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1.  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
2.  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
3.  Cortisol Awakening Response Is Linked to Disease Course and Progression in Multiple Sclerosis 
PLoS ONE  2013;8(4):e60647.
Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has frequently been reported in multiple sclerosis (MS). So far, HPA axis function in MS has predominantly been studied under pharmacological stimulation which is associated with a series of methodological caveats. Knowledge of circadian cortisol patterns and cortisol awakening response (CAR) is still limited.
A total of 77 MS patients (55 relapsing-remitting MS (RRMS)/22 secondary-progressive MS (SPMS)) as well as 34 healthy control (HC) subjects were enrolled. Diurnal cortisol release was assessed by repeated salivary cortisol sampling. Neurological disability was rated by the Kurtzke’s Expanded Disability Status Scale (EDSS). Depressive symptoms and perceived stress were assessed by self-report measures.
RRMS but not SPMS patients differed in circadian cortisol release from HC subjects. Differences in cortisol release were restricted to CAR. Treated and treatment naïve RRMS patients did not differ in CAR. In a RRMS follow-up cohort (nine months follow-up), RRMS patients with EDSS progression (≥0.5) expressed a significantly greater CAR compared to HC subjects. RRMS patients with a stable EDSS did not differ from HC subjects. Neither depressive symptoms nor perceived stress ratings were associated with CAR in RRMS patients. In a step-wise regression analysis, EDSS at baseline and CAR were predictive of EDSS at follow-up (R2 = 67%) for RRMS patients.
Circadian cortisol release, in particular CAR, shows a course specific pattern with most pronounced release in RRMS. There is also some evidence for greater CAR in RRMS patients with EDSS progression. As a consequence, CAR might be of predictive value in terms of neurological disability in RRMS patients. The possible role of neuroendocrine-immune interactions in MS pathogenesis is further discussed.
PMCID: PMC3628870  PMID: 23613736
4.  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
5.  Fast Left Prefrontal rTMS Acutely Suppresses Analgesic Effects of Perceived Controllability on the Emotional Component of Pain Experience 
Pain  2010;152(1):182-187.
The prefrontal cortex may be a promising target for transcranial magnetic stimulation (TMS) in the management of pain. It is not clear how prefrontal TMS affects pain perception, but previous findings suggest that ventral lateral and medial prefrontal circuits may comprise an important part of a circuit of ‘perceived controllability’ regarding pain, stress and learned helplessness. While the left dorsolateral prefrontal cortex is a common TMS target for treating clinical depression as well as modulating pain, little is known about whether TMS over this area may affect perceived controllability. The present study explored the immediate effects of fast TMS over the left dorsolateral prefrontal cortex on the analgesic effects of perceived pain controllability. Twenty-four healthy volunteers underwent a laboratory pain task designed to manipulate perception of pain controllability. Real TMS, compared to sham, suppressed the analgesic benefits of perceived-control on the emotional dimension of pain, but not the sensory/discriminatory dimension. Findings suggest that, at least acutely, fast TMS over the left dorsolateral prefrontal cortex may interrupt the perceived-controllability effect on the emotional dimension of pain experience. While it is not clear whether this cortical area is directly involved with modulating perceived controllability or whether downstream effects are responsible for the present findings, it appears possible that left dorsolateral prefrontal TMS may produce analgesic effects by acting through a cortical ‘perceived control’ circuit regulating limbic and brainstem areas of the pain circuit.
PMCID: PMC3017430  PMID: 21122992
6.  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
7.  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
8.  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
9.  Comparing Postoperative Pain Experiences of the Adolescent and Adult Athlete After Anterior Cruciate Ligament Surgery 
Journal of Athletic Training  2003;38(2):154-157.
To examine age-related differences in pain, catastrophizing, and affective distress (depression and anxiety) after athletic injury and knee surgery.
Design and Setting:
Participants were assessed with measures of pain intensity, pain-related catastrophizing, depression, and anxiety symptoms at 24 hours after anterior cruciate ligament (ACL) surgery.
Twenty patients (10 adolescents, 10 adults) with an acute complete tear of the ACL.
