Acute stress reduces out-group related safety signaling during fear reinstatement in women.

When using in-group and out-group faces as conditional stimuli (CS) in fear conditioning designs, extinction learning is selectively impaired for out-group faces. Additionally, stress seems to inhibit extinction retrieval leading to a higher return of fear, which might be especially the case for out-group faces. To test this hypothesis, 51 healthy women underwent fear acquisition training, consisting of repeated presentations of two in-group and two out-group faces. One of each (CS+) was paired with an electrical stimulation (unconditional stimulus, UCS), whereas the other was not coupled with the UCS (CS-). During immediate extinction training, all CS were presented again. On the next day, a retrieval and reinstatement test took place after a stress or a control procedure. Confirming previous research, impaired extinction learning occurred for out-group relative to in-group faces. During the reinstatement test, stress specifically increased responding towards the out-group CS-, thus reducing its safety signaling properties. So, stress seems to reduce the ability to adequately distinguish threat and safety cues after aversive experiences mimicked by reinstatement shocks.

An oral presentation causes stress and memory impairments.

Laboratory experiments revealed the stress hormone cortisol to decrease memory retrieval of emotional material, but a translation to real-life settings is missing so far. In this study, 51 students encoded a list of neutral, positive, and negative words as well as two neutral, biographical notes one day before attendance at a seminar at the university. In the stress condition, students gave a graded oral presentation, whereas they just attended the same seminar in the control condition immediately before retrieval took place. Measures of state anxiety, salivary cortisol and alpha-amylase confirmed the oral presentation to constitute a potent stressor. Importantly, stress significantly impaired retrieval of negative words, but not retrieval of the biographical notes. These results indicate that a real-life stressor decreases memory retrieval for negative items. In contrast, delayed memory retrieval of neutral information and interrelated details of biographical notes seems to be less prone to stress effects. These results have critical implications for educational settings.

Neural Underpinnings of Cortisol Effects on Fear Extinction.

Extinction of conditioned fear embodies a crucial mechanism incorporated in exposure therapy. Clinical studies demonstrated that application of the stress hormone cortisol before exposure sessions facilitates exposure success, but the underlying neural correlates remain unknown. Context- and stimulus-dependent cortisol effects on extinction learning will be characterized in this study and tested in the extinction and in a new context. Forty healthy men participated in a 3-day fear conditioning experiment with fear acquisition in context A (day 1), extinction training in context B (day 2), and recall in context B and a new context C one week later (day 3). Hydrocortisone (30 mg) or placebo was given before extinction training. Blood-oxygen-level-dependent responses and skin conductance responses (SCRs) served as dependent measures. At the beginning of extinction training, cortisol reduced conditioned SCRs, diminished activation of the amygdala-hippocampal complex, and enhanced functional connectivity of the anterior parahippocampal gyrus with the ventromedial prefrontal cortex (vmPFC). After one week, the cortisol group showed increased hippocampal activation and connectivity to the vmPFC toward an extinguished stimulus and reduced insula activation toward a nonextinguished stimulus in the extinction context. However, this inhibitory cortisol effect did not extend to the new context. Taken together, cortisol reduced fear recall at the beginning of extinction and facilitated the consolidation of the extinction memory as evidenced by an inhibitory activation pattern one week later. The stress hormone exerted a critical impact on the amygdala-hippocampus-vmPFC network underlying fear and extinction memories. However, cortisol did not attenuate the context dependency of extinction.

Examination of cortisol and state anxiety at an academic setting with and without oral presentation.

Holding oral presentations in a university course is perceived as stressful and can increase stress hormone concentrations and state anxiety. In such a naturalistic setting, further attention should be paid to the relationship between psychological and hormonal measures of acute stress, as well as women's intake of hormonal contraceptives as a potential moderating variable. In the present study, 76 healthy students gave saliva samples before and after their oral presentations in a university course as well as on a second, control day in the same course without giving an oral presentation. Anticipatory state anxiety was rated on both days. Cortisol concentrations as well as state anxiety were substantially higher on the presentation relative to the control day. During the oral presentation, an increase in cortisol concentrations was observed, whereas a decrease occurred on the control day. Nearly the same picture emerged for both variables when looking at men, women taking hormonal contraceptives and free-cycling women separately. A positive correlation was found between the change in anticipatory state anxiety in the presentation compared to the control day and cortisol concentrations before and after the oral presentation. Concluding, oral presentations constitute a potent stressor and do not seem to be substantially different between men, free-cycling women and women taking hormonal contraceptives. Future studies may want to explore changes associated with specific menstrual cycle phases and with specific hormonal contraceptives.

