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The cortisol awakening response: More than a measure of HPA axis function
Abstract
In most healthy people morning awakening is associated with a burst of cortisol secretion: the cortisol awakening response (CAR). It is argued that the CAR is subject to a range physiological regulatory influences that facilitate this rapid increase in cortisol secretion. Evidence is presented for reduced adrenal sensitivity to rising levels of ACTH in the pre-awakening period, mediated by an extra-pituitary pathway to the adrenal from the suprachiasmatic nucleus (SCN). A role for the hippocampus in this pre-awakening regulation of cortisol secretion is considered. Attainment of consciousness is associated with 'flip-flop' switching of regional brain activation, which, it is argued, initiates a combination of processes: (1) activation of the hypothalamic pituitary adrenal (HPA) axis; (2) release of pre-awakening reduced adrenal sensitivity to ACTH; (3) increased post-awakening adrenal sensitivity to ACTH in response to light, mediated by a SCN extra-pituitary pathway. An association between the CAR and the ending of sleep inertia is discussed.
... This pattern can be assessed through various biospecimens, including saliva, blood, and urine. Salivary cortisol is commonly used due to its non-invasive nature and its ability to reflect biologically active free cortisol levels [9]. Blood cortisol measurements provide total cortisol concentrations, encompassing both free and protein-bound fractions, whereas urinary cortisol offers an Figure 1. ...
... This pattern can be assessed through various biospecimens, including saliva, blood, and urine. Salivary cortisol is commonly used due to its non-invasive nature and its ability to reflect biologically active free cortisol levels [9]. Blood cortisol measurements provide total cortisol concentrations, encompassing both free and protein-bound fractions, whereas urinary cortisol offers an integrated measure of cortisol excretion over 24 h [4]. ...
... This mechanism ensures that cortisol secretion remains synchronized with the light-dark cycle. However, disruptions in the SCN or misalignment with external cues can impair this delicate balance, leading to dysregulation of cortisol rhythms [9,11] (Figure 3). ...
The circadian rhythm of cortisol, a key hormone essential for maintaining metabolic balance and stress homeostasis, is profoundly disrupted by night-shift work. This narrative review examines the physiological mechanisms underlying cortisol regulation, the effects of shift work on its circadian rhythm, the associated health risks, and potential mitigation strategies. Night-shift work alters the natural secretion pattern of cortisol, leading to dysregulation of the hypothalamic–pituitary–adrenal axis, which in turn can contribute to metabolic disorders, cardiovascular diseases, and impaired cognitive function. Understanding the physiological pathways mediating these changes is crucial for developing targeted interventions to mitigate the adverse effects of circadian misalignment. Potential strategies, such as controlled light exposure, strategic napping, and personalized scheduling, may help to stabilize cortisol rhythms and improve health outcomes. This review aims to provide insights that can guide future research and inform occupational health policies for night-shift workers by addressing these challenges.
... Despite their impressive performance, these sensors encounter challenges when applied to cortisol detection from sweat, such as issues related to stability, accuracy, reproducibility, and surface biofouling in body fluid [1]. Moreover, antibody-based sensors typically necessitate additional external reagents, stringent storage, and complex fabrication steps, making continuous monitoring over extended periods difficult [2,18]. Additionally, these sensors require harsh operating environments and must be equipped with specific instruments, hindering their suitability as wireless, wearable, and battery-free sensors [11]. ...
... Additionally, these sensors require harsh operating environments and must be equipped with specific instruments, hindering their suitability as wireless, wearable, and battery-free sensors [11]. In contrast, aptasensors, utilizing artificial antibodies, have demonstrated high sensitivity, low detection limits, selectivity, and successful detection of cortisol from human sweat [2,19]. Attempts have been made to develop aptamer-based sensors for real-time wireless monitoring of cortisol levels using smartwatches, demonstrating the promise of such wearable cortisol sensors in applications within human healthcare [2]. ...
... Attempts have been made to develop aptamer-based sensors for real-time wireless monitoring of cortisol levels using smartwatches, demonstrating the promise of such wearable cortisol sensors in applications within human healthcare [2]. However, aptasensors face challenges such as high costs, the need for expert skills, complex fabrication procedures, and strict storage conditions due to antibody instability [2,16]. Moreover, the requirement for identifying deoxyribonucleic acid (DNA) sequences has impeded practical applications and mass production. ...