Pain was assessed by Visual Analog Scale (VAS), catastrophizing with the Pain Catastrophizing Scale (PCS), depressive symptoms with the Beck Depression Inventory (BDI), and anxiety with the state form of the State-Trait Anxiety Inventory (STAI-S).
At 24 hours postsurgery, adolescents reported greater pain, catastrophizing, and anxiety than adults. Ancillary analyses showed that helplessness and rumination were significant contributors to the differences in catastrophizing. Further, an analysis of covariance showed that controlling for the effects of catastrophizing, the adolescent and adult differences in pain scores were reduced to a null effect.
After ACL surgery, athletic adolescents and adults differed significantly in pain, catastrophizing, and anxiety. Catastrophizing seemed to be a particularly strong factor in postoperative pain differences between adolescents and adults, with clinical-management implications. These data indicate the need for continued research into specific pain- and age-related factors during the acute postoperative period for athletes undergoing ACL surgery.
PMCID: PMC164905  PMID: 12937527
catastrophizing; knee surgery
10.  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
11.  Increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of learned helplessness behavior 
Uncontrollable stress can have a profound effect on an organism's ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive learned helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to learned helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET) and 2-deoxy-2[18F]fluoro-D-glucose (18FDG) to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula.
PMCID: PMC3909949  PMID: 24550809
metabolism; whole-brain; imaging; FDG; PET; circuitry; depression; DBS
12.  Salivary alpha-amylase and cortisol responsiveness following electrically stimulated physical stress in bipolar disorder patients 
Bipolar disorder (BP) is often associated with a change in hypothalamus– pituitary–adrenal axis function change due to chronic stress. Salivary α-amylase (sAA) levels increase in response to psychosocial stress and thus function as a marker of sympathoadrenal medullary system activity. However, sAA has been studied less often than salivary cortisol in BP patients.
We measured Profile of Mood States and State-Trait Anxiety Inventory scores, heart rate variability, and salivary cortisol levels during electrical stimulation stress in 25 BP patients and 22 healthy volunteers.
Tension–anxiety, depression–dejection, anger–hostility, fatigue, and confusion scores in BP patients significantly increased compared with those of the healthy controls. In contrast, the vigor scores of BP patients significantly decreased compared with those of the healthy controls. Significant difference in the sAA levels was observed between BP patients and healthy controls. sAA of female patients was significantly higher than that of female healthy controls, and sAA in male patients tended to be higher than that of male healthy controls. No difference in salivary cortisol was observed between BP patients and the healthy controls. Only three time points were measured before and after the electrical stimulation stress. Furthermore, sAA secretion by BP patients increased before and after electrical stimulation.
These preliminary results suggest that sAA may be a useful biological marker for BP patients.
PMCID: PMC3862394  PMID: 24353422
HPA axis; bipolar disorder; α-amylase; cortisol; SAM activity
13.  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
14.  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
15.  Effect of snack eating on sensitive salivary stress markers cortisol and chromogranin A 
To investigate the effect of snack eating on salivary cortisol and chromogranin A (CgA).
From 14∶00 to 18∶00, starting two hours after consumption of a midday meal, saliva samples were collected every 30 minutes from 15 healthy males, 7 of whom (snack group) ate a snack immediately after the sampling at 15∶00. Salivary cortisol and CgA levels were determined by ELISA. Samples were controlled according to salivary flow rates.
For the snack group, after snack consumption, salivary cortisol increased to exceed significance (p<0.05) at 15∶30 and rose even higher at 16∶00. In the control group, there was no such change. There was no significant change in salivary CgA in either the snack group or the control groups during the sampling period.
These findings suggest that no food should be consumed for at least 90 mins before saliva sampling for cortisol determination and that salivary CgA is probably not affected by snack eating.