Cortisol modifies extinction learning of recently acquired fear in men.

Exposure therapy builds on the mechanism of fear extinction leading to decreased fear responses. How the stress hormone cortisol affects brain regions involved in fear extinction in humans is unknown. For this reason, we tested 32 men randomly assigned to receive either 30 mg hydrocortisone or placebo 45 min before fear extinction. In fear acquisition, a picture of a geometrical figure was either partially paired (conditioned stimulus; CS+) or not paired (CS-) with an electrical stimulation (unconditioned stimulus; UCS). In fear extinction, each CS was presented again, but no UCS occurred. Cortisol increased conditioned skin conductance responses in early and late extinction. In early extinction, higher activation towards the CS- than to the CS+ was found in the amygdala, hippocampus and posterior parahippocampal gyrus. This pattern might be associated with the establishment of a new memory trace. In late extinction, the placebo compared with the cortisol group displayed enhanced CS+/CS- differentiation in the amygdala, medial frontal cortex and nucleus accumbens. A change from early deactivation to late activation of the extinction circuit as seen in the placebo group seems to be needed to enhance extinction and to reduce fear. Cortisol appears to interfere with this process thereby impairing extinction of recently acquired conditioned fear.

The impact of self-reported childhood trauma on emotion regulation in borderline personality disorder and major depression.

Early life stress is said to play a critical role in the development of borderline personality disorder (BPD) and major depressive disorder (MDD), but the underlying mediating factors remain uncertain. This study aimed to investigate self-reported childhood trauma, emotion regulation difficulties, and their associations in a sample of BPD (n = 49) and MDD (n = 48) patients and healthy control participants (n = 63). Multiple regressions were used to evaluate the impact of the quality and severity of self-reported childhood trauma on self-reported emotion regulation. The results supported an association between self-reported maltreatment experiences, especially emotional abuse and neglect, and emotion regulation difficulties. Additional analyses showed that emotion regulation difficulties influence the association between self-reported emotional abuse and acute symptomatology in the BPD subgroup. Emotion regulation difficulties may be 1 pathway through which early life stress, particularly emotional abuse, increases the risk for developing BPD symptomatology.

Acute glucocorticoid effects on response inhibition in borderline personality disorder.

INTRODUCTION: Growing evidence suggests inhibition dysfunctions in borderline personality disorder (BPD). Moreover, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis functioning have also been found in BPD patients. In healthy individuals, response inhibition has been sensitive to acute stress, and previous research indicates that effects mediated by the HPA axis become particularly apparent when emotional stimuli are processed. This study aimed to explore the influence of acute hydrocortisone administration on response inhibition of emotional stimuli in BPD patients compared to healthy control participants. METHODS: After a single administration of 10mg hydrocortisone or placebo, 32 female BPD patients and 32 healthy female participants performed an adapted emotional go/no-go paradigm to assess response inhibition for emotional face stimuli in a cross-over study. RESULTS: Acute cortisol elevations decreased the reaction times to target stimuli in both BPD patients and healthy controls. Patients and controls did not differ in task performance; however, BPD patients with comorbid posttraumatic stress disorder (PTSD) displayed longer reaction times than patients without PTSD. In contrast, the occurrence of comorbid eating disorder had no significant impact on go/no-go performance. No significant interaction effect between the treatment condition and the emotional valence of the face stimuli was found. CONCLUSIONS: Acute hydrocortisone administration enhances response inhibition of face stimuli in BPD patients and healthy controls, regardless of their emotional valence. Our results agree with the suggestion that moderate cortisol enhancement increases the inhibition of task-irrelevant distracters.

Stress differentially affects fear conditioning in men and women.

Stress and fear conditioning processes are both important vulnerability factors in the development of psychiatric disorders. In behavioral studies considerable sex differences in fear learning have been observed after increases of the stress hormone cortisol. But neuroimaging experiments, which give insights into the neurobiological correlates of stress × sex interactions in fear conditioning, are lacking so far. In the current functional magnetic resonance imaging (fMRI) study, we tested whether a psychosocial stressor (Trier Social Stress Test) compared to a control condition influenced subsequent fear conditioning in 48 men and 48 women taking oral contraceptives (OCs). One of two pictures of a geometrical figure was always paired (conditioned stimulus, CS+) or never paired (CS-) with an electrical stimulation (unconditioned stimulus). BOLD responses as well as skin conductance responses were assessed. Sex-independently, stress enhanced the CS+/CS- differentiation in the hippocampus in early acquisition but attenuated conditioned responses in the medial frontal cortex in late acquisition. In early acquisition, stress reduced the CS+/CS- differentiation in the nucleus accumbens in men, but enhanced it in OC women. In late acquisition, the same pattern (reduction in men, enhancement in OC women) was found in the amygdala as well as in the anterior cingulate. Thus, psychosocial stress impaired the neuronal correlates of fear learning and expression in men, but facilitated them in OC women. A sex-specific modulation of fear conditioning after stress might contribute to the divergent prevalence of men and women in developing psychiatric disorders.