The significant impact of stress on health necessitates accurate assessment methods, where traditional questionnaires lack reliability and objectivity. Current advancements like wearables with electrocardiogram (ECG) and galvanic skin response (GSR) sensors face accuracy and artifact challenges. Molecular biosensors detecting cortisol, a critical stress hormone, present a promising solution. However, existing cortisol assays, requiring saliva, urine, or blood, are complex, expensive, and unsuitable for continuous monitoring. Our study introduces a passive, molecularly imprinted polymer-radio-frequency (MIP-RF) wearable sensing system for real-time, non-invasive sweat cortisol assessment. This system is wireless, flexible, battery-free, reusable, environmentally stable, and designed for long-term monitoring, using an inductance-capacitance transducer. The transducer translates cortisol concentrations into resonant frequency shifts with high sensitivity (~ 160 kHz/(log (μM))) across a physiological range of 0.025–1 μM. Integrated with near-field communication (NFC) for wireless and battery-free operation, and three-dimensional (3D)-printed microfluidic channel for in-situ sweat collection, it enables daily activity cortisol level tracking. Validation of cortisol circadian rhythm through morning and evening measurements demonstrates its effectiveness in tracking and monitoring sweat cortisol levels. A 28-day stability test and the use of cost-effective 3D nanomaterials printing enhance its economic viability and reusability. This innovation paves the way for a new era in realistic, on-demand health monitoring outside the laboratory, leveraging wearable technology for molecular stress biomarker detection.
... Meanwhile, cortisol secretion also follows a circadian rhythm [15]; cortisol levels in serum and saliva robustly increase and reach a circadian peak within the first hour after morning awakening from nocturnal sleep in men and women of all ages [16,17]. this phenomenon is called the cortisol awakening response (caR), resulting from the suprachiasmatic nucleus (scN)-mediated activation of the hypothalamic-pituitary-adrenal (hPa) axis [18,19]. the levels and patterns of cortisol secretion in the caR are confounded by various types of perceived physical, psychological, and upcoming anticipatory stress and are nowadays used as a biomarker for the function of the hPa axis [18]. ...
... this phenomenon is called the cortisol awakening response (caR), resulting from the suprachiasmatic nucleus (scN)-mediated activation of the hypothalamic-pituitary-adrenal (hPa) axis [18,19]. the levels and patterns of cortisol secretion in the caR are confounded by various types of perceived physical, psychological, and upcoming anticipatory stress and are nowadays used as a biomarker for the function of the hPa axis [18]. ...
... the circadian signal generated in the scN is transmitted to the adrenal gland via sympathetic outflow, which increases adrenal responsivity to acth [43]. Based on the similar organization of scN-related neural pathways between rodents and humans [40], it has been suggested that the scN-mediated activation of the neuroendocrine pathway, which stimulates acth secretion and the sympathetic nervous system that modulates adrenal sensitivity for acth, is involved in the initiation of the caR [18,44]. Meanwhile, the majority of gonadotropin-releasing hormone neurons contacted by scN efferent neurons are located in the preoptic area in rodents [45][46][47], and the scN coordinates the timing of the gonadotropin-releasing and luteinizing hormone secretion via a rhythmic release of ViP and aVP [48]. ...
Background
The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CAR) in the hypothalamic–pituitary–adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men.
Methods
Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males’ Symptoms (AMS) questionnaire were obtained from 225 healthy adult men.
Results
A typical CAR (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CAR). In the subgroup exhibiting CAR, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15–17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CAR (n = 70).
Conclusions
The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CAR may be useful for assessing HPG axis function and LOH.
... Upon awakening from night sleep, cortisol, the major glucocorticoid stress hormone in humans, exhibits a burst typically by 50-160 % within thirty to forty-five minutesthat is known as the cortisol awakening response (CAR) (Clow et al., 2010;Pruessner et al., 1997). Since its first discovery, the CAR, a hallmark of the hypothalamus-pituitary-adrenal (HPA) axis activity as well as a crucial point of reference within the healthy cortisol circadian rhythm, is thought to prepare the body for anticipated challenges of the upcoming day (Adam et al., 2006;Elder et al., 2014;Fries et al., 2009;Law et al., 2013). ...
... Specifically, the CAR consists of a superimposed response (reflected by a burst effect of cortisol increase) to awakening, which is not a mere continuation of pre-awakening cortisol increase (Wilhelm et al., 2007). It is regulated by multiple neuroendocrine and psychological processes, including i) rapid attainment of consciousness followed by slow re-establishment of one's full alertness (Clow et al., 2010), ii) activation of hippocampal-dependent prospective memory representations for upcoming stress (Fries et al., 2009), and iii) an interplay with concurrent catecholaminergic activation when facing demanding tasks (Arnsten, 2009). Moreover, findings from previous studies point to a critical role of hippocampal and/or prefrontal involvement in regulating CAR. ...
