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1.  Depressive attribution style and stressor uncontrollability increase perceived pain intensity after electrical skin stimuli in healthy young men 
Depressive and pain symptoms often occur concurrently in patients with psychiatric disorders or somatic diseases, but the contribution of pre-existing dysfunctional cognitive schemata to pain perception remains unclear.
To investigate the relationship between depression-related attribution styles and perceived pain intensity (PPI) after controllable versus uncontrollable electrical skin stimulation in healthy male individuals.
Causal attributions for negative events were measured using the attribution style questionnaire (ASQ) on the dimensions internal versus external (INT), global versus specific (GLO) and stable versus unstable (STA) in 50 men (20 to 31 years of age). Additionally, symptoms of anxiety and depression (measured using the Depression Scale) as well as baseline helplessness were assessed. Participants were randomly assigned to receive self-administered (controllable) or experimenter-administered (uncontrollable) painful skin stimuli. PPI was assessed after stress exposure using a visual analogue scale (0 to 100). Relationships between PPI and depression-related cognitions were calculated using correlation and multiple regression analyses.
Correlation analyses revealed a moderate correlation between PPI and ASQ-INT scores (r=0.46). Following uncontrollable stress exposure, significantly higher PPI ratings (P=0.001) and a higher correlation between PPI and ASQ-INT (r=0.70) were observed. Multiple regression analysis showed an independent influence of stressor controllability (ß=0.39; P=0.003) and ASQ-INT (ß=0.36; P=0.006) on PPI.
These findings highlight the interaction of specific depression-related cognitions and stress controllability on pain intensity perception.
The results of the present study may facilitate understanding of the cognitive aspects of pain intensity perception and improve psychological pain therapies focusing on attributions and controllability.
PMCID: PMC3812192  PMID: 23717827
Attribution styles; Controllability; Pain intensity
2.  Novelty-evoked activity in open field predicts susceptibility to helpless behavior 
Physiology & behavior  2010;101(5):746-754.
Learned helplessness in animals has been used to model disorders such as depression and post-traumatic stress disorder (PTSD), but there is a lack of knowledge concerning which individual behavioral characteristics at baseline can predict helpless behavior after exposure to inescapable stress. The first aim of this study was to determine behavioral predictors of helplessness using the novel and familiar open-field tests, sucrose consumption, and passive harm-avoidance tasks before learned helplessness training and testing. Individual differences in physiologic responses to restraint stress were also assessed. A cluster analysis of escape latencies from helplessness testing supported the division of the sample population of Holtzman rats into approximately 50% helpless and 50% non-helpless. Linear regression analyses further revealed that increased reactivity to the novel environment, but not general activity or habituation, predicted susceptibility to learned helplessness. During restraint stress there were no mean differences in heart rate, heart rate variability, and plasma corticosterone between helpless and non-helpless rats; however, a lower heart rate during stress was associated with higher activity levels during exploration. Our most important finding was that by using an innocuous screening tool such as the novel and familiar open-field tests, it was possible to identify subjects that were susceptible to learned helplessness.
PMCID: PMC2975894  PMID: 20804778
Novelty; open field test; learned helplessness; individual differences; inescapable stress; heart rate
3.  Sex Differences in the Association Between Cortisol Concentrations and Laboratory Pain Responses in Healthy Children 
Gender medicine  2009;6(Suppl 2):193-207.
Research in adult populations has highlighted sex differences in cortisol concentrations and laboratory pain responses, with men exhibiting higher cortisol concentrations and reduced pain responses compared with women. Yet, less is known about the relationship of cortisol concentrations to pain in children.
This study examined associations between sex, cortisol, and pain responses to laboratory pain tasks in children.
Salivary cortisol samples from subjects aged 8 to 18 years were obtained at baseline after entering the laboratory (SCb), after the completion of all pain tasks (SC1), and at the end of the session (SC2), 20 minutes later. Blood cortisol samples were also taken after completion of the pain tasks (BC1) and at the end of the session (BC2), 20 minutes later. Subjects completed 3 counterbalanced laboratory pain tasks: pressure, heat, and cold pressor tasks. Pain measures included pain tolerance, and self-reported pain intensity and unpleasantness for all 3 tasks.
The study included 235 healthy children and adolescents (119 boys, 116 girls; mean age, 12.7 years; range, 8–18 years; 109 [46.4%] were in early puberty; 94 [40.0%] white). Salivary and blood cortisol levels were highly correlated with each other. Salivary cortisol levels for the total sample and for boys and girls declined significantly from SCb to SC1 (P < 0.01), although there were no significant changes from SC1 to SC2. No significant sex differences in salivary or blood cortisol levels were evident at any assessment point. Separate examination of the cortisol–laboratory pain response relationships by sex (controlling for age and time of day) suggested different sex-specific patterns. Higher cortisol levels were associated with lower pain reactivity (ie, increased pressure tolerance) among boys compared with girls at SC1, SC2, and BC1 (SC1: r = 0.338, P = 0.003; SC2: r = 0.271, P = 0.020; and BC1: r = 0.261, P = 0.026). However, higher cortisol levels were related to higher pain response (ie, increased cold intensity [BC2: r = 0.229, P = 0.048] and unpleasantness [BC1: r = 0.237, P = 0.041]) in girls compared with boys.
These findings suggest important sex differences in cortisol–pain relationships in children and adolescents. Cortisol levels were positively associated with increased pain tolerance in boys and increased pain sensitivity in girls.
PMCID: PMC3486740  PMID: 19406369
pain; children; cortisol; sex differences
4.  Feelings of helplessness increase ERN amplitudes in healthyindividuals 
Neuropsychologia  2013;51(4):613-621.
Experiencing feelings of helplessness has repeatedly been reported to contribute to depressive symptoms and negative affect. In turn, depression and negative affective states are associated, among others, with impairments in performance monitoring. Thus, the question arises whether performance monitoring is also affected by feelings of helplessness.
To this end, after the induction of feelings of helplessness via an unsolvable reasoning task, 37 participants (20 females) performed a modified version of a Flanker task. Based on a previously validated questionnaire, 17 participants were classified as helpless and 20 as not-helpless. Behavioral measures revealed no differences between helpless and not-helpless individuals. However, we observed enhanced Error-Related Negativity (ERN) amplitude differences between erroneous and correct responses in the helpless compared to the not-helpless group. Furthermore, correlational analysis revealed that higher scores of helplessness were associated with increased ERN difference scores. No influence of feelings of helplessness on later stages of performance monitoring was observed as indicated by Error-Positivity (Pe) amplitude.
The present study is the first to demonstrate that feelings of helplessness modulate the neuronal correlates of performance monitoring. Thus, even a short-lasting subjective state manipulation can lead to ERN amplitude variation, probably via modulation of mesencephalic dopamine activity.
► Research on neural performance monitoring correlates after helplessness induction. ► Increased feelings of helpless induced ERN amplitude enhancement. ► Behavioral measures were not affected by feelings of helplessness. ► Subjective state manipulation manifests itself in increased ERN amplitudes.
PMCID: PMC3610020  PMID: 23267824
Performance monitoring; ERN; Pe; Helplessness
5.  Intimate partner violence exposure, salivary cortisol, and childhood asthma 
Child abuse & neglect  2012;36(0):596-601.
Neuroendocrine alterations may help explain health differences between intimate partner violence (IPV) exposed children and non-exposed children. We sought to determine the feasibility of having families, recruited at a child asthma visit, collect at home and return via mail child salivary samples, and whether socio-demographic variables were associated with sample return. For those returning samples, we examined whether past-year IPV exposure was associated with total cortisol output (AUC) and the magnitude of the cortisol awakening response (CAR), and whether these cortisol values were associated with asthma control.
Fifty five families with an asthmatic child of any age were recruited from 2 pediatric asthma clinics. At the time of the visit, parents completed a survey packet which included a modified version of the Conflict Tactics Scale to assess IPV. Parents were given supplies to collect 3 child salivary cortisol samples (awakening, 30-minutes after awakening, bedtime) at home on a typical day, and return them via mail. Medical records also were abstracted.
Fifty-three percent (n = 29) returned child salivary samples. Families who returned samples typically returned them within two weeks, most commonly before we made a reminder call. Parental male sex was associated (p = .06) with increased rate of return at the trend level. In multivariable models, a one-unit increase in IPV was significantly associated with a .93 SD increase in root-transformed total cortisol output (AUC) (un-standardized beta = 2.5; SE .59; p = 0.001). The odds of uncontrolled asthma were marginally higher for every nmol/l increase in CAR (OR 1.04; 95% CI 1.0, 1.1; p = .06).
This study provides support for the feasibility of obtaining a moderate return of salivary specimens from a convenience sample. Findings that IPV was associated with elevated total cortisol output and uncontrolled asthma was marginally associated with cortisol awakening response suggest that future studies should investigate whether cortisol mediates the IPV-child asthma relationship.
PMCID: PMC3424283  PMID: 22858093
6.  Differences in Salivary Alpha-Amylase and Cortisol Responsiveness following Exposure to Electrical Stimulation versus the Trier Social Stress Tests 
PLoS ONE  2012;7(7):e39375.
Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM) system.
Principal Findings
We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST) and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS) tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations), while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation.
These preliminary results suggest that the HPA axis (but not the SAM system) may show differential response patterns to distinct kinds of stressors.
PMCID: PMC3408464  PMID: 22859941
7.  Salivary cortisol concentrations and behavior in a population of healthy dogs hospitalized for elective procedures 
Applied animal behaviour science  2012;141(3-4):10.1016/j.applanim.2012.08.007.
Identification of severe stress in hospitalized veterinary patients may improve treatment outcomes and welfare. To assess stress levels, in Study 1, we collected salivary cortisol samples and behavioral parameters in 28 healthy dogs hospitalized prior to elective procedures. Dogs were categorized into two groups; low cortisol (LC) and high cortisol (HC), based on the distribution of cortisol concentrations (< or ≥ 0.6 µg/dL). We constructed a stress research tool (SRT) based on three behaviors, (head resting, panting and lip licking) that were most strongly related to salivary cortisol concentrations. In Study 2, we collected salivary cortisol samples from 39 additional dogs, evaluated behavior/cortisol relationships, assigned each dog to an LC or HC group, and tested the ability of the SRT to predict salivary cortisol. Median (interquartile range) salivary cortisol concentrations were not different between Study 1 (0.43 µg/dL, 0.33 to 1.00 µg/dL) and Study 2 dogs (0.41 µg/dL, 0.28 to 0.52 µg/dL). The median salivary cortisol concentration was significantly lower (P ≤ 0.001) in LC versus HC dogs in each study; (Study 1 LC: 0.38 µg/dL, (0.19 to 0.44), n = 19, HC: 2.0 µg/dL, (1.0 to 2.8), n = 9, and Study 2 LC: 0.35 µg/dL, (0.25 to 0.48), n = 28, HC: 0.89 µg/dL, (0.66 to 1.4), n = 7). In Study 1, three behaviors were found to be associated with salivary cortisol concentrations. Duration of head resting was negatively associated with salivary cortisol (ρ = −0.60, P = 0.001), panting and lip licking were positively associated with cortisol (ρ = 0.39, P = 0.04, and 0.30, P = 0.05, respectively), Head resting (p = 0.001) and panting (p = 0.003) were also associated with LC/HC group assignment. In Study 2 dogs, the three behaviors correlated (but not significantly) with salivary cortisol concentration; of the three, only head resting was significantly associated with LC/HC group assignment (P = 0.03). The SRT derived from Study 1 was effective at prediction of salivary cortisol concentrations when applied to 20 min but not 2 min of behavioral data from Study 2. Additionally, we note that dexmedetomidine and butorphanol sedation more than 6 h prior to measurement was found to be significantly (P = 0.05) associated with lower salivary cortisol concentrations when compared to unsedated dogs. Our work offers support for eventual construction of a rating tool that utilizes the presence or absence of specific behaviors to identify higher salivary cortisol concentrations in dogs subjected to hospitalization, which may be tied to greater psychogenic stress levels. Future work to investigate the effects of stress on dogs and its mitigation in clinical situations may be approached by studying a combination o f parameters, and should consider the possible beneficial effects of sedatives.
PMCID: PMC3817620  PMID: 24204086
Salivary cortisol; hospitalization; stress; dogs; dexmedetomidine; butorphanol
8.  Lack of cortisol response in patients with posttraumatic stress disorder (PTSD) undergoing a diagnostic interview 
BMC Psychiatry  2007;7:54.
According to DSM-IV, the diagnosis of posttraumatic stress disorder (PTSD) requires the experience of a traumatic event during which the person's response involved intense fear, helplessness, or horror. In order to diagnose PTSD, clinicians must interview the person in depth about his/her previous experiences and determine whether the individual has been traumatized by a specific event or events. However, asking questions about traumatic experiences can be stressful for the traumatized individual and it has been cautioned that subsequent "re-traumatization" could occur. This study investigated the cortisol response in traumatized refugees with PTSD during a detailed and standardized interview about their personal war and torture experiences.
Participants were male refugees with severe PTSD who solicited an expert opinion in the Psychological Research Clinic for Refugees of the University of Konstanz. 17 patients were administered the Vivo Checklist of War, Detention, and Torture Events, a standardized interview about traumatic experiences, and 16 subjects were interviewed about absorption behavior. Self-reported measures of affect and arousal, as well as saliva cortisol were collected at four points. Before and after the experimental intervention, subjects performed a Delayed Matching-to-Sample (DMS) task for distraction. They also rated the severity of selected PTSD symptoms, as well as the level of intrusiveness of traumatic memories at that time.
Cortisol excretion diminished in the course of the interview and showed the same pattern for both groups. No specific response was detectable after the supposed stressor. Correspondingly, ratings of subjective well-being, memories of the most traumatic event(s) and PTSD symptoms did not show any significant difference between groups. Those in the presumed stress condition did not perform worse than persons in the control condition after the stressor. However, both groups performed poorly in the DMS task, which is consistent with memory and concentration problems demonstrated in patients with PTSD.
A comprehensive diagnostic interview including questions about traumatic events does not trigger an HPA-axis based alarm response or changes in psychological measures, even for persons with severe PTSD, such as survivors of torture. Thus, addressing traumatic experiences within a safe and empathic environment appears to impose no unacceptable additional load to the patient.
PMCID: PMC2175503  PMID: 17916253
9.  Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression and dysthymia 
Psychological Medicine  2008;39(1):77-86.
The experience of uncontrollability and helplessness in the face of stressful life events is regarded as an important determinant in the development and maintenance of depression. The inability to successfully deal with stressors might be linked to dysfunctional prefrontal functioning. We assessed cognitive, behavioural and physiological effects of stressor uncontrollability in depressed and healthy individuals. In addition, relationships between altered cortical processing and cognitive vulnerability traits of depression were analysed.
A total of 26 unmedicated depressed patients and 24 matched healthy controls were tested in an expanded forewarned reaction (S1–S2) paradigm. In a factorial design, stressor controllability varied across three consecutive conditions: (a) control, (b) loss of control and (c) restitution of control. Throughout the experiment, error rates, ratings of controllability, arousal, emotional valence and helplessness were assessed together with the post-imperative negative variation (PINV) of the electroencephalogram.
Depressed participants showed an enhanced frontal PINV as an electrophysiological index of altered information processing during both loss of control and restitution of control. They also felt more helpless than controls. Furthermore, frontal PINV magnitudes were associated with habitual rumination in the depressed subsample.
These findings indicate that depressed patients are more susceptible to stressor uncontrollability than healthy subjects. Moreover, the experience of uncontrollability seems to bias subsequent information processing in a situation where control is objectively re-established. Alterations in prefrontal functioning appear to contribute to this vulnerability and are also linked to trait markers of depression.
PMCID: PMC2830060  PMID: 18466665
Depression; learned helplessness; post-imperative negative variation; rumination; stress
10.  Distress related to myocardial infarction and cardiovascular outcome: a retrospective observational study 
BMC Psychiatry  2011;11:98.
During acute coronary syndromes patients perceive intense distress. We hypothesized that retrospective ratings of patients' MI-related fear of dying, helplessness, or pain, all assessed within the first year post-MI, are associated with poor cardiovascular outcome.
We studied 304 patients (61 ± 11 years, 85% men) who after a median of 52 days (range 12-365 days) after index MI retrospectively rated the level of distress in the form of fear of dying, helplessness, or pain they had perceived at the time of MI on a numeric scale ranging from 0 ("no distress") to 10 ("extreme distress"). Non-fatal hospital readmissions due to cardiovascular disease (CVD) related events (i.e., recurrent MI, elective and non-elective stent implantation, bypass surgery, pacemaker implantation, cerebrovascular incidents) were assessed at follow-up. The relative CVD event risk was computed for a (clinically meaningful) 2-point increase of distress using Cox proportional hazard models.
During a median follow-up of 32 months (range 16-45), 45 patients (14.8%) experienced a CVD-related event requiring hospital readmission. Greater fear of dying (HR 1.21, 95% CI 1.03-1.43), helplessness (HR 1.22, 95% CI 1.04-1.44), or pain (HR 1.27, 95% CI 1.02-1.58) were significantly associated with an increased CVD risk without adjustment for covariates. A similarly increased relative risk emerged in patients with an unscheduled CVD-related hospital readmission, i.e., when excluding patients with elective stenting (fear of dying: HR 1.26, 95% CI 1.05-1.51; helplessness: 1.26, 95% CI 1.05-1.52; pain: HR 1.30, 95% CI 1.01-1.66). In the fully-adjusted models controlling for age, the number of diseased coronary vessels, hypertension, and smoking, HRs were 1.24 (95% CI 1.04-1.46) for fear of dying, 1.26 (95% CI 1.06-1.50) for helplessness, and 1.26 (95% CI 1.01-1.57) for pain.
Retrospectively perceived MI-related distress in the form of fear of dying, helplessness, or pain was associated with non-fatal cardiovascular outcome independent of other important prognostic factors.
PMCID: PMC3126764  PMID: 21663602
Myocardial infarction; pain; retrospective study; psychological stress; risk factor
11.  Cortisol and ghrelin concentrations following a cold pressor stress test in overweight individuals with and without Night Eating 
To explore appetite-related hormones following stress in overweight individuals, and their interaction with Night Eating (NE) status.
We measured plasma cortisol and ghrelin concentrations, and recorded ratings of stress and hunger in response to a physiological laboratory stressor (Cold Pressor Test, CPT) in overweight women with (n=11; NE) and without (n=17; non-NE) night eating.
Following the CPT, cortisol (p < .001) and ghrelin (p < .05) levels increased, as did stress and hunger ratings (all p < .001), across all subjects (NE and non-NE). NE exhibited higher baseline cortisol (p < .05) levels than non-NE. NE also had greater cortisol area under the curve (AUC) than non-NE (p = .019), but not when controlling for baseline cortisol levels. Ghrelin baseline and AUC did not differ between groups. NE showed higher AUC stress (p < .05), even when controlling for baseline stress.
Overweight individuals showed increased cortisol, ghrelin, stress and hunger following a laboratory stressor, and there was some evidence for greater increases in cortisol and subjective stress among NE. The greater AUC cortisol in NE was due to higher baseline levels but the group difference in stress was in direct response to the CPT stressor. Our results support a role for cortisol and stress in Night Eating.
PMCID: PMC3610846  PMID: 23247680
eating disorders; HPA axis; sleep; circadian; appetite hormones; gut peptides
12.  An eight-week yoga intervention is associated with improvements in pain, psychological functioning and mindfulness, and changes in cortisol levels in women with fibromyalgia 
Journal of Pain Research  2011;4:189-201.
Fibromyalgia (FM) is a chronic condition characterized by widespread musculoskeletal pain, fatigue, depression, and hypocortisolism. To date, published studies have not investigated the effects of yoga on cortisol in FM. This pilot study used a time series design to evaluate pain, psychological variables, mindfulness, and cortisol in women with FM before and after a yoga intervention.
Participants (n = 22) were recruited from the community to participate in a 75 minute yoga class twice weekly for 8 weeks. Questionnaires concerning pain (intensity, unpleasantness, quality, sum of local areas of pain, catastrophizing, acceptance, disability), anxiety, depression, and mindfulness were administered pre-, mid- and post-intervention. Salivary cortisol samples were collected three times a day for each of two days, pre- and post-intervention.
Repeated measures analysis of variance (ANOVA) revealed that mean ± standard deviation (SD) scores improved significantly (p < 0.05) from pre- to post-intervention for continuous pain (pre: 5.18 ± 1.72; post: 4.44 ± 2.03), pain catastrophizing (pre: 25.33 ± 14.77; post: 20.40 ± 17.01), pain acceptance (pre: 60.47 ± 23.43; post: 65.50 ± 22.93), and mindfulness (pre: 120.21 ± 21.80; post: 130.63 ± 20.82). Intention-to-treat analysis showed that median AUC for post-intervention cortisol (263.69) was significantly higher (p < 0.05) than median AUC for pre-intervention levels (189.46). Mediation analysis revealed that mid-intervention mindfulness scores significantly (p < 0.05) mediated the relationship between pre- and post-intervention pain catastrophizing scores.
The results suggest that a yoga intervention may reduce pain and catastrophizing, increase acceptance and mindfulness, and alter total cortisol levels in women with FM. The changes in mindfulness and cortisol levels may provide preliminary evidence for mechanisms of a yoga program for women with FM. Future studies should use an RCT design with a larger sample size.
PMCID: PMC3160832  PMID: 21887116
fibromyalgia; pain; cortisol; yoga; psychological variables
13.  A matter of timing: harm reduction in learned helplessness 
Learned helplessness has excellent validity as an animal model for depression, but problems in reproducibility limit its use and the high degree of stress involved in the paradigm raises ethical concerns. We therefore aimed to identify which and how many trials of the learned helplessness paradigm are necessary to distinguish between helpless and non-helpless rats.
A trial-by-trial reanalysis of tests from 163 rats with congenital learned helplessness or congenital non-learned helplessness and comparison of 82 rats exposed to inescapable shock with 38 shock-controls revealed that neither the first test trials, when rats showed unspecific hyperlocomotion, nor trials of the last third of the test, when almost all animals responded quickly to the stressor, contributed to sensitivity and specificity of the test. Considering only trials 3–10 improved the classification of helpless and non-helpless rats.
The refined analysis allows abbreviation of the test for learned helplessness from 15 trials to 10 trials thereby reducing pain and stress of the experimental animals without losing statistical power.
PMCID: PMC4232717  PMID: 25365925
Learned helplessness; Reliability; Refinement; Harm reduction; Latency measures; ROC-curves
14.  Neonatal Procedural Pain and Preterm Infant Cortisol Response to Novelty at 8 Months 
Pediatrics  2004;114(1):e77-e84.
Objectives. Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; ≤28 weeks), very low gestational age (VLGA; 29–32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit.
Methods. Seventy-six infants, 54 preterm (≤32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2).
Results. Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants.
Conclusions. ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than more maturely born, VLGA preterm and term-born infants. Exposure to high numbers of skin-breaking procedures may contribute to “resetting” basal arousal systems in preterm infants.
PMCID: PMC1351380  PMID: 15231977
15.  Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers 
BMC Endocrine Disorders  2014;14(1):91.
Glucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following “physiological” and “stress” doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement.
Cortisol profiles were measured in plasma, saliva and urine following “physiological” (20 mg oral) or “stress” (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens’ equation.
Plasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P <0.0001, correlation coefficient between 0.61 and 0.94). There was no difference in CBG levels across the sampling period.
An oral dose of hydrocortisone 20 mg is supraphysiological for routine maintenance, while stress doses above 50 mg 6-hourly would rarely be necessary in managing acute illness. Salivary cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in hypoadrenal patients.
PMCID: PMC4280712  PMID: 25425285
Adrenal Cortex; HPA axis (hypothalamic-pituitary-adrenal); Cortisol; Hydrocortisone
16.  Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: The role of stress and of antipsychotic treatment 
Schizophrenia research  2009;116(2-3):234-242.
First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60 min after awakening, and at 12 and 8 pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p < 0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.
PMCID: PMC3513410  PMID: 19751968
First-episode psychosis; Cortisol; Stress; Antipsychotic; Childhood trauma; HPA axis
17.  The Relationship Between Fluticasone Furoate Systemic Exposure and Cortisol Suppression 
Clinical Pharmacokinetics  2013;52(10):885-896.
The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta2-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner.
The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration–time curve over 24 h postdose (AUC24)] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma.
The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0–24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC24. A sigmoid maximum effect (Emax) model was fitted to fluticasone furoate AUC24 and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM®.
Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC24 and WM24 and 24-h urine cortisol excretion was well described by an Emax model. The average estimate of AUC producing 50 % of maximum effect (AUC50) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C0) and AUC50 in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C0 and AUC50 in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents.
A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC50 of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC24 values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC24 of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.
PMCID: PMC3779313  PMID: 23719680
18.  Simultaneous transcutaneous electrical nerve stimulation mitigates simulator sickness symptoms in healthy adults: a crossover study 
Flight simulators have been used to train pilots to experience and recognize spatial disorientation, a condition in which pilots incorrectly perceive the position, location, and movement of their aircrafts. However, during or after simulator training, simulator sickness (SS) may develop. Spatial disorientation and SS share common symptoms and signs and may involve a similar mechanism of dys-synchronization of neural inputs from the vestibular, visual, and proprioceptive systems. Transcutaneous electrical nerve stimulation (TENS), a maneuver used for pain control, was found to influence autonomic cardiovascular responses and enhance visuospatial abilities, postural control, and cognitive function. The purpose of present study was to investigate the protective effects of TENS on SS.
Fifteen healthy young men (age: 28.6 ± 0.9 years, height: 172.5 ± 1.4 cm, body weight: 69.3 ± 1.3 kg, body mass index: 23.4 ± 1.8 kg/m2) participated in this within-subject crossover study. SS was induced by a flight simulator. TENS treatment involved 30 minutes simultaneous electrical stimulation of the posterior neck and the right Zusanli acupoint. Each subject completed 4 sessions (control, SS, TENS, and TENS + SS) in a randomized order. Outcome indicators included SS symptom severity and cognitive function, evaluated with the Simulator Sickness Questionnaire (SSQ) and d2 test of attention, respectively. Sleepiness was rated using the Visual Analogue Scales for Sleepiness Symptoms (VAS-SS). Autonomic and stress responses were evaluated by heart rate, heart rate variability (HRV) and salivary stress biomarkers (salivary alpha-amylase activity and salivary cortisol concentration).
Simulator exposure increased SS symptoms (SSQ and VAS-SS scores) and decreased the task response speed and concentration. The heart rate, salivary stress biomarker levels, and the sympathetic parameter of HRV increased with simulator exposure, but parasympathetic parameters decreased (p < 0.05). After TENS treatment, SS symptom severity significantly decreased and the subjects were more able to concentrate and made fewer cognitive test errors (p < 0.05).
Sympathetic activity increased and parasympathetic activity decreased after simulator exposure. TENS was effective in reducing SS symptoms and alleviating cognitive impairment.
Trial registration number
Australia and New Zealand Clinical Trials Register: http://ACTRN12612001172897
PMCID: PMC3637548  PMID: 23587135
Transcutaneous electrical nerve stimulation; Motion sickness; Simulator sickness; Crossover; Autonomic nervous system; Heart rate variability; Salivary biomarker; Alpha amylase; Cortisol
19.  High correlation between salivary cortisol awakening response and the psychometric profiles of healthy children 
Cortisol awakening response (CAR) as an indicator of psychological stress and related physical and psychiatric diseases has attracted growing attention from researchers. Although CAR changes have been investigated extensively in children with behavioral and psychiatric disorders, the association between CAR and conventional psychometric scales for healthy children has not been reported. The aim of this study was to investigate the association between salivary CAR and subscales of Profiles of Mood States (POMS), a self-assessment questionnaire widely used to evaluate the temporal emotional states of healthy children.
This study included 18 healthy girls aged 13–16 years. Saliva was collected immediately on awakening, 30 min and 60 min after waking, and then at 2-hour intervals from 9 am to 5 pm. The current mood state, including depression, anxiety, fatigue, and other psychometric profiles were assessed using POMS. The magnitude of salivary CAR and the area under the concentration-time curve (AUC) for diurnal salivary cortisol were compared with the profiles. There were significant positive correlations between the magnitude of CAR and the POMS subscales for "Depression-Dejection", "Tension-Anxiety", "Fatigue", and "Confusion". No correlation was found between the AUC salivary cortisol level and the psychometric profiles.
Salivary CAR was associated with various mood states of healthy female children but diurnal salivary cortisol AUC was not. Salivary CAR may be a biomarker of the physical and mental condition of healthy female children.
PMCID: PMC3995602  PMID: 24625309
Cortisol awakening response; Hypothalamus-pituitary-adrenal axis; Saliva; Children
20.  Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents 
Arthritis Research & Therapy  2005;7(5):R992-R1000.
In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latter, rather than the pain, might explain the HPA results. A population study ascertained pain and psychological status in subjects aged 25 to 65 years. Random samples were selected from the following three groups: satisfying criteria for chronic widespread pain; free of chronic widespread pain but with strong evidence of somatisation ('at risk'); and a reference group. HPA axis function was assessed from measuring early morning and evening salivary cortisol levels, and serum cortisol after physical (pain pressure threshold exam) and chemical (overnight 0.25 mg dexamethasone suppression test) stressors. The relationship between HPA function with pain and the various psychosocial scales assessed was modelled using appropriate regression analyses, adjusted for age and gender. In all 131 persons with chronic widespread pain (participation rate 74%), 267 'at risk' (58%) and 56 controls (70%) were studied. Those in the chronic widespread pain and 'at risk' groups were, respectively, 3.1 (95% CI (1.3, 7.3)) and 1.8 (0.8, 4.0) times more likely to have a saliva cortisol score in the lowest third. None of the psychosocial factors measured were, however, associated with saliva cortisol scores. Further, those in the chronic widespread pain (1.9 (0.8, 4.7)) and 'at risk' (1.6 (0.7, 3.6)) groups were also more likely to have the highest serum cortisol scores. High post-stress serum cortisol was related to high levels of psychological distress (p = 0.05, 95% CI (0.02, 0.08)). After adjusting for levels of psychological distress, the association between chronic widespread pain and post-stress cortisol scores remained, albeit slightly attenuated. This is the first population study to demonstrate that those with established, and those psychologically at risk of, chronic widespread pain demonstrate abnormalities of HPA axis function, which are more marked in the former group. Although some aspects of the altered function are related to the psychosocial factors measured, we conclude that the occurrence of HPA abnormality in persons with chronic widespread pain is not fully explained by the accompanying psychological stress.
PMCID: PMC1257426  PMID: 16207340
21.  Influence of Consumption of a High-Protein vs. High-Carbohydrate Meal on the Physiological Cortisol and Psychological Mood Response in Men and Women 
PLoS ONE  2011;6(2):e16826.
Consumption of meals with different macronutrient contents, especially high in carbohydrates, may influence the stress-induced physiological and psychological response. The objective of this study was to investigate effects of consumption of a high-protein vs. high-carbohydrate meal on the physiological cortisol response and psychological mood response. Subjects (n = 38, 19m/19f, age = 25±9 yrs, BMI = 25.0±3.3 kg/m2) came to the university four times, fasted, for either condition: rest-protein, stress-protein, rest-carbohydrate, stress-carbohydrate (randomized cross-over design). Stress was induced by means of a psychological computer-test. The test-meal was either a high-protein meal (En% P/C/F 65/5/30) or a high-carbohydrate meal (En% P/C/F 6/64/30), both meals were matched for energy density (4 kJ/g) and daily energy requirements (30%). Per test-session salivary cortisol levels, appetite profile, mood state and level of anxiety were measured. High hunger, low satiety (81±16, 12±15 mmVAS) confirmed the fasted state. The stress condition was confirmed by increased feelings of depression, tension, anger, anxiety (AUC stress vs. rest p<0.02). Consumption of the high-protein vs. high-carbohydrate meal did not affect feelings of depression, tension, anger, anxiety. Cortisol levels did not differ between the four test-sessions in men and women (AUC nmol·min/L p>0.1). Consumption of the test-meals increased cortisol levels in men in all conditions (p<0.01), and in women in the rest-protein and stress-protein condition (p<0.03). Men showed higher cortisol levels than women (AUC nmol·min/L p<0.0001). Consumption of meals with different macronutrient contents, i.e. high-protein vs. high-carbohydrate, does not influence the physiological and psychological response differentially. Men show a higher meal-induced salivary cortisol response compared with women.
PMCID: PMC3033415  PMID: 21304815
22.  Prospective Association of Morning Salivary Cortisol with Depressive Symptoms in Mid-Life: A Life-Course Study  
PLoS ONE  2013;8(11):e77603.
Associations of cortisol and depression vary at different life-stages, yet population-based, prospective studies are scarce. We aimed to assess associations of morning cortisol with depressive symptoms in mid-life taking account of lifetime psychological health.
Participants were 5,403 men and women from the 1958 British Birth Cohort whose salivary cortisol was assessed at 45y (45min after waking (T1) and 3h later (T2)) and who completed the 5-item Mental-Health Index (MHI-5) about depressive symptoms at age 50y. Lifetime psychological health was identified from child and adult measures.
For women, higher T2 cortisol at 45y predicted depression (MHI-5 scores ≤52) at 50y (odds ratio [OR]=1.17; 95% confidence intervals [CI] 1.05,1.30 per standard deviation increase in T2 cortisol), attenuating when adjusted for current (45y) and previous (7-42y) psychological health (OR=1.11; 95% CI 0.98, 1.24). Similarly, an association in women of flatter cortisol delta (T2-T1) with depressive symptoms at 50y weakened after adjustment for current (45y) and previous (7-42y) psychological health. For men, lower T2 cortisol at 45y predicted greater depressive symptoms at 50y and the association strengthened when adjusted for lifetime psychological health. Likewise, lower cortisol AUC predicted higher risk of depression for men after adjusting for prior psychological health (OR=0.85; CI 0.72, 1.00). Associations were largely unaltered by control for covariates.
In women, higher cortisol in late morning at 45y is prospectively associated with depressive symptoms at 50y through a link with lifetime psychological health. In men, lower cortisol predicts subsequent symptoms, independent of depressive history.
PMCID: PMC3827055  PMID: 24265676
23.  Neurogenesis and Helplessness are Mediated by Controllability in Males but not in Females 
Biological psychiatry  2007;62(5):487-495.
Numerous studies have implicated neurogenesis in the hippocampus in animal models of depression, especially those related to controllability and learned helplessness. Here, we tested the hypothesis that uncontrollable, but not controllable stress would reduce cell proliferation in the hippocampus of male and female rats, and would relate to the expression of helplessness behavior.
To manipulate controllability, groups of male and female rats were trained in one session (acute stress) or over seven sessions (repeated stress) to escape a footshock, while yoked controls could not escape, but were exposed to the same amount of stress. Cell proliferation was assessed with immunohistochemistry of BrdU and immunofluorescence of BrdU and NeuN. Separate groups were exposed to either controllable or uncontrollable stress and their ability to learn to escape during training on a more difficult task was used as a behavioral measure of helplessness.
Acute stress reduced cell proliferation in males, but did not affect proliferation in the female hippocampus. When animals were given the opportunity to learn to control the stress over days, males produced more cells than the yoked males without control. Repeated training with controllable stress did not influence proliferation in females. Under all conditions, males were more likely than females to express helplessness behavior, even males that were not previously stressed.
The modulation of neurogenesis by controllability was evident in males but not in females, as was the expression of helplessness behavior, despite the fact that men are less likely than women to experience depression.
PMCID: PMC2692748  PMID: 17306770
dentate gyrus; depression; sex differences; neurogenesis; controllability; stress; learned helplessness
24.  Cortisol Diurnal Rhythm and Stress Reactivity in Male Adolescents with Early-Onset or Adolescence-Onset Conduct Disorder 
Biological Psychiatry  2008;64(7):599-606.
Previous studies have reported lower basal cortisol levels and reduced cortisol responses to stress in children and adolescents with conduct disorder (CD). It is not known whether these findings are specific to early-onset CD. This study investigated basal and stress-induced cortisol secretion in male participants with early-onset and adolescence-onset forms of CD.
Forty-two participants with early-onset CD, 28 with adolescence-onset CD, and 95 control subjects participated in the study. They collected saliva across the day to assess their cortisol awakening response and diurnal rhythm. Subsequently, salivary cortisol was measured before, during, and after a psychosocial stress procedure designed to elicit frustration. Cardiovascular activity and subjective mood states were also assessed during stress exposure.
There were no group differences in morning cortisol levels or the size of the cortisol awakening response. Basal cortisol levels in the evening and at 11 am during the laboratory visit were higher in both CD subgroups relative to control subjects. In contrast, cortisol and cardiovascular responses to psychosocial stress were reduced in both CD subgroups compared with control subjects. All groups reported similar increases in negative mood states during stress.
Our findings suggest that group differences in cortisol secretion are most pronounced during stress exposure, when participants with CD show cortisol hyporeactivity compared with control subjects. There was no evidence for reduced basal cortisol secretion in participants with CD, but rather increased secretion at specific time points. The results do not support developmentally sensitive differences in cortisol secretion between CD subtypes.
PMCID: PMC2568813  PMID: 18620338
Antisocial behavior; conduct disorder; cortisol; cortisol awakening response; HPA axis; stress reactivity
25.  Cortisol, obesity and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature 
Obesity (Silver Spring, Md.)  2013;21(1):E105-E117.
Circulating cortisol and psychosocial stress may contribute to the pathogenesis of obesity and metabolic syndrome. To evaluate these relationships, we performed a cross-sectional study of 369 overweight and obese subjects and 60 healthy volunteers and reviewed the previous literature.
Overweight and obese subjects had at least two other features of Cushing’s syndrome. They underwent measurements representing cortisol dynamics (24h urine cortisol excretion (UFC), bedtime salivary cortisol, 1 mg dexamethasone suppression test) and metabolic parameters (BMI, blood pressure (BP); fasting serum triglycerides, HDL, insulin, and glucose). Subjects also completed the Perceived Stress Scale (PSS). UFC, salivary cortisol and weight from 60 healthy volunteers were analyzed.
No subject had Cushing’s syndrome. UFC and dexamethasone responses were not associated with BMI or weight. However, salivary cortisol showed a trend to increase as BMI increased (P< 0.0001), and correlated with waist circumference (WC) in men (rs=0.28, P=0.02) and systolic BP in women (rs=0.24, P =0.0008). Post-dexamethasone cortisol levels were weak to moderately correlated with fasting insulin (rs=− 0.31, P=0.01) and HOMA-IR (rs=−0.31, P=0.01) in men and systolic (rs=0.18, P= 0.02) and diastolic BP (rs=0.20, P=0.009) in women. PSS results were higher in obese subjects than controls, but were not associated with cortisol or metabolic parameters. As expected, WC correlated with fasting insulin, HOMA-IR and systolic BP (adjusted for BMI and gender; P < 0.01). Literature showed inconsistent relationships between cortisol and metabolic parameters.
Taken together, these data do not support a strong relationship between systemic cortisol or stress and obesity or metabolic syndrome.
PMCID: PMC3602916  PMID: 23505190
cortisol; metabolic syndrome; insulin resistance; obesity

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