Cortisol effects on autobiographic memory retrieval in PTSD: an analysis of word valence and time until retrieval.

In healthy participants, cortisol administration has been found to impair autobiographic memory retrieval. We recently reported that administration of 10 mg of hydrocortisone had enhancing effects on autobiographical memory retrieval, i.e. more specific memory retrieval, in patients with posttraumatic stress disorder (PTSD), while in healthy controls the impairing effects were replicated. We here report a re-analysis of these data with respect to cue-word valence and retrieval time. In a placebo-controlled cross-over study, 43 patients with PTSD and 43 age- and sex-matched healthy controls received either placebo or hydrocortisone orally before the autobiographical memory test was performed. We found that the effects of cortisol on memory retrieval depended on cue-word valence and group (significant interaction effects of drug by group and drug by valence by group). The enhancing effect of cortisol on memory retrieval in PTSD seemed to be relatively independent of cue-word valence, while in the control group the impairing effects of cortisol were only seen in response to neutral cue-words. The second result of the study was that in patients as well as in controls, cortisol administration led to faster memory retrieval compared to placebo. This was seen in response to positive and (to lesser extend) to neutral cue-words, but not in response to negative cue-words. Our findings illustrate that the opposing effects of cortisol on autobiographical memory retrieval in PTSD patients and controls are further modulated by the emotionality of the cue-words.

Effects of acute cortisol administration on response inhibition in patients with major depression and healthy controls.

Glucocorticoids (GCs) have repeatedly been shown to impair hippocampus-mediated, declarative memory retrieval and prefrontal cortex-based working memory in healthy subjects. However, recent experimental studies indicated that patients with major depressive disorder (MDD) lack these impairing effects. These missing effects have been suggested to result from dysfunctional brain GC receptors. The purpose of the present study was to investigate whether response inhibition, an executive function relying on the integrity of the prefrontal cortex, would be impaired after cortisol administration in patients with MDD. In a placebo-controlled, double blind crossover study, 50 inpatients with MDD and 54 healthy control participants conducted an emotional go/no-go task consisting of human face stimuli (fearful, happy, and neutral) after receiving a dose of 10 mg hydrocortisone and after placebo. GC administration had an enhancing effect on inhibitory performance in healthy control participants, indicated by faster responses, while no GC effect was revealed for the patients group. Moreover, patients showed an overall worse performance than healthy participants. In conclusion, this study further supports the hypothesis of impaired central glucocorticoid receptor function in MDD patients. Regarding the importance of inhibitory functioning for daily living, further studies are needed to examine the impact of glucocorticoids on response inhibition.

Stress hormones are associated with the neuronal correlates of instructed fear conditioning.

The effects of sex and stress hormones on classical fear conditioning have been subject of recent experimental studies. A correlation approach between basal cortisol concentrations and neuronal activation in fear-related structures seems to be a promising alternative approach in order to foster our understanding of how cortisol influences emotional learning. In this functional magnetic resonance imaging study, participants with varying sex hormone status (20 men, 15 women taking oral contraceptives, 15 women tested in the luteal phase) underwent an instructed fear conditioning protocol with geometrical figures as conditioned stimuli and an electrical stimulation as unconditioned stimulus. Salivary cortisol concentrations were measured and afterwards correlated with fear conditioned brain responses. Results revealed a positive correlation between basal cortisol levels and differential activation in the amygdala in men and OC women only. These results suggest that elevated endogenous cortisol levels are associated with enhanced fear anticipation depending on current sex hormone availability.

Oral contraceptive usage alters the effects of cortisol on implicit fear learning.