... S1 to S4 represent the measurements of 4 samples collected within 1 hour immediately after awakening. The AUCi reflects the dynamics of the cortisol awakening response and emphasizes diurnal changes over time (Clow et al., 2010;Pruessner et al., 2003). ...
Emotion and cognition involve an intricate crosstalk of neural and endocrine systems that support allostatic processes for maintenance of dynamic equilibrium and rapid adaptation for upcoming challenges. As a hallmark of human endocrine activity, the cortisol awakening response (CAR) is recognized to play a critical role in modulating emotional and executive functions. Yet, the underlying mechanisms of such effects remain elusive. By leveraging pharmacological neuroimaging technique and Hidden Markov Modeling of brain state dynamics, we show that the CAR proactively modulates rapid reconfigurations (state) of large-scale brain networks across multi-task demands. Behaviorally, suppression of CAR proactively and selectively impaired accuracy for emotional discrimination task but not for working memory (WM). In parallel, suppressed CAR led to a decrease in the occurrence rate of brain state dominant to emotional processing, but an increase in brain state linking to executive control under high WM demand. Further energy-based analyses revealed an increase in transition frequency and sequence complexity along with an increased entropy during emotional tasks when suppressed CAR, suggesting a decreased energy supply. Moreover, an increased transition frequency was observed when shifting from neutral to emotional conditions, but an opposite pattern during WM task, with n decreased transition frequency shifts from low to high-executive demands. Our findings establish a causal link between CAR and dynamic allocation of neural resources for emotional and executive functions, suggesting a cognitive neuroendocrine account for CAR-mediated proactive effects and human allostasis.
... Early-morning light exposure has been observed to influence the hormone cortisol and the cortisol awakening response (CAR), a typical rise in cortisol levels upon awakening [40][41][42]. Cortisol in turn, the CAR in particular, is believed to play a role in regaining alertness in the morning [43]. However, sex differences in cortisol reactivity have been observed, likely influenced by sex hormones such as estradiol [44]. ...
... Similarly, time of day of light exposure is of interested to compare (see e.g., [57]). Biological measures known to correlate with or influence alertness, such as caffeine intake, cortisol, or melatonin (see e.g., [19,43,58,59]), might also provide further insight into potential mediating or modulating factors in the relationship between light exposure and alertness. ...
Introduction:
Light is a key factor in moderating human alertness, both subjective and objective. However, the methodology applies in research on the effects of exposure to light of different wavelengths and intensities on objective and subjective alertness varies greatly and evidence on objective alertness in particular is still inconclusive. Thus, the present, highly standardized within-subject laboratory study on N = 44 healthy males explored how LED light of different intensities (dim vs. bright light) and wavelengths (red vs. blue) affected objective (reaction time/RT) as well as subjective (sleepiness) alertness in the morning after wake-up.
Methods:
Participants spent two separate nights in the laboratory and were exposed to either one of the two light intensities or colors for 60 min after wake-up. Additionally, they indicated their sleepiness on the Karolinska Sleepiness Scale and participated in an auditory RT task before and after light intervention. It was hypothesized that both bright and blue light would lead to greater subjective and objective alertness when compared to dim and red light, respectively.
Results:
Results indicated that average RTs were longer for participants in the bright light condition (p = 0.004, f2 = 0.07) and that RTs decreased post-light exposure irrespective of light being dim or bright (p = 0.026, f2 = 0.07). However, dim versus bright light and RT did not interact (p = 0.758, f2 = 0.07). Chronotype was a significant covariate in the interaction of dim versus bright light and subjective sleepiness (p = 0.008, f2 = 0.22). There was no difference in RTs when comparing exposure to red or blue light (p = 0.488, f2 = 0.01). Findings on subjective sleepiness and light of different wavelengths revealed that sleepiness was reduced after light exposure (p = 0.007, f2 = 0.06), although the wavelength of light did not appear to play a role in this effect (p = 0.817, f2 = 0.06).
Conclusion:
Hence, neither of the hypotheses could be confirmed. However, they indicated that evening types might benefit from exposure to bright light regarding sleepiness, but not morning types.
... In addition, MDD is characterized by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which controls the body's stress response [17]. Prolonged stress has the potential to induce hyperactivity of the HPA axis, leading to increased cortisol secretion [18]. This, in turn, could potentially exacerbate hippocampal atrophy, hinder neurogenesis, and cause disturbances in neurotransmitter functionality. ...
