were larger in response to neutral faces. During disengagement, our EEG data revealed a reduced N2pc amplitude when participants disengaged from neutral compared to negative facial expressions when these were not presented before, as well as earlier onset latencies for the N400f (for disengagement from negative and old faces), the N2pc, and the LPP (for disengagement from negative faces). In addition, early visual processing of negative faces, as reflected in the P1 amplitude, was enhanced specifically in stressed participants. Our findings indicate that attentional disengagement is improved for negative and familiar stimuli and that stress facilitates not only attentional disengagement but also emotional processing in general. Together, these processes may represent important mechanisms enabling efficient performance and rapid threat detection.

An endocannabinoid receptor polymorphism modulates affective processing under stress.

Stress has a critical impact on affective and cognitive processing. Based on rodent data suggesting that endocannabinoid signaling via CB1 receptors serves as an emotional buffer, we hypothesized that a common variant of the gene coding for the CB1 receptor modulates affective processing under stress (CNR1; rs1049353 A vs G allele). Therefore, 139 participants, genotyped for this polymorphism, underwent a stress or control manipulation before they viewed emotionally neutral and negative pictures in a magnetic resonance imaging scanner. The ventromedial prefrontal cortex, known for its crucial role in emotion regulation, was significantly more activated in AA/AG vs GG genotype carriers when viewing negative pictures after stress. Under no-stress conditions, AA/AG genotype carriers showed enhanced crosstalk between the ventrolateral prefrontal cortex and the amygdala. We further assessed participants' 24 h-delayed memory for the presented pictures and found that memory performance correlated with amygdala and hippocampus activity and connectivity in stressed carriers of the AA/AG but not the GG genotype. These findings underline the modulatory role of the endocannabinoid system in stress effects on emotion and cognition and provide insights into the neural mechanisms that may contribute to the suggested protective effect of the AA/AG genotype of the CB1 receptor polymorphism against stress-related psychopathologies.

A Haplotype Associated with Enhanced Mineralocorticoid Receptor Expression Facilitates the Stress-Induced Shift from "Cognitive" to "Habit" Learning.

Stress induces a shift from hippocampus-dependent "cognitive" toward dorsal striatum-dependent "habit" memory. However, not all individuals are susceptible to this shift under stress. Based on pharmacological studies indicating a critical role of the mineralocorticoid receptor (MR) in the stress-induced bias toward dorsal striatal learning, we hypothesized that MR gene variants contribute to these individual differences. In two experiments, healthy participants were genotyped, exposed to a stressor or control manipulation and performed a learning task that can be solved using hippocampal or dorsal striatal systems, while electroencephalography (EEG; Experiment I) or functional magnetic resonance imaging (fMRI; Experiment II) measurements were taken. Stress led to a shift from hippocampal to dorsal striatal learning which was more pronounced in homo- and heterozygous carriers of a six single nucleotide polymorphisms (SNPs)-comprising haplotype containing the alleles of two MR SNPs associated with increased MR expression and transactivational activity (MR-2G/C C [rs2070951], MR-I180V A [rs5522]). This stress-induced shift toward habit memory was paralleled by an increased feedback-related negativity (FRN), which may reflect striatal processing, and increased caudate activation. Carriers of the MR haplotype showed a reduced P3a, an event-related potential thought to indicate cognitive processing, and reduced hippocampal activity after stress. Moreover, stress resulted in reduced amygdala-hippocampus connectivity and the decrease in amygdala connectivity to the parahippocampal cortex was particularly pronounced in MR haplotype carriers. Our findings indicate that genetic variants associated with enhanced MR expression facilitate a stress-induced shift from hippocampal toward dorsal striatal learning, most likely via impaired hippocampal processing and reduced amygdala-hippocampus cross talk, allowing the dorsal striatum to guide behavior under stress.

A Deletion Variant of the α2b-Adrenoceptor Modulates the Stress-Induced Shift from "Cognitive" to "Habit" Memory.

Stress induces a shift from hippocampus-based "cognitive" toward dorsal striatum-based "habitual" learning and memory. This shift is thought to have important implications for stress-related psychopathologies, including post-traumatic stress disorder (PTSD). However, there is large individual variability in the stress-induced bias toward habit memory, and the factors underlying this variability are completely unknown. Here we hypothesized that a functional deletion variant of the gene encoding the α2b-adrenoceptor (ADRA2B), which has been linked to emotional memory processes and increased PTSD risk, modulates the stress-induced shift from cognitive toward habit memory. In two independent experimental studies, healthy humans were genotyped for the ADRA2B deletion variant. After a stress or control manipulation, participants completed a dual-solution learning task while electroencephalographic (Study I) or fMRI measurements (Study II) were taken. Carriers compared with noncarriers of the ADRA2B deletion variant exhibited a significantly reduced bias toward habit memory after stress. fMRI results indicated that, whereas noncarriers of the ADRA2B deletion variant showed increased functional connectivity between amygdala and putamen after stress, this increase in connectivity was absent in carriers of the deletion variant, who instead showed overall enhanced connectivity between amygdala and entorhinal cortex. Our results indicate that a common genetic variation of the noradrenergic system modulates the impact of stress on the balance between cognitive and habitual memory systems, most likely via altered amygdala orchestration of these systems.SIGNIFICANCE STATEMENT Stressful events have a powerful effect on human learning and memory. Specifically, accumulating evidence suggests that stress favors more rigid dorsal striatum-dependent habit memory, at the expense of flexible hippocampus-dependent cognitive memory. Although this shift may have important implications for understanding mental disorders, such as post-traumatic stress disorder, little is known about the source of individual differences in the sensitivity for the stress-induced bias toward habit memory. We report here that a common genetic variation of the noradrenergic system, a known risk factor for post-traumatic stress disorder, modulates the stress-induced shift from cognitive to habit memory, most likely through altered crosstalk between the hippocampus and dorsal striatum with the amygdala, a key structure in emotional memory.