An important feature of the human defense system comprises fear learning, which stress hormones can crucially modulate. However, stress hormones might influence men and women differently, in part because of interactions with sex hormones. In women, distinct stages of the menstrual cycle or the intake of oral contraceptives (OC) affect sex hormone levels. In this study, we used a differential fear conditioning paradigm with electrical stimulation as unconditioned stimulus (UCS) following one neutral stimulus (conditioned stimulus, CS+), but not another (CS-).To investigate implicit fear learning, participants were distracted from detecting the contingencies between CS and UCS. To address interaction effects of sex and stress hormones, 32 men, 30 women in the early follicular phase of the menstrual cycle (FO), 30 women in the luteal phase (LU), and 30 OC women received either 30 mg cortisol or a placebo. In the contrast CS+ minus CS-, an interaction between cortisol administration and sex hormone status emerged in the anterior parahippocampal gyrus and the hippocampus. Cortisol reduced fear learning in men, FO, and LU women, but enhanced it in OC women. Additionally, cortisol attenuated differential amygdala activation in the entire group. These results demonstrate that OC usage substantially modifies cortisol effects on emotional learning in women, particularly in memory-related medial temporal lobe regions. Further, a high dose of cortisol reduces amygdala differentiation pointing to a lowered learning ability of the defense system under high cortisol concentrations, irrespective of current sex hormone availability.

Associations of childhood trauma with hypothalamic-pituitary-adrenal function in borderline personality disorder and major depression.

BACKGROUND: Alterations of the hypothalamus-pituitary-adrenal (HPA) axis are hallmarks in major depressive disorder (MDD) and there is some evidence about similar patterns in borderline personality disorder (BPD). This study examines HPA axis abnormalities with respect to clinical characteristics in both BPD (n=24) and MDD patients (n=33) as well as in healthy control participants (n=41). METHOD: A 0.5mg dexamethasone suppression test was administered to evaluate basal cortisol release and HPA feedback sensitivity via salivary cortisol. Traumatic experiences in childhood as well as severity of borderline and depressive symptom severity and dissociation were obtained by self-report questionnaires. RESULTS: Compared to the healthy control group, BPD and MDD patients exhibited both enhanced cortisol concentrations before and after the administration of 0.5mg dexamethasone. Higher cortisol levels were positively correlated to a history of childhood trauma, current dissociative symptoms and severity of borderline and depressive symptoms. Regression analyses revealed that some aspects of early trauma were associated with cortisol release before and after dexamethasone, whereas psychopathology did not contribute to the regression model. CONCLUSIONS: HPA dysfunctions appear to be related rather to childhood trauma than to psychopathology in adulthood. Exposure to childhood trauma may contribute to long-lasting alterations in HPA activity and might enhance the risk for the development of later mental disorder.

Subjective, autonomic, and endocrine reactivity during social stress in children with social phobia.

Reports of exaggerated anxiety and physiological hyperreactivity to social-evaluative situations are characteristic of childhood social phobia (SP). However, laboratory research on subjective, autonomic and endocrine functioning in childhood SP is scarce, inconsistent and limited by small sample sizes, limited breadth of measurements, and the use of non-standardized stressor tasks. We exposed 8-12-year-old children with DSM-IV SP (n = 41) and matched healthy control children (HC; n = 40) to the Trier Social Stress Test for Children (TSST-C) while measuring subjective anxiety, heart rate (HR) and salivary alpha-amylase (sAA) as well as salivary cortisol. The SP children showed heightened reactivity to the TSST-C on subjective anxiety compared to the HC children but not a heightened reactivity in HR, sAA or cortisol. However, the SP children showed chronically elevated HR levels throughout the whole laboratory session. Whereas subjective anxiety seems to respond specifically to social-evaluative stress in childhood SP, HR levels may be chronically elevated suggesting a more generalized autonomic hyperreactivity.

Cortisol has enhancing, rather than impairing effects on memory retrieval in PTSD.

BACKGROUND: In the present study, we aimed to compare the effect of exogenous cortisol on memory retrieval in posttraumatic stress disorder (PTSD) with the effects in healthy controls. In healthy participants, administration of cortisol impairs declarative memory retrieval. Only a few studies have investigated these effects in PTSD yielding mixed results. METHODS: In a placebo-controlled crossover study, 44 patients with PTSD and 65 healthy controls received either placebo or 10mg of hydrocortisone orally before memory testing. In addition to declarative memory retrieval (word list learning), we also tested autobiographical memory retrieval specificity. RESULTS: In both tasks opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval, while in PTSD patients cortisol had enhancing effects on memory retrieval in both memory domains. CONCLUSIONS: The present results suggest beneficial effects of acute cortisol elevations on hippocampal mediated memory processes in PTSD. Possible neurobiological mechanisms underlying these findings are discussed.

Effects of acute hydrocortisone administration on declarative memory in patients with major depressive disorder: a placebo-controlled, double-blind crossover study.