... The results of ROC curve analysis of serum MIP-1β and MCP-2 levels as potential diagnostic biomarkers for MDD are presented in Table 4 and Fig 2. The optimal cut-off value for discriminating between MDD patients and HCs was determined to be 63. 18 ...
Background
Major depressive disorder (MDD) is a common and debilitating mental illness characterized by persistent feelings of sadness, hopelessness, and a lack of interest in daily activities. The objective of this study was to investigate whether levels of macrophage inflammatory protein-1β (MIP-1β) and macrophage chemoattractant protein-2 (MCP-2) in the blood were associated with the pathophysiology and development of MDD compared to healthy controls (HCs).
Methods
This case-control study was conducted involving 50 MDD patients and 38 HCs. We performed a comprehensive assessment to match age, sex, BMI, and socio-demographic profile between the groups. The study excluded participants with chronic infection, inflammatory diseases, coexisting psychiatric disorder, history of liver and kidney diseases, and individuals who are under antipsychotic medications. A professional psychiatrist diagnosed MDD patients and evaluated HCs based on the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria. The severity of depression was assessed using the Hamilton Depression (Ham-D) rating scale. Commercially available enzyme-linked immunosorbent assay (ELISA) kits were used to quantify the serum MIP-1β and MCP-2 levels.
Results
The results indicated elevated serum MIP-1β levels (207.73±24.24 pg/ml) in MDD patients compared to HCs (58.77±9.14 pg/ml). This difference in concentration is positively correlated with severity of disease symptoms (r = 0.451; p<0.001). Similarly, the levels of MCP-2 were found to be elevated in patients compared to controls (143.61±19.92 vs. 56.84±4.02 pg/ml; p = 0.003), with a positive correlation with the Ham-D scores (r = 0.373; p = 0.004).
Conclusion
According to this study, elevated levels of MIP-1β and MCP-2 may be associated with the pathophysiology and development of MDD. These increased serum MIP-1β and MCP-2 levels could be used as risk assessment tools for MDD. The present findings urge further research and the development of therapeutic and diagnostic approaches for depression.
... 14 The CAR indicates the reactivity of the HPA axis to natural challenges in the awakening process, and it has been studied and used as a biomarker of the function of the HPA axis in recent years. [15][16][17] The CAR also has value as a diagnostic biomarker in that it reflects unified stress and time conditions. 15 Considering CAR in the context of depression, studies have shown heterogeneous activity, with hypoactivity in the severe depression group and hyperactivity in the acute and mild-to-moderate depression groups, creating an inverted U-shape. ...
... [15][16][17] The CAR also has value as a diagnostic biomarker in that it reflects unified stress and time conditions. 15 Considering CAR in the context of depression, studies have shown heterogeneous activity, with hypoactivity in the severe depression group and hyperactivity in the acute and mild-to-moderate depression groups, creating an inverted U-shape. 18 Another study showed that patients with low CAR had a chronic, unfavorable course of depression. ...
Objective This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity.Methods Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic–pituitary–adrenal (HPA) axis.Results Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with “adrenal exhaustion stage” was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034).Conclusion This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.
... Convincing evidence for an influence of amygdala, hippocampus, and mPFC on HPA axis stress responses has been found in animal as well as human studies [2][3][4] . Moreover, while the regulation of the CAR was shown to be modulated by prelimbic regions 33,64 and associations between the CAR and chronic stress have been found 34 , it was mainly reported to be unrelated to cortisol reactivity to experimentally-induced psychological stress 65 . This is in line with the assumption that the CAR is modulated by additional regulatory mechanisms, for instance a direct influence of the adrenal cortex by the suprachiasmatic nucleus 33 . ...
... Moreover, while the regulation of the CAR was shown to be modulated by prelimbic regions 33,64 and associations between the CAR and chronic stress have been found 34 , it was mainly reported to be unrelated to cortisol reactivity to experimentally-induced psychological stress 65 . This is in line with the assumption that the CAR is modulated by additional regulatory mechanisms, for instance a direct influence of the adrenal cortex by the suprachiasmatic nucleus 33 . This and perhaps other mechanisms may partly explain why on the one hand academic stress in our study affected the CAR, and why on the other hand, this alteration was not associated with activation changes in our limbic ROIs. ...
The importance of amygdala, hippocampus, and medial prefrontal cortex (mPFC) for the integration of neural, endocrine, and affective stress processing was shown in healthy participants and patients with stress-related disorders. The present manuscript which reports on one study-arm of the LawSTRESS project, aimed at investigating the predictive value of acute stress responses