PMCID: PMC2723385  PMID: 21432335
cortisol; chromogranin A (CgA); stress marker; human saliva; snack eating
16.  Negative learning bias is associated with risk aversion in a genetic animal model of depression 
The lateral habenula (LHb) is activated by aversive stimuli and the omission of reward, inhibited by rewarding stimuli and is hyperactive in helpless rats—an animal model of depression. Here we test the hypothesis that congenital learned helpless (cLH) rats are more sensitive to decreases in reward size and/or less sensitive to increases in reward than wild-type (WT) control rats. Consistent with the hypothesis, we found that cLH rats were slower to switch preference between two responses after a small upshift in reward size on one of the responses but faster to switch their preference after a small downshift in reward size. cLH rats were also more risk-averse than WT rats—they chose a response delivering a constant amount of reward (“safe” response) more often than a response delivering a variable amount of reward (“risky” response) compared to WT rats. Interestingly, the level of bias toward negative events was associated with the rat's level of risk aversion when compared across individual rats. cLH rats also showed impaired appetitive Pavlovian conditioning but more accurate responding in a two-choice sensory discrimination task. These results are consistent with a negative learning bias and risk aversion in cLH rats, suggesting abnormal processing of rewarding and aversive events in the LHb of cLH rats.
PMCID: PMC3893716  PMID: 24474914
lateral habenula; reinforcement learning; depression; helplessness; cLH; risk aversion; reward; behavior
Biological psychiatry  2008;64(6):521-526.
As observed in depressed adults, there is considerable variability in the degree and direction of hypothalamic-pituitary-adrenal (HPA) dysfunction in depressed adolescents. The variability in HPA findings may be attributed to experiential factors.
A modified version of a standard psychosocial stressor used in adults, the Trier Social Stress Test (TSST), was administered to 30 adolescents with major depressive disorder and 25 healthy adolescent volunteers. Cortisol concentrations were measured in saliva samples collected before and after the stressor. Information also was gathered on early and recent adverse experiences with standard interviews.
Participants from both groups had increased cortisol secretion in response to TSST. Compared with controls, depressed subjects showed more elevated and prolonged cortisol secretion in response to TSST. The combination of early-life adversity and high levels of chronic stress during adolescence was the most powerful predictor of enhanced adrenal response to the TSST.
These results support previous findings on the role of experiential factors on HPA response to stress and in the development of mood disorders. Dissection of the heterogeneous pathophysiology of adolescent depression will assist in developing more specific interventions for different subgroups of patients.
PMCID: PMC2559463  PMID: 18597740
adolescent; depression; early adversity; hypothalamic-pituitary-adrenal axis; psychosocial; stress
18.  Hypothalamic-pituitary-gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism 
Annals of the Rheumatic Diseases  2004;63(11):1504-1506.
Methods: Follicle stimulating hormone (FSH), luteinising hormone (LH), oestradiol, progesterone, prolactin, and cortisol concentrations in 63 women with FM were compared with those in 38 matched healthy controls; all subjects aged <35 years. The depression rate was assessed by the Beck Depression Inventory (BDI) and patients with high and low BDI scores were compared. Additionally, patients were divided according to sleep disturbance and fatigue and compared both with healthy controls and within the group.
Results: No significant differences in FSH, LH, oestradiol, prolactin, and progesterone levels were found between patients with FM and controls, but cortisol levels were significantly lower in patients than in controls (p<0.05). Cortisol levels in patients with high BDI scores, fatigue, and sleep disturbance were significantly lower than in controls (p<0.05). Correlation between cortisol levels and number of tender points in all patients was significant (r = –0.32, p<0.05).
Conclusion: Despite low cortisol concentrations in young women with FM, there is no abnormality in HPG axis hormones. Because fatigue, depression rate, sleep disturbance, and mean age of patients affect cortisol levels, these variables should be taken into account in future investigations.
PMCID: PMC1754816  PMID: 15479904
19.  Cortisol elimination from plasma in premenopausal women with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2003;62(7):674-676.
Methods: Twelve premenopausal female patients with RA (39.8 (1.8) years) and nine healthy control women matched for age and body mass index (42 (3.3) years) were enrolled in the study. None of the patients had previously been receiving treatment with glucocorticoids. After dexamethasone suppression (2 mg by mouth) the evening before the study, 20 mg of hydrocortisone was given. Blood and saliva samples were drawn six hours after injection of hydrocortisone. Plasma and salivary cortisol were measured.