OBJECTIVE: Major depressive disorder (MDD) has been associated with hypercortisolism, reduced glucocorticoid feedback sensitivity, and impaired memory function. In healthy subjects, administration of hydrocortisone impairs declarative memory. The aim of this study was to examine the effects of acute hydrocortisone administration on memory retrieval in MDD patients and healthy controls. We further tested whether the enhancing or impairing effects of hydrocortisone would prevail when it was given after encoding and when delayed retrieval was tested at a time point when glucocorticoid levels were still elevated. METHOD: In a placebo-controlled, double-blind crossover study, 44 patients with DSM-IV MDD and 51 healthy control participants received either placebo or 10 mg of hydrocortisone orally before memory testing. A word list paradigm and the Logical Memory Test from the Wechsler Memory Scale were applied. The study was conducted from April 2008 until April 2010 at sites in Bielefeld and Hamburg, Germany. RESULTS: In both memory tests, patients with MDD performed worse than controls. Healthy controls showed impaired memory performance after hydrocortisone administration compared to placebo. In contrast, hydrocortisone had no effects on memory in MDD patients. Furthermore, in healthy controls we found that administration of hydrocortisone immediately after learning did not lead to an enhanced free recall during increased cortisol levels. CONCLUSIONS: It appears that the impairing effects of hydrocortisone on memory performance are missing in patients with MDD. This might be interpreted in the context of reduced central glucocorticoid receptor functioning.

Hydrocortisone impairs working memory in healthy humans, but not in patients with major depressive disorder.

OBJECTIVE: Several studies have shown that stress or the administration of glucocorticoids can impair hippocampus-based declarative memory retrieval and prefrontal dependent working memory performance in healthy subjects. Major Depressive Disorder (MDD) is often characterized by memory impairment and increased cortisol secretion. Studies indicate that the impairing effects of glucocorticoids on declarative memory performance are missing in patients with MDD. The purpose of our study was to investigate whether the finding of missing effects of acute cortisol administration on memory performance in MDD is also seen when examining prefrontal-based working memory. METHODS: In a placebo-controlled study, 57 patients with MDD and 56 sex- and age-matched healthy control subjects received either placebo or 10 mg of hydrocortisone orally before memory testing. To test the verbal modality of working memory, the Word Suppression Test was applied with one negative and one neutral test part. RESULTS: After hydrocortisone intake, healthy subjects showed a significantly poorer working memory performance compared to placebo treatment when negative interference words were administered. In contrast, memory performance of MDD patients was not affected by hydrocortisone treatment. CONCLUSIONS: The missing effects of glucocorticoid administration on working memory in MDD might be interpreted in the context of reduced central glucocorticoid receptor function.

Effects of acute cortisol administration on autobiographical memory in patients with major depression and healthy controls.

OBJECTIVE: Overgeneral autobiographical memory has become a well established phenomenon within major depressive disorder (MDD). Neuroendocrinologically, MDD is often characterized by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, i.e. hypercortisolemia and reduced feedback sensitivity. In healthy participants cortisol administration has been found to impair autobiographical memory retrieval. The purpose of this study was to compare the effects of acute cortisol administration on autobiographical memory in MDD patients with the effects observed in healthy controls. We hypothesized that in contrast to healthy control subjects acute cortisol administration would not affect autobiographical memory performance in MDD due to reduced central glucocorticoid sensitivity. METHODS: In a placebo-controlled, double-blind crossover study, 16 patients with MDD and 16 healthy control subjects received a placebo or 10mg of hydrocortisone orally before autobiographical memory testing (AMT). RESULTS: In the placebo condition depressed patients performed poorer than controls. After hydrocortisone intake, healthy subjects reported significantly fewer specific memories on the AMT compared to placebo treatment. In contrast, memory specificity of MDD patients was not affected by hydrocortisone treatment. CONCLUSIONS: The present findings replicate previous findings of impaired autobiographical memory retrieval after hydrocortisone treatment in healthy subjects and of impaired AMT performance in depressed patients. We speculate that the missing acute impairing effect of hydrocortisone on autobiographical memory in depressed patients might reflect reduced central glucocorticoid sensitivity. However alternative explanations cannot be ruled out.

Autobiographic memory impairment following acute cortisol administration.

Previous experimental studies in humans have reported that the administration of cortisol impairs retrieval of hippocampal dependent, episodic memory. In particular, cortisol impaired recall of previously learnt words. In the present study, we investigated if cortisol also affects autobiographical memory, which reflects a subcategory of hippocampal dependent, episodic memory. Twenty two male students participated in this placebo-controlled, double-blind crossover study. One hour after the administration of 10 mg hydrocortisone, subjects generated significantly fewer specific memories in the Autobiographical Memory Test (AMT) when compared to placebo. In contrast, cortisol did not affect mood and attention. The present findings extend the current knowledge about cortisol effects on memory retrieval and raise the possibility that impaired autobiographical memory in depression may be at least partly due to elevated cortisol levels which often accompany this disorder.