Search

Disruptions to historic disturbance and herbivory regimes have altered plant assemblages in forests worldwide. An emerging consensus suggests that these disruptions often result in impoverished forest biotas. This is particularly true for eastern U.S. deciduous forests where large gaps and understory fires were once relatively common and browsers were far less abundant. Although much research has focused on how disturbance and browsers affect tree diversity, far less attention has been devoted to forest understories where the vast majority (>75%) of the vascular species reside. Here we test the hypothesis that the reintroduction of disturbances resembling historic disturbance regimes and moderate levels of ungulate browsing enhance plant diversity. We explore whether once-common disturbances and their interaction with the top-down influence of browsers can create conditions favorable for the maintenance of a rich herbaceous layer in a region recognized as a temperate biodiversity hotspot in West Virginia, U.S.A. We tested this hypothesis via a factorial experiment whereby we manipulated canopy gaps (presence/absence) of a size typically found in old-growth stands, low-intensity understory fire (burned/unburned), and deer browsing (fenced/unfenced). We tracked the abundance and diversity of more than 140 herb species for six years. Interactions among our treatments were pervasive. The combination of canopy gaps and understory fire increased herbaceous layer richness, cover, and diversity well beyond either disturbance alone. Furthermore, we documented evidence that deer at moderate levels of abundance promote herbaceous richness and abundance by preferentially browsing fast-growing pioneer species that thrive following co-occurring disturbances (i.e., fire and gaps). This finding sharply contrasts with the negative impact browsers have when their populations reach levels well beyond those that occurred for centuries. Although speculative, our results suggest that interactions among fire, canopy gaps, and browsing provided a variable set of habitats and conditions across the landscape that was potentially capable of maintaining much of the plant diversity found in temperate forests.

Objective: To examine whether dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis associated with disadvantaged social position in working populations also occurs in older age groups., Methods: This study examines the association of several indicators of social position with two measures of cortisol secretion, a product of the HPA axis. We examined the cortisol awakening response (CAR), and slope of the decline in cortisol secretion across the day. We examine whether the association is mediated by behavioral, psychosocial, and biological factors in 3992 participants of phase 7 (2002-2004) of the Whitehall II study, who provided six salivary cortisol samples across the day., Results: In this older cohort (mean age = 61 years; range = 50-74 years), lowest social position (assessed by current or previous occupational grade and wealth) was associated with a flatter slope in the decline in cortisol secretion. For example, over the course of the day, men in the lowest employment grades had a reduction in their cortisol by 0.125 (nmol/L/h), which was a shallower slope than those in the high grades (-0.129 nmol/L/h). The difference in slopes by employment grade among men, but not women, was statistically significant (p = .003). The difference in slopes was explained primarily by poor health and sleep behaviors, although financial insecurity also played a role. No effects were apparent with the CAR or other measures of social position., Conclusions: In men, poorer health and sleep behaviors (primarily smoking and short sleep duration), and financial insecurity mediate the impact of occupational status and wealth on cortisol secretion.

The ability to produce appropriate physiological and psychological responses to stressful situations depends on accurate recognition and appraisal of such situations. Such ability is also important for proper emotion regulation. A number of studies have suggested that the medial prefrontal cortex (mPFC) plays a significant role in emotion regulation, as well as in the control of physiological endpoints of emotion regulation such as the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). Further, recent work has suggested that men and women may differ in these mechanisms of neural control of emotion regulation. Here, we examined the role of the human mPFC in self-report, ANS, and HPA stress reactivity by testing a group of participants with damage to this region (9 women and 9 men), a brain damaged comparison group (6 women and 6 men), and healthy comparison participants (27 women and 27 men) on an orthostatic challenge and the Trier Social Stress Test (TSST). The mPFC participants showed heightened self-reported stress in response to the TSST. In women, mPFC damage led to an increased cortisol response to the TSST. By contrast, in men, greater volume of mPFC damage was correlated with a decreased cortisol response. Finally, men with mPFC damage showed altered autonomic control of the heart (higher heart rate and lower high frequency heart rate variability) during an orthostatic challenge. These findings support the idea that the mPFC is involved in the regulation of physiological and psychological responses to stress and that this regulation may differ between men and women.

Previous findings on planning abilities in individuals with high-functioning autism spectrum disorder (HFA) are inconsistent. Exploring possible reasons for these mixed findings, the current study investigated the involvement of memory in planning performance in 15 children with HFA and 17 typically developing controls. In addition to planning abilities (measured with the Tower of London), short-term memory and delayed recall for verbal as well as visuospatial material were assessed. Findings suggest that particularly reduced efficiency in visuospatial short-term memory is associated with Tower task planning deficits in children with HFA.

Genetic variation of the serotonin transporter (SCL6A4, 5-HTT) has been associated with fear- and anxiety-related behaviors, while a polymorphism in exon III of the D4 dopamine receptor gene (DRD4) has been linked to novelty seeking. The dopaminergic and the serotonergic neurotransmitter system have been found to modulate the amygdala-connected circuitries that are crucial in emotional modulation and response to fearful stimuli. Additionally, reactivity of amygdala-innervated effector systems is also essential for our understanding of anxiety-related behaviors. Here, we used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the impact of 5-HTTLPR and DRD4 on the cortisol stress response in 84 healthy adults. Saliva cortisol was measured during and after the Trier Social Stress Test. We found a significant main effect of DRD4: Carriers of the 7R allele exhibited lower cortisol responses. Additionally, a DRD4 by 5-HTTLPR interaction emerged: 5-HTTLPR LA/LA homozygotes showed a lower cortisol response than did S or LG allele carriers but only if they possessed at least one copy of the DRD4 7R allele. The results point to independent and joint effects of these polymorphisms on stress responsivity.

The association between fatigue and reduced activity in the hypothalamo-pituitary-adrenal (HPA) axis has been described. However the temporal association between fatigue and HPA activity is under debate. We examine whether alterations in cortisol secretion play a role in the development of fatigue or whether changes occur later as a consequence of fatigue in a longitudinal cohort study of 4299 community dwelling adults (mean age 61). Cortisol secretion was measured from saliva samples collected waking, waking + 0.5, 2.5, 8, 12 h and bedtime at phase 7 (2003-2004) of the Whitehall II study. Fatigue was measured at phase 6 (2001), phase 7 and phase 8 (2006) of the Whitehall II study. Three elements of secretion were examined: waking cortisol, the cortisol awakening response and diurnal slope in cortisol secretion. Fatigue was determined using the vitality sub-scale of the Short Form-36. A wide variety of co-variates were measured. We find that fatigue measured at phase 6 was not associated with cortisol secretion at phase 7. At phase 7, low waking cortisol levels and a flat slope in diurnal cortisol secretion were associated with fatigue independently of co-variates. In participants low or free of fatigue at phase 7 low waking cortisol and flatter slope in cortisol secretion were associated with new-onset fatigue at phase 8 (for example, odds ratio for lowest vs. highest tertile of waking cortisol 1.50; 95% confidence intervals, 1.08, 2.09 after adjusting for all co-variates). In conclusion, we find that low waking salivary cortisol and a flat slope in cortisol secretion is associated with fatigue. Cortisol is also associated with future onset of fatigue suggesting that changes in cortisol secretion are etiologic or occur early in the genesis of fatigue.

Background: Simulator training is well established to improve technical and non-technical skills in critical situations. Few data exist about stress experienced during simulator training. This study aims to evaluate performance and stress in intensivists before and after two different simulator-based training approaches., Methods: Thirty-two intensivists took part in one of six 1-day simulator courses. The courses were randomised to either crew resource management (CRM) training, which contains psychological teaching and simulator scenarios, or classic simulator training (MED). Before and after the course each participant took part in a 10-min test scenario. Before (T1) and after (T2) the scenario, and then again 15 min later (T3), saliva samples were taken, and amylase and cortisol were measured. Non-technical skills were evaluated using the Anaesthetist's Non-Technical Skills (ANTS) assessment tool. Clinical performance of the participants in the test scenarios was rated using a checklist., Results: Twenty-nine participants completed the course (17-CRM, 12-MED). ANTS scores as well as clinical performances were significantly better in the post-intervention scenario, with no differences between the groups. Both cortisol concentration and amylase activity showed a significant increase during the test scenarios. In the post-intervention scenario, the increase in amylase but not cortisol was significantly smaller. There were no differences between the CRM and MED group., Conclusions: High fidelity patient simulation produces significant stress. After a 1-day simulator training, stress response measured by salivary alpha-amylase was reduced. Clinical performance and non-technical skills improved after 1 day of simulator training. Neither stress nor performance differed between the groups.

Previous research has shown that psychosocial stress is associated with an increased activity of the transcription factor nuclear factor-kappaB (NF-kappaB), a major inducer of inflammatory genes. While considerable individual variation has been noted, factors contributing to this variation have not been described so far. Therefore, 29 healthy participants (35.8+/-12 yrs) were exposed to the Trier Social Stress Test. Blood was collected before and repeatedly afterward for determination of NF-kappaB activity, leukocyte subset numbers, cortisol, norepinephrine, and in vitro-stimulated IL-6 production. Additionally, age, sex, and ratings of perceived chronic and acute stress were assessed. Regression analyses revealed that older participants showed a lower NF-kappaB stress response compared to younger adults (beta= -.42, p=.026). Higher NF-kappaB stress responses were associated with lower cortisol stress responses (beta= -.37, p=.05), higher pre-stress IL-6 production (beta=.38, p=.043), and high chronic in combination with low acute stress, or vice versa (beta= -.61, p=.06). Norepinephrine and sex were not associated with NF-kappaB stress responses (all p.13). In summary, the present study shows for the first time in human psychosocial stress the negative association of cortisol and NF-kappaB. This parallels results from in vitro studies. Our finding of lower NF-kappaB stress responses in older age and in people with high chronic and acute stress might be interpreted as an adaptive dampening of NF-kappaB activity. In the absence of longitudinal data, however, this interpretation remains speculative.

The "Trier Social Stress Test" (TSST) is one of the most prominent laboratory stress paradigms. It is often used to investigate the effects of stress on cognitive or affective parameters. Such studies need a non-stress control condition. However, control conditions currently employed are often rather ill defined and do not parallel important modulating variables, e.g., physical or cognitive load of the TSST. We here introduce a placebo version of the TSST, which contains a free speech and a simple mental arithmetic task without uncontrollability and social-evaluative threat. In two studies, this control condition was evaluated using salivary markers of stress reactivity (cortisol and alpha-amylase) and a questionnaire for anticipatory cognitive stress appraisal (PASA). In experiment 1 participants who were treated with the placebo condition showed no cortisol response and a small, but significant salivary alpha-amylase (sAA) response. Both responses were significantly smaller than those of TSST-treated participants. The placebo-treated participants also rated the treatment situation as less stressful. In experiment 2 a crossover study with the use of an intercom to instruct the participants and ensure their compliance was conducted. Again there was a strong cortisol response to the TSST, which differed significantly from the cortisol levels observed during the placebo condition. Importantly the cortisol response was not influenced by treatment order (TSST or placebo first). However, in this study we found similar reactions between TSST- and placebo-treated participants with regard to sAA-response. We suggest that the introduced placebo protocol for the TSST is a promising tool for future psychobiological research. The exact procedure for a given experiment should be tailored to the specific needs of the empirical question studied.

The hippocampus (HC) is necessary for learning and memory, but it also plays a role in other behaviors such as those related to stress and anxiety. In support of the latter idea, we show here that bilateral HC damage abolishes the cortisol response to psychosocial stress. We collected salivary cortisol, heart rate, and affective responses to the Trier Social Stress Test (TSST) from 7 participants with bilateral HC lesions, 12 participants with damage outside the HC, and 28 healthy normal comparison participants matched to the HC participants on age and sex. HC participants showed elevated pre-stress cortisol, but no cortisol response to the TSST. Heart rate and affective responses in the HC group were similar to those of the comparison groups. Participants with brain damage outside the HC showed stress responses that were comparable to those of the healthy comparison group. These findings support the idea that the functions of the human HC extend beyond learning and memory, and suggest that the HC is necessary for producing the cortisol response to psychosocial stress.

Neglect and abuse early in life have been associated with increased and decreased cortisol levels, and also with an altered diurnal cortisol slope. In the present study, we investigated the long-term relationship between early maltreatment - at different levels of severity - and basal cortisol secretion in adults adopted as children. A sample of international adoptees was followed from childhood to adulthood. In childhood, adoptive parents had provided information about neglect and abuse prior to adoption. As adults, adoptees collected saliva samples four times a day. The relationship between early maltreatment and cortisol secretion was examined, primarily with multilevel analyses in 623 adoptees. Morning cortisol levels were lower in adoptees whose adoptive parents had reported severe neglect or abuse than in non-neglected or non-abused participants (respective estimates (standard errors (SEs)) and p-values: -0.33 (0.090), p=0.0002 and -0.63 (0.20), p=0.002). Relative to non-neglected adoptees, those who had allegedly experienced severe neglect also had a flatter diurnal slope (estimate (SE) and p-value: 0.028 (0.0088), p=0.002). In contrast, relative to non-abused participants, adoptees whose reported abuse was moderately severe had high cortisol levels and a steeper cortisol diurnal slope (respective estimates (SEs) and p-values: 0.29 (0.13), p=0.003 and -0.039 (0.012), p=0.01). Thus, early neglect and abuse appear to have associations with cortisol levels and the diurnal slope, even when children are raised in another environment after their early maltreatment. Our study suggests that the severity of the early maltreatment may be related to the basal cortisol pattern.

Cortisol responses to stress have important physiological effects on several target tissues throughout the body, including the central nervous system and the immune system. The ability of target tissues to receive cortisol signals has been shown to vary between individuals and over time. Conflicting data exist on whether different target tissues' glucocorticoid (GC) sensitivity is related. In a double-blind, placebo-controlled design, n=19 participants (n=15 men, n=4 women) received an oral dose of 30 mg of cortisol and placebo in randomized order. Memory retrieval of previously learned neutral and emotional words was tested after cortisol or placebo application. Peripheral GC sensitivity was tested by measuring in-vitro stimulated production of interleukin-6 (IL-6) in whole blood before and after cortisol vs. placebo application. Cortisol treatment reduced retrieval of neutral and emotional words (marginally significant at p=0.07), and significantly reduced stimulated IL-6 production (p<0.001). Relative suppression of IL-6 production was associated with impairment of memory retrieval of emotional (r=0.48; p=0.039), but not neutral words (r=-0.17; p=0.48). In summary, results show an association of peripheral glucocorticoid sensitivity with emotional, but not neutral, memory retrieval. Given that these findings can be extended to clinical populations, the association of peripheral glucocorticoid sensitivity with emotional memory retrieval might have important implications for understanding and treatment of stress-related disorders.

In humans, the secretion of cortisol from the adrenal glands follows a diurnal cycle with a profound increase after awakening. This increase after awakening, a phenomenon termed the cortisol awakening response (CAR), appears to be a distinct feature of the hypothalamus-pituitary-adrenal (HPA) axis, superimposing the circadian rhythmicity of cortisol secretion. Several studies point towards an important role of the hippocampus and, additionally, other brain structures (e. g. amygdala, prefrontal cortex, suprachiasmatic nucleus) in the regulation of the CAR. There is increasing knowledge that the CAR is influenced by a variety of factors such as gender, health status, and health behavior or stress perception. However, the exact function of the profound cortisol increase after awakening is still not clarified. We hypothesize that the anticipation of the upcoming day is of major relevance for the magnitude of the CAR. The present paper reviews the current knowledge on the neural regulation of the CAR and factors influencing this phenomenon and considerations are addressed concerning the exact function of the CAR.

Genetic variation of the serotonin transporter (5-HTT) has been associated with fear- and anxiety-related behaviours. The amygdala is considered crucial in emotional modulation and stronger amygdala reactivity in response to fearful stimuli has been found in carriers of the short (S) allele of the 5-HTT gene in imaging studies. Additionally, reactivity of amygdala-innervated effectory systems is also of particular interest. We recently reported the impact of a functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) on the acoustic startle reflex. Here, we attempted to replicate and extend these findings. Startle magnitudes to intense noise bursts as measured with the eyeblink response were recorded in 106 healthy volunteers during baseline without additional stimulation and while they viewed pictures of three valence conditions: unpleasant, pleasant and neutral. Subjects were genotyped for the tri-allelic functional polymorphism 5-HTTLPR. In replication of our previous findings we found that carriers of the low-expressing S or LG alleles exhibited stronger overall startle responses across conditions than LA/LA homozygotes, while there were no differences in emotional startle modulation between the two genetic groups. In addition, we found that the recent experience of stressful life events resulted in overall higher startle responses and less startle habituation across blocks. The results replicate and emphasize the role of 5-HTTLPR and stress on the overall startle response as a possible genetically driven endophenotype for anxiety-related behaviour.

Hair has long been used in toxicology, forensic science, doping control and other fields as a biological specimen for the detection of environmental agents, drugs, or toxins. Most recent evidence suggests that also hormones are incorporated and trapped inside the growing hair. This has led to the hypothesis that cortisol measurement of distinct hair segments could provide a retrospective calendar of cortisol production for the individual. In this first proof-of-concept study in humans, we analyzed cortisol in hair donated by mothers with a neonate child (n-Mothers; N=103), mothers with toddlers 3-9 months of age (t-Mothers; N=19), and control women (N=20). We cut hair strands from each women into at least three 3-cm segments, which, based on an average hair growth rate of 1cm per month, would represent hair grown over the past three, six, and nine months, respectively. Since in the third trimester of pregnancy there is a well-documented increased production of cortisol, we expected to see elevated levels of cortisol in the most proximal hair segment of women who had just given birth to a child (n-Mothers) compared with the control women. Likewise, we expected to see elevated levels in the second, third, or fourth segment of mothers of 3-month olds, 6-months olds, and 9-months olds, respectively. These hair segments, cut at 4-12 cm from the scalp, would represent hair grown throughout the third trimester of pregnancy. Results showed that there was a strong monotonic decline in cortisol concentration from the segment closest to the scalp to the most distal hair segment (p<0.0001). Cortisol levels decreased by 30-40% from one segment to the next for the most recent four hair segments. Segments from hair older than one year had similarly, low levels of cortisol. Comparisons of cortisol levels in hair between n-Mothers and control women yielded the expected results: cortisol levels in the first 3-cm hair segment (i.e., closest to the scalp) of n-Mothers were two-fold higher than in controls (p<0.0001), probably reflecting increased cortisol levels throughout the third trimester of pregnancy. No differences in cortisol content were apparent for the second or third 3-cm segments in n-Mothers (p>0.2). When hair from mothers with 6-9 months old toddlers was analyzed, the hair segment representing the third trimester period contained the same amount of cortisol as the hair grown more recently in mothers with 3-4 months old toddlers only. Age of the women, hair curvature, hair color, and frequency of hair washes per week were unrelated to cortisol levels. We conclude that cortisol measured in human hair can be a valid reflection of increased cortisol production for a period of up to six months. Due to a rapid decline of cortisol levels in human adult hair, a retrospective calendar of cortisol exposure may be limited to the past six months.

Background: There is evidence from cross-sectional studies that posttraumatic stress disorder (PTSD) may be associated with obesity. The aim of this study was to examine prospective longitudinal associations between PTSD and obesity in a community sample., Methods: A prospective, longitudinal, epidemiologic study with a representative community sample of adolescents and young adults (N=3021, aged 14-24 years at baseline) was conducted in Munich, Germany. Participants were assessed four times between 1995 and 2005 with the Munich-Composite International Diagnostic Interview. Associations between obesity (BMI > or =30) and DSM-IV PTSD were evaluated in 2007, using cross-sectional and prospective data during young adulthood., Results: The cumulative lifetime incidence of obesity in the sample at 10-year follow-up during young adulthood was 4.3% (women, 4.6%; men, 4.0%). Among women but not among men, obesity was associated with a lifetime history of PTSD (OR=3.8; 95% CI=1.4, 10.7) in the cross-sectional analyses. Prospective longitudinal analyses from 4-year follow-up to 10-year follow-up confirmed that obesity was predicted by antecedent subthreshold and full PTSD (OR=3.0; 95% CI=1.3, 7.0) among women but not among men. There were no associations between other mental disorders and obesity in the prospective analyses., Conclusions: The findings indicate a possible causal pathway for the onset of obesity in females with PTSD symptoms. These findings need replication with regard to the pathophysiologic and behavioral mechanisms underlying this relationship.

Background: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary-adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population., Methods and Results: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline., Results: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (beta = 0.08 per sd of AUC, 95% confidence interval 0.00-0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09-0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score., Conclusion: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries.

The prefrontal cortex (PFC) has been well known for its role in higher order cognition, affect regulation and social reasoning. Although the precise underpinnings have not been sufficiently described, increasing evidence also supports a prefrontal involvement in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. Here we investigate the PFC's role in HPA axis regulation during a psychosocial stress exposure in 14 healthy humans. Regional brain metabolism was assessed using positron emission tomography (PET) and injection of fluoro-18-deoxyglucose (FDG). Depending on the exact location within the PFC, increased glucose metabolic rate was associated with lower or higher salivary cortisol concentration in response to a psychosocial stress condition. Metabolic glucose rate in the rostral medial PFC (mPFC) (Brodman area (BA) 9 and BA 10) was negatively associated with stress-induced salivary cortisol increases. Furthermore, metabolic glucose rate in these regions was inversely coupled with changes in glucose metabolic rate in other areas, known to be involved in HPA axis regulation such as the amygdala/hippocampal region. In contrast, metabolic glucose rate in areas more lateral to the mPFC was positively associated with saliva cortisol. Subjective ratings on task stressfulness, task controllability and self-reported dispositional mood states also showed positive and negative associations with the glucose metabolic rate in prefrontal regions. These findings suggest that in humans, the PFC is activated in response to psychosocial stress and distinct prefrontal metabolic glucose patterns are linked to endocrine stress measures as well as subjective ratings on task stressfulness, controllability as well as dispositional mood states.

Context: Evidence for an association between alcohol consumption and activity of the hypothalamic-pituitary-adrenal (HPA) axis is inconclusive., Objective: Our objective was to assess the relationship between indices of alcohol consumption and salivary cortisol concentration., Design: This was a cross-sectional study of alcohol consumption and cortisol secretion from phase 7 (2002-2004) of the Whitehall II study., Setting: An occupational cohort originally recruited in 1985-1987 was included in the study., Participants: A total of 2693 men and 977 women had information on cortisol levels and alcohol consumption., Outcome Measures: Saliva samples were taken on waking, waking+0.5, 2.5, 8, and 12 h, and bedtime for the assessment of cortisol., Results: In men there was a positive association between cortisol and units of alcohol intake per week (3% increase in cortisol per unit of alcohol consumed; P=0.010). The slope of cortisol decline over the day in heavy drinkers was reduced (heavy drinkers beta=-0.155, moderate drinkers beta=-0.151), indicating reduced control of the HPA axis in heavy drinkers. In women the cortisol awakening response was greater in heavy drinkers 14.15 nmol/liter (9.12-19.17) compared with moderate drinkers 8.69 nmol/liter (7.72-9.67) (P=0.037)., Conclusions: This study suggests that alcohol consumption is associated with activation of the HPA axis. These results are not due to alcohol consumption on the day, suggesting chronic changes of the HPA axis in heavy drinking groups.

Objective: The cortisol awakening response (CAR) is considered a reliable measure for the acute reagibility of the hypothalamus-pituitary-adrenal (HPA) axis. Whether repeated nightly awakenings at different times during the night also stimulate the HPA-axis and whether, consequently, the CAR is altered has not been tested, so far. We aimed to investigate whether three experimentally induced awakenings during three consecutive nights would be associated with HPA-axis stimulation and an altered morning CAR., Methods: The study sample consisted of 13 healthy adult women who were waken up three times in each of three consecutive nights. Cortisol levels were measured immediately and 15 min after each awakening in the night and in the morning, respectively. Also, the morning CARs after three nights of undisturbed sleep were assessed., Results: A significant difference between night time cortisol responses to awakening and the morning CAR was found. While cortisol levels during the first half of the night did not rise significantly after awakening in the night, some reactivity was seen during awakenings in the very early morning hours, and pronounced awakening responses were observed in the morning before getting out of bed. Interestingly, the morning CAR after disturbed sleep did not differ from the morning CAR following undisturbed sleep., Conclusion: In healthy female individuals, the morning CAR appears to be unchanged even if sleep was repeatedly interrupted by forced wakings.

The influence of adversity over long periods of the life-span on adult cortisol metabolism is not established. We assess whether morning cortisol levels are associated with socio-economic position (SEP) from birth to mid-adulthood, and if so, whether the association is due primarily to SEP in childhood, adulthood or both. Data are from 6335 participants in the 1958 British birth cohort, with salivary cortisol samples collected at 45 yr. Two saliva samples were obtained on the same day: 45 min post-waking (t1) and 3 h later (t2). Median t1 and t2 cortisol values were 18.80 and 7.10 nmol/l for men; 19.60 and 6.60 nmol/l for women. Three outcomes were constructed: (1) extreme t1 cortisol (top and bottom 5%), (2) area-under-curve (AUC), and (3) abnormal t1-t2 pattern. All three outcomes were associated with lifetime SEP but the relative contribution of childhood and adulthood SEP varied by outcome measure. Our results suggest that the impact of less advantaged SEP over a lifetime would lead to an approximate doubling of the proportion of extreme post-waking cortisol levels for both sexes; an 8% and 10% increase, respectively for females and males in AUC, and an increased risk of having an abnormal cortisol pattern of 60% and 91%. SEP differences were independent of time of waking and sample collection, and in most instances, remained after adjustment for smoking and body mas index (BMI). Thus, our study provides evidence for effects of chronic adversity on cortisol in mid-adult life.

Purpose of Review: Past studies in humans and animals have shown that low blood glucose concentrations due to fasting negatively interfere with the ability to mount a hypothalamus-pituitary-adrenal (HPA) axis response to psychological stress or to pharmacological activation, respectively. This contradicts the classical view of the proposed primary glucocorticoid function of providing the individual with energy in fight-or-flight situations., Recent Findings: Not many studies have followed up on this phenomenon in recent years, but our understanding of how appetite and satiety is regulated has significantly improved. Many of the neuropeptides involved in regulation of energy homeostasis interact with key areas of the HPA axis. The majority of orexigenic peptides have been shown to activate the HPA axis, while some anorexic peptides negatively modulate HPA axis activation and others also stimulate it., Summary: The effects of orexigenic peptides on the HPA axis are incompatible with the phenomenon of blunted HPA axis activity in states of low energy available, while the fact that some anorexigenic peptides activate the HPA axis might point to a permissive role. In conclusion, current data insufficiently explain negative HPA axis modulation by low glucose levels.

Objective: Previous data from our group and others have shown that salivary alpha-amylase activity increases in response to stress. It has been suggested that salivary alpha-amylase may be a marker for adrenergic activity. Less is known about other determinants of salivary alpha-amylase activation. The objective of the current study was to describe the diurnal pattern of salivary amylase and its determinants., Methods: Saliva samples were collected immediately after waking-up, 30 and 60 min later, and each full hour between 0900 and 2000 h by 76 healthy volunteers (44 women, 32 men). Compliance was controlled by electronic monitors. In order to control factors which might influence the diurnal profile of salivary alpha-amylase (such as momentary stress, mood, food, or body activity), at each sampling time point the subjects filled out a diary examining the activities they had carried out during the previous hour., Results: Salivary alpha-amylase activity shows a distinct diurnal profile pattern with a pronounced decrease within 60 min after awakening and a steady increase of activity during the course of the day. Mixed models showed a relative independence of diurnal salivary alpha-amylase from momentary stress and other factors, but significant associations with chronic stress and mood., Conclusions: Our results suggest that diurnal profiles of salivary alpha-amylase are relatively robust against momentary influences and therefore may prove useful in the assessment of sympathetic nervous system activity. The findings underscore the need to control for time of day in studies using salivary alpha-amylase as a dependent variable.

Context: Evidence for an association of smoking status with cortisol secretion is mixed., Objective: The objective of the study was to assess the relationship between smoking status and salivary cortisol., Design: This was a cross-sectional study of smoking status and cortisol secretion from phase 7 (2002-2004) of the Whitehall II study., Setting: An occupational cohort was originally recruited in 1985-1987., Participants: The study population consisted of 3103 men (1514 never-smokers, 1278 ex-smokers, and 311 smokers) and 1128 women (674 never-smokers, 347 ex-smokers, and 107 smokers). Information was collected on smoking status, average number of cigarettes smoked, and additional covariates., Outcome Measures: Saliva samples were taken on waking; waking + 0.5, 2.5, 8, and 12 h; and bedtime for the assessment of cortisol., Results: Smoking status was significantly associated with increased salivary cortisol release throughout the day (P < 0.001) adjusted for covariates; this was apparent for the cortisol awakening response (P < 0.001) when examined separately. Compared with never-smokers, smokers had higher release of total cortisol (P = 0.002), whereas no difference was observed between never-smokers and ex-smokers (P = 0.594): mean release per hour (nanomoles per liter), never-smokers, 4.13 [confidence interval (CI) 4.02-4.24]; ex-smokers, 4.21 (CI 4.08-4.35); smokers, 4.63 (CI 4.35-4.93). There was no significant relationship between number of cigarettes smoked and total cortisol release. However, a difference was observed for the cortisol awakening response: mean release by tertiles of cigarettes smoked (nanomoles per liter): high, 13.49 (CI 10.74-16.23); medium, 9.58 (CI 7.40-11.76); low, 8.49 (CI 5.99-10.99), P = 0.029., Conclusion: Salivary cortisol is increased in current smokers, compared with nonsmokers; no differences were observed between ex-smokers and never-smokers, suggesting that smoking has a short-term effect on the neuroendocrine system.

The social self-preservation theory states that humans have a fundamental motivation to preserve the social self and that threats to the social self perturb biological markers such as cortisol. Five studies were designed to examine the cortisol response to competitive ballroom dancing as a paradigm for real-life social-evaluative threat. Competitive dancing produced substantial increases in cortisol compared to a control day. These increases were not due to the physical strain of dancing and were greater than those found during social-evaluative laboratory stressors. Responses did not habituate across competitions and were mostly elevated under highly focused conditions of threat (couple vs. group competition). These findings support the notion of a social self-preservation system that is physiologically responsive to threats to the social self.

Pregnancy is associated with considerable physiological adaptations, some of which long outlast the state of pregnancy. Although it is well documented that pregnancy produces alterations of the hypothalamus-pituitary-adrenal axis, the longer-term effects of pregnancy on this system have not been systematically examined in humans. Subjects in the present study were 159 nulliparous and 265 parous women. Data analysis revealed no impact of parity on baseline activity (salivary cortisol: response to awakening, F

Anxiety-related behaviors are closely linked to neural circuits relaying fear-specific information to the amygdala. Many of these circuits, like those underlying processing of innate fear, are remarkably well understood. Recent imaging studies have contributed to this knowledge by discriminating more detailed corticoamygdalar associations mediating processing fear and anxiety. However, little is known about the underlying molecular mechanisms. We used the acoustic startle paradigm to investigate the impact of molecular genetic variation of serotonergic function on the acoustic startle response and its fear potentiation. Startle magnitudes to noise bursts as measured with the eye blink response were recorded in 66 healthy volunteers under four conditions: presenting unpleasant and pleasant affective pictures as well as neutral pictures, and presenting the startle stimulus without additional stimuli as a baseline. Subjects were genotyped for functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-hydroxytryptamine transporter gene-linked region: 5-HTTLPR). Analyses of variance revealed a significant effect of 5-HTTLPR on overall startle responses across conditions. Carriers of the short (s) allele exhibited stronger startle responses than l/l homozygotes. However, we could not confirm our hypothesis of enhanced fear potentiation of the startle in s allele carriers. In conclusion, the results provide first evidence that the startle response is sensitive to genetic variation in the serotonin pathway. Despite some issues remaining to be resolved, the startle paradigm may provide a valuable endophenotype of fear processing and underlying serotonergic influences.

Objective: The adrenal excretion of cortisol in animals is dependent on the production of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus. The a priori hypothesis of this study was that hypothalamic regional cerebral blood flow (rCBF) would correlate positively with salivary cortisol levels in patients with social anxiety disorder (SAD) during anxiety provocation. Another objective was to evaluate whether salivary cortisol levels correlated with rCBF in other brain areas., Method: Regional CBF was measured with oxygen-15-labeled water and positron emission tomography during a public speaking task before and after placebo treatment in 12 subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined SAD. Cortisol concentrations in saliva were measured 15 minutes after the task. The a priori hypothesis of a salivary cortisol-dependent activation of the hypothalamus was studied with region-of-interest analysis. In addition, the covariation between rCBF and salivary cortisol was studied in the whole brain using the general linear model., Results: The region-of-interest analysis revealed a positive correlation between salivary cortisol and hypothalamic rCBF. In the whole brain analysis, a positive covariation between rCBF and salivary cortisol levels was found in a midbrain cluster encompassing the hypothalamus with its statistical maximum in the mamillary bodies. Negative covariations were observed in the medial prefrontal cortex as well as in the motor and premotor cortices., Conclusion: Like in animals, stress-induced cortisol excretion in humans may be inhibited by activity in the medial prefrontal cortex and enhanced by activity in the hypothalamus.

The stress response of salivary alpha-amylase (sAA) has been suggested as an index for sympathetic nervous system activation. However, concurrent inhibition of the parasympathetic nervous system is discussed as a confounder due to suppression of saliva flow rate. Here we set out to test the influence of stress-induced changes in flow rate on sAA secretion. Twenty-six subjects underwent the Trier Social Stress Test and a control condition. Saliva was sampled by passive drooling or salivettes. Saliva flow rate, sAA levels and output, salivary cortisol, and heart rate variability were measured. Flow rate increased only when sampled by passive drooling. Stress-induced increases in amylase levels were correlated with increases of amylase output but not with flow rate. Results indicate that flow rate is not a confounder of stress-induced sAA activation and suggest that valid measurements of sAA can be obtained by salivettes without the need for assessment of flow rate.

Psychosocial stress has been shown to induce inflammatory reactions, followed by the release of immunosuppressive glucocorticoids. This may be mediated by catecholamines or other stress reactive substances such as neuropeptides or cytokines. We here set out to explore the effects of acute psychosocial stress on plasma levels of substance P (SP), a possible mediator of stress-induced inflammatory reactions, and interleukin-1 receptor antagonist (IL-1ra). Twelve healthy male subjects (mean age 27 yrs.) were subjected to the psychosocial stress test "Trier Social Stress Test" (TSST) and a resting control condition. Blood and saliva samples were taken before, as well as 1, 20, 45, and 90 min after TSST or rest, respectively. Salivary cortisol and plasma SP and IL-1ra were measured using immunoassays, salivary alpha-amylase (sAA) was measured by an enzyme kinetic method, and plasma epinephrine (E) and norepinephrine (NE) were measured by HPLC. The TSST induced immediate increases of E, NE, and sAA, and a delayed increase of free cortisol. Plasma IL-1ra showed an even further delayed peak at 90 min after stress. Plasma levels of SP did not respond to stress. No significant associations between changes of stress hormones and IL-1ra or SP were found. We conclude that substance P, epinephrine, and norepinephrine are probably not involved in mediating peripheral inflammation following psychosocial stress, at least with respect to IL-1ra. Further studies have to reveal the mechanisms involved in the stress-induced up regulation of IL-1ra.

Nicotine is a strong activator of the hypothalamus pituitary adrenal (HPA) axis. Smoking of only two cigarettes consistently activates the HPA axis of habitual smokers. However, while being a habitual smoker only induces small changes of basal HPA axis activity, smoking induces an attenuated responsiveness of the HPA axis to psychological stress, but not to injection of corticotropin releasing hormone (CRH) or physiological load. The latter points to alterations at hypothalamic or other central structures. The further consequences of decreased HPA axis responsiveness are discussed. Chronic inflammation of the airways is a common consequence of habitual smoking, and smokers often present with low-grade systemic inflammation, which may be mediated by HPA axis alterations. However, habitual smokers' monocytes are reported to show an increased sensitivity towards the inflammation suppressing effects of cortisol, while on the one hand, inflammation of the airways appears to be relatively resistant towards glucocorticoid treatment. In conclusion, this pattern of attenuated cortisol responses and decreased glucocorticoid sensitivity may be causally related to disinhibition of inflammatory processes and thereby further stimulate adverse health outcomes, such as airway inflammation or atherosclerosis.

Background: Exploration of the degree to which perceived chronic stress is heritable is important as these self-reports have been linked to stress-related health outcomes. The aims of this study were to estimate whether perceived stress is a heritable condition and to assess whether heritability estimates vary between subjective stress reactivity and stress related to external demands., Method: A sample of 103 monozygotic and 77 dizygotic twin pairs completed three questionnaires designed to measure perceived stress: the Perceived Stress Scale (PSS), the Measure for the Assessment of Stress Susceptibility (MESA) and the Trier Inventory for the Assessment of Chronic Stress (TICS). The TICS assesses the frequency of stressful experiences on six scales, the MESA assesses subjective stress reactivity, and the PSS takes both factors into account., Results: A multivariate model-fitting procedure revealed that a model with common additive genetic and shared environmental factors best fit the eight scales (PSS, MESA, six TICS scales). Heritabilities for the best-fitting model varied between 5% and 45%, depending on the scale., Conclusions: The present data suggest that perceived stress is in part heritable, that nearly half of the covariance between stress scales is due to genetic factors, and that heritability estimates vary considerably, depending on the questionnaire. Beyond methodological considerations that pertain to the validity of the questionnaires, these data suggest that studies assessing the heritability of perceived chronic stress should take the specific questionnaire focus into account.

An altered function of the hypothalamic-pituitary-adrenal axis is assumed to be characteristic for Posttraumatic Stress Disorder (PTSD), although there is inconsistent empirical evidence. Only few studies examined the awakening cortisol response and a daytime profile in PTSD. Salivary cortisol levels were measured at seven intervals from awakening until 8 PM in trauma-exposed subjects with (N=29) and without PTSD (N=19) and in 15 non-exposed controls. While the three groups did not differ with respect to their first cortisol level immediately after awakening, the expected cortisol increase to awakening 15-60 min later was significantly lower in PTSD patients compared to non-PTSD subjects and healthy controls. This effect remained stable when trauma-exposed subjects with comorbid major depression were excluded from the analysis. A significant negative correlation between the overall cortisol secretion (AUC(G)) and overall PTSD symptomatology and hyper-arousal symptoms was found. The findings are discussed in light of the hypothesis of a counterregulation of hyper-arousal symptoms and chronic stress in PTSD.

It has been shown that stress changes stimulated pro-inflammatory cytokine production and the sensitivity of stimulated cytokine production to glucocorticoid suppression. While glucocorticoid secretion habituates in response repeated stimulation, it is not known whether stimulation and suppression of cytokine production are also subject to adaptation. Eight healthy young subjects were exposed to repeated nauseogenic body rotation on four consecutive days. On each day subjects were rotated around the vertical axis up to five times for a period of 1 min or until subjects chose to stop due to nausea. Blood and saliva samples were obtained before and after rotation for assessment of cortisol, ACTH, plasma vasopressin (ADH), in vitro TNF-alpha and IL-6 production and glucocorticoid sensitivity of TNF-alpha and IL-6 production. Rotation induced increases of ACTH, cortisol, and ADH in the first session. All endocrine responses habituated over time, except for the free cortisol response in men. Pro-inflammatory cytokine production showed a sex-specific response pattern with increases in men and decreases in women in the first session vs. increases in men and women in the last session. Response patterns of GC sensitivity also changed over time: in the first session, sensitivity increased only in men, but in the last session, GC sensitivity decreased in all subjects. In conclusion, in response to repeated nausea induction, habituation occurs only in the endocrine system and predominantly in women. In the immune system, response patterns change in the favor of inflammatory conditions, with increases in stimulated IL-6 and TNF-alpha and decreases in the effectiveness of glucocorticoid suppression of these cytokines. These presumably unfavorable changes in the inflammatory system are more pronounced men.

Objectives: The objectives of this study were to assess whether socioeconomic status (SES) is associated with dysregulation of the cortisol diurnal rhythm and whether this association is independent of race and occurs equally in whites and blacks; and to determine if an association between SES and cortisol can be explained (is mediated) by behavioral, social, and emotional differences across the SES gradient., Methods: Seven hundred eighty-one subjects from a multisite sample representing both whites and blacks provided six saliva cortisol samples over the course of the day: at awakening, 45 minutes, 2.5 hours, 8 hours, and 12 hours after awakening, and at bedtime., Results: Both lower SES (education and income) and being black were associated with higher evening levels of cortisol. These relationships were independent of one another and SES associations with cortisol were similar across racial categories. The evidence was consistent with poorer health practices (primarily smoking), higher levels of depressive symptoms, poorer social networks and supports, and feelings of helplessness (low mastery) mediating the link between SES and cortisol. However, we found no evidence for psychosocial or behavioral mediation of the association between race and cortisol response., Conclusions: Lower SES was associated in a graded fashion with flatter diurnal rhythms as a result of less of a decline during the evening. This association occurred independent of race and the data were consistent with mediation by health practices, emotional and social factors. Blacks also showed a flatter rhythm at the end of the day. This association was independent of SES and could not be explained by behavioral, social, or emotional mediators.

To understand the underlying genetic and environmental sources of individual variation in basal cortisol levels, we collected salivary cortisol at awakening and at six fixed time points during the day in adult twins and their singleton siblings. Reported time of awakening was verified with heart rate and body movement recordings. Cortisol data were available for 199 MZ twins, 272 DZ twins and 229 singleton siblings from 309 twin families. No differences in cortisol means and variances were found between twins and singleton siblings. Additionally, the correlations for DZ twins and siblings were not significantly different, indicating generalizability of twin study results to the general population. Genetic model fitting showed heritability for cortisol levels during the awakening period (34% for cortisol level at awakening and 32% for cortisol level at 30 min after awakening) but not for cortisol levels later during the day. The current study shows that, while cortisol levels in the awakening period are influenced by genetic factors, cortisol levels throughout most of the day are not heritable, indicating that future gene finding studies for basal cortisol should focus on the first hour post-awakening.

Objective: This study examined whether clinical depression is associated with a differential inflammatory response to an acute bout of psychological stress., Methods: A total of 72 women participated in the study; half met diagnostic criteria for clinical depression; the others had no history of psychiatric illness. The groups were matched with respect to age and ethnicity. All subjects were exposed to a 17-minute mock-job interview; blood was drawn to assess secretion and regulation of inflammatory molecules., Results: The stressor was associated with feelings of shame and anxiety, a mobilization of monocytes, neutrophils, and C-reactive protein into the circulation, and greater endotoxin-stimulated production of interleukin-6 and tumor necrosis factor-alpha by white blood cells in vitro. Depressed subjects began the session with greater sensitivity to the antiinflammatory properties of glucocorticoids than control subjects. Following exposure to the stressor protocol, however, sensitivity decreased among depressed subjects and increased among controls. This was manifest by disparities in interleukin-6 and tumor necrosis factor-alpha production in the presence of dexamethasone., Conclusions: These findings suggest that under acutely challenging conditions, depression is associated with greater resistance to molecules that normally terminate the inflammatory cascade. An impaired capacity to regulate inflammation could underlie some of the excess morbidity and mortality that has been associated with depression.

The relevance of estrogens for cognition in older women is still debated. In this double-blind experiment hysterectomized women (age 58-75 years) received placebo (n = 13), estradiol (n = 12) or estradiol/progesterone (n = 10) treatment. Cognitive testing (nine different tests) took place at baseline, after 4 and 24 weeks of treatment. Strong hormone increases occurred in both active treatment groups. However, no beneficial effects in any of the cognitive tests could be detected. This study, therefore, does not support the notion that treatment with sex hormones has beneficial effects on cognition in older hysterectomized women. The human brain might loose its responsiveness to gonadal steroids with aging or prolonged hormone depletion.

We measured affect in 334 healthy adults on each of 7 days over a 3-week period. On the last day, salivary cortisol was assessed 14 times yielding scores for total concentration, morning rise amplitude, and slope of the time function. Trait negative affect (NA) was associated with higher total cortisol concentrations and greater morning rise in men. Cortisol levels for men low in trait positive affect (PA) did not decrease in the afternoon, resulting in a relatively high, flat rhythm. In contrast, women high in trait PA had low morning cortisol resulting in a low flat rhythm. State (person-centered) NA was not associated with same-day cortisol measures. State PA was associated with decreased total cortisol concentration in women. These are the first results showing associations between cortisol and trait PA. Differences in rhythmicity found here are noteworthy given the possible role of cortisol dysregulation in disease incidence, morbidity, mortality, and severity.

Studies in rodents have demonstrated that glucocorticoids enhance memory consolidation but impair delayed memory retrieval. Similar findings have been reported in humans. Emotional items are better remembered than neutral items. However, it is unknown if emotional valence influences the effects of cortisol on retrieval. In this double-blind crossover study, 16 healthy women learned a wordlist containing 15 neutral and 15 negative words. Delayed recall was tested 5h later. Cortisol administered before recall testing significantly reduced retrieval (p<.01). Exploratory follow-up analysis revealed that cortisol significantly impaired retrieval of negative words (p<.01), while having no significant effect on neutral words (p=.47). The current findings could suggest that emotional material is especially sensitive to the memory modulating effects of stress hormones.

Patients with postoperative ongoing sciatic pain have been shown to exhibit reduced cortisol levels along with enhanced IL-6 levels. The aim of the present study was to clarify the relationship between a reduced cortisol secretion and enhanced cytokine levels by performing a prospective study on patients with disc herniation. Twenty-two patients were examined before and after their disc surgery. Twelve healthy, pain-free subjects matched for age, education and gender constituted the control group. The preoperative examinations included the assessment of the diurnal pattern of cortisol secretion and the feedback sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis. Patients' subjective stress levels also were assessed during the preoperative examination. The diurnal pattern of cortisol secretion was again assessed during the postoperative examination. Furthermore, blood samples were collected to measure catecholamine, adrenocorticotropic hormone (ACTH)- and interleukin-6 (IL-6) levels before and after measuring the pressure pain thresholds (PPTs). An assessment of the sensitivity of circulating monocytes to the immunosuppressive effects of glucocorticoids was further included in the postoperative examinations. Failed back syndrome (FBS) patients (n=12) showed a reduced cortisol secretion in the morning hours and enhanced feedback sensitivity of the HPA axis. Furthermore, FBS patients displayed an increased in-vitro production of proinflammatory cytokines and a relative glucocorticoid resistance of pro-inflammatory cytokine producing monocytes as compared to non-FBS patients (n=10) and controls. After PPT measurement FBS patients exhibited an increased norepinephrine but decreased epinephrine response, together with lower ACTH levels and a four times higher plasma IL-6 response. These findings suggest that chronically stressed patients are at a higher risk for a poor surgical outcome as their reduced cortisol secretion promotes the postoperative ongoing synthesis of proinflammatory cytokines.

Objectives: Pre-exposure to an environment in which a nausea-inducing body rotation will subsequently be given constitutes a latent inhibition procedure that might act to reduce anticipatory and postrotation nausea., Methods: This was tested in 24 healthy subjects randomly assigned to receive no pre-exposure (group 0), a single pre-exposure (group 1), or three pre-exposures (group 3). Rotation was standardized as 5 x 1 minute rotation, but the subjects could terminate it on request. Nausea was determined on a 7-item symptom rating scale before, during, and after rotation on days 3 and 4, whereas anticipatory nausea was measured before presumed rotation on day 5. Saliva cortisol and tumor necrosis factor alpha (TNF-alpha) levels were determined at baseline before, directly, and 15 and 30 minutes after rotation every day, and before presumed rotation on day 5., Results: Pre-exposure significantly reduced the degree of anticipatory nausea on day 5. Cortisol levels increased with rotation and were higher at baseline on days 4 and 5, but subjects habituated from day 3 to day 4; levels were lower in women than in men. In contrast, TNF-alpha decreased with rotation but showed no habituation. For both cortisol and TNF-alpha, no effects on postrotational nausea were found., Conclusion: It is concluded that repetitive pre-exposure (latent inhibition) reduces anticipatory but not postrotation nausea; behavioral measures (rotation time) and measures of acute stress (cortisol, TNF-alpha) do not respond to latent inhibition. Thus, Pavlovian conditioning rules are effective in healthy humans with anticipatory nausea but not with postrotation nausea. Hormonal responses--TNF-alpha decrease with stress, compensatory cortisol increase--and gender-related effects on learning and habituation are discussed with regard to psychophysiological and psychoimmunological processes.

Biological indicators for stress reactions are valuable markers in psychophysiological research and clinical practice. Since the release of salivary enzyme alpha-amylase was reported to react to physiological and psychological stressors, we set out to investigate human salivary alpha-amylase changes employing a reliable laboratory stress protocol to investigate the reactivity of salivary alpha-amylase to a brief period of psychosocial stress. In a within-subject repeated-measures design, 24 healthy adults were exposed to the TSST and a control condition on separate days with randomized sequence. Salivary alpha-amylase, salivary cortisol and heart rate were repeatedly measured before, during and after both conditions. Significant differences between psychosocial stress and the rest condition in alpha-amylase activity [F(3.74,86.06)=4.52; P=0.003], cortisol levels [F(4.21,88.32)=12.48; P<0.001] and heart rate [F(1,22)=81.15; P<0.001] were observed, with marked increases before and after stress. The data corroborate findings from other studies that showed increased levels of alpha-amylase before and after psychological stress. We discuss the role of salivary alpha-amylase as a promising candidate for a reliable, noninvasive marker of psychosocial stress.

Background: Tryptophan depletion (TD) has been shown to induce a transient mood-lowering effect in psychiatric patients and susceptible healthy subjects. We investigated the effects of TD on cortisol secretion in psychiatric patients and healthy subjects based on the hypothesis that the potential mood-lowering effects may be associated with increased activity of the hypothalamic-pituitary-adrenal axis, thus leading to a rise of cortisol secretion., Methods: After TD at 18.00 h, salivary cortisol was sampled in the evening and on the following morning. The first study was a randomized, placebo-controlled, crossover study in healthy subjects. Two further open trials in patients with obsessive-compulsive disorder (OCD) and primary insomnia compared the effects of TD on cortisol with baseline conditions., Results: In healthy subjects, TD significantly diminished cortisol the next morning compared with placebo. In OCD patients and primary insomniacs, cortisol the morning after TD was lowered compared with baseline. Evening cortisol was not affected by TD in any of the groups., Conclusions: Contrary to expectation, TD led to a comparable decrease of morning cortisol in all groups investigated. However, these findings are consistent with former studies analyzing the impact of antiserotonergic drugs on cortisol secretion. The results underline that the antiserotonergic effects caused by TD may influence cortisol secretion.

Activity of the hypothalamus pituitary adrenal (HPA) axis is characterized by a pronounced circadian rhythm. An acute increase in cortisol levels occurs after awakening in the morning with continuously declining levels over the course of the remaining day. The morning cortisol increase probably reflects an activational response of the HPA axis aimed at preparing the body for the day. Some studies found patterns of enhanced or blunted waking cortisol responses observed under chronic stress, burnout, or post traumatic stress disorder. The present study wanted to characterize the morning cortisol response and the circadian cortisol day profile in a sample of six male patients with severe amnesia due to hypoxia, herpes simplex encephalitis or closed head injury. Age and gender matched relatives or friends served as controls. Cortisol was measured from saliva samples collected at home on two consecutive days. The patients were woken up in the morning by their partners or caregivers. The morning cortisol increase typically observed in healthy subjects and also observed in the control group was absent in the amnesic patients. In contrast, a normal circadian day profile was found in the amnesic patients, with a pronounced circadian cortisol decrease. Further studies are needed to understand the neurological or psychological mechanisms leading to a missing morning cortisol response in amnesic patients.

Gonadal steroids (estradiol and progesterone) can alter neuronal functioning, but electrophysiological evidence in women is still sparse. Therefore, the present study investigated event-related potentials (ERPs) to neutral stimuli over the course of the menstrual cycle. In addition, associations between ERPs and salivary estradiol and progesterone concentrations were investigated. Eighteen young healthy women were tested at three different phases of their menstrual cycle (menses, and follicular and luteal phases). ERPs (i.e., the N1 and P2 components, reflecting cortical arousal and the orienting response, the N2, P3, and the Slow Wave (SW), reflecting controlled processing) were measured using two different paradigms. In the luteal phase, early ERPs reflecting the cortical arousal response were diminished in the first stimulus block indicating an attenuated orienting response. These changes were significantly correlated with estradiol as well as progesterone levels. As to the later ERP components, the N2 latency was shorter during menses compared to the other two phases. No menstrual cycle-associated changes were apparent in other late ERP components. In sum, this study documents changes in auditory ERPs across the menstrual cycle with the most prominent changes occurring during the luteal phase. Future ERP studies therefore need to be more attentive to the issue of menstrual phase when studying female subjects or female patients.

Glucocorticoids secreted in response to stress modulate memory in animals and humans. Studies in rodents suggest that glucocorticoids enhance memory consolidation but impair delayed retrieval. Similar negative effects on memory retrieval have been reported in humans. The human studies so far have not addressed the issue of emotional valence, which conceivably could modulate the effects of cortisol on retrieval. The present mini-review discusses two recent studies from our laboratories that investigate the influence of emotional valence on the retrieval-impairing effects of cortisol. Both studies observed that cortisol impaired retrieval and that emotional valence influenced these effects. For autobiographical memory the impairing effects were stronger for neutral than for emotional items, whereas for word retrieval the opposite pattern was observed (stronger effects on emotional words). Possible reasons for these results are the different memory domains tested as well as the different sex of the subjects. Future studies will address these issues, which are of relevance for psychiatric disorders such as posttraumatic stress disorder or major depression.

Assessment of sympathoadrenal medullary system (SAM) activity is only possible to date via measurement of catecholamines in blood plasma or via electrophysiological methods. Both ways of measurement are restricted to endocrinological or psychophysiological laboratories, as both require either immediate freezing of blood samples or complex recording devices. Efforts have therefore been undertaken to find a method comparable to salivary cortisol measurements, in which noninvasive samples can be taken at any place and stored at room temperature for sufficient time before later analysis in the laboratory. Salivary alpha-amylase (sAA) is a candidate that may prove useful in this context. We show here that sAA activity is increased by acute psychosocial stress (Trier Social Stress Test) and that increases in sAA correlate with increases in norepinephrine. We further report that sAA exhibits a stable circadian pattern that mirrors that of salivary cortisol. In conclusion, the current data show that salivary alpha-amylase may serve as an easy-to-use index for SAM activity. However, some questions remain to be answered; for example, what impact does salivary flow rate exert on stress-induced sAA activity?