Results: Dexamethasone administration suppressed plasma cortisol concentrations to an almost undetectable level in all subjects, except one with RA. In this subject, a raised concentration of plasma cortisol was verified by repeated analysis despite the fact that cortisol concentration in the saliva sample measured simultaneously was not raised. No significant difference in the disappearance curve of cortisol in plasma or in salivary cortisol levels was found between the patients with RA and the healthy controls.
Conclusions: The profile of disappearance of total cortisol from plasma, and salivary cortisol levels during the elimination phase after its intravenous administration, are unchanged in premenopausal women with RA. Alterations in cortisol clearance are not likely to have a role in cortisol availability in patients with RA.
PMCID: PMC1754603  PMID: 12810434
20.  Depression and Anxiety Correlate Differently with Salivary Free Cortisol in the Morning in Patients with Functional Somatic Syndrome 
Patients presenting with functional somatic syndrome (FSS) are common, and the symptoms are persistent and difficult to treat for doctors and costly for society. The aim of this study was to clarify the common pathophysiology of FSS, especially the relationship between hypothalamic-pituitary-adrenal (HPA) axis function and psychological characteristics of patients with FSS. The subjects were 45 patients with FSS and 29 healthy controls. Salivary free cortisol was measured in the morning, and psychological tests examining depression, anxiety and quality of life (QOL) were performed on the same day. In patients with FSS, depressive scores showed a significant negative correlation with salivary free cortisol in the morning, although in healthy controls, cortisol showed a significant positive correlation with depressive scores. In addition, the correlation between other psychological test scores and cortisol secretion in patients with FSS contrasted with that of controls. The relationship between cortisol and depression, anxiety or QOL, suggests that the HPA axis of patients with FSS is dysfunctional and does not function properly when patients with FSS are under stress. This dysfunction may explain the pathology of medically unexplained persistent symptoms of patients with FSS.
PMCID: PMC2782128  PMID: 19662526
Functional somatic syndrome (FSS); Salivary free cortisol; Hypothalamic-pituitary-adrenal (HPA) axis; Depression; Anxiety
21.  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
22.  Morning Cortisol Levels Affected by Sex and Pubertal Status in Children and Young Adults 
Objective: Morning cortisol levels are frequently used as screening tests for adrenal insufficiency in both adults and children. Reports differ on the specificity of this measurement. The present study was undertaken to determine whether sex or pubertal status affected morning cortisol values.
Methods: We measured morning cortisol levels and performed low-dose adrenocorticotropic hormone stimulation test in 35 healthy male and female subjects (ages 6-34) ranging in Tanner stage (TS) from TS 1 to TS 5. Testing was initiated at 08:00 after an overnight fast. Morning serum total cortisol, free cortisol, cortisol-binding globulin, estradiol (males and females), and testosterone (males) were obtained.
Results: Morning total and free cortisol levels were significantly higher in TS 5 participants than in prepubertal children. Using a morning cortisol of 248 nmol/L todefine a normal value, 19/21(90%) of healthy TS 5 subjects exhibit normal values. In contrast, 0/8 TS 1 healthy subjects exhibited a value greater than 248 nmol/L (p=0.0005). We also observed sex differences in morning cortisol levels in pubertal but not in prepubertal subjects. We observed sex differences in morning cortisol levels in TS 5 individuals.
Conclusions: Morning cortisol measurements may be more useful as screening tests for adrenal function in adults than in children. TS and sex may be considered in the decision to screen for adrenal insufficiency using morning cortisol or whether to proceed directly to stimulation testing.
Conflict of interest:None declared.
PMCID: PMC3701927  PMID: 23748059
Morning cortisol; diurnal rhythm; adrenal insufficiency screening
23.  Recent depressive and anxious symptoms predict cortisol responses to stress in men 
Psychoneuroendocrinology  2009;34(7):10.1016/j.psyneuen.2009.02.005.
Individuals with major depressive disorder show blunted cortisol responses to psychosocial stressors, but the extent to which this pattern of dampened responding characterizes individuals experiencing sub-clinical levels of depressive symptoms is unknown. This study investigated whether self-reports of depressive and anxious symptoms over the previous two weeks were associated with cortisol responses to a laboratory social stress task. In addition, we tested whether these associations were mediated by baseline cortisol, subjective responses to the task, or health behaviors. Healthy adults (N = 76) completed the Mood and Anxiety Symptom Questionnaire prior to engaging in the Trier Social Stress Task. Salivary cortisol was measured at 8 points before and after the task to assess cortisol responding. Linear regressions revealed that men reporting more distress and somatic symptoms had smaller cortisol responses, but anhedonic symptoms were not related to cortisol. Distress was associated with lower baseline cortisol, which in turn statistically mediated the relationship between distress and cortisol response. These results demonstrate that the recent experience of depressive and anxious symptoms is associated with smaller cortisol responses to a psychosocial stressor in a nonclinical population.
PMCID: PMC3845823  PMID: 19272714
cortisol; stress; negative emotion; men; depression; anxiety
24.  Do acute psychological and psychobiological responses to trauma predict subsequent symptom severities of PTSD and depression? 
Psychiatry Research  2008;161(1):67-75.
The study investigated the relationship between the acute psychological and psychobiological trauma response and the subsequent development of posttraumatic stress disorder (PTSD) and depressive symptoms in 53 accident survivors attending an emergency department. Lower levels of salivary cortisol measured in the emergency room predicted greater symptom levels of PTSD and depression 6 months later, and lower diastolic blood pressure, past emotional problems, greater dissociation and data-driven processing predicted greater PTSD symptoms. Heart rate was not predictive. Low cortisol levels correlated with data-driven processing during the accident, and, in female participants only, with prior trauma and prior emotional problems. Higher evening cortisol 6 months after the accident correlated with PTSD and depressive symptoms at 6 months, but this relationship was no longer significant when levels of pain were controlled. The results support the role of the acute response to trauma in the development and maintenance of PTSD and provide promising preliminary evidence for a meaningful relationship between psychobiological and psychological factors in the acute trauma phase.
PMCID: PMC2943071  PMID: 18789538
Cortisol; Cardiovascular arousal; Cognitive processing; Posttraumatic stress disorder; Depression; Predictors
25.  Cortisol and hypothalamic–pituitary–gonadal axis hormones in follicular-phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones 
Arthritis Research & Therapy  2004;6(3):R232-R238.
We investigated abnormalities of the hypothalamic–pituitary–gonadal axis and cortisol concentrations in women with fibromyalgia and chronic fatigue syndrome (CFS) who were in the follicular phase of their menstrual cycle, and whether their scores for depressive symptoms were related to levels of these hormones. A total of 176 subjects participated – 46 healthy volunteers, 68 patients with fibromyalgia, and 62 patients with CFS. We examined concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, prolactin, and cortisol. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Cortisol levels were significantly lower in patients with fibromyalgia or CFS than in healthy controls (P < 0.05); there were no significant differences in other hormone levels between the three groups.
Fibromyalgia patients with high BDI scores had significantly lower cortisol levels than controls (P < 0.05), and so did CFS patients, regardless of their BDI scores (P < 0.05). Among patients without depressive symptoms, cortisol levels were lower in CFS than in fibromyalgia (P < 0.05). Our study suggests that in spite of low morning cortisol concentrations, the only abnormalities in hypothalamic–pituitary–gonadal axis hormones among follicular-phase women with fibromyalgia or CFS are those of LH levels in fibromyalgia patients with a low BDI score. Depression may lower cortisol and LH levels, or, alternatively, low morning cortisol may be a biological factor that contributes to depressive symptoms in fibromyalgia. These parameters therefore must be taken into account in future investigations.
PMCID: PMC416440  PMID: 15142269
chronic fatigue syndrome; cortisol; depression; fibromyalgia; hypothalamic–pituitary–gonadal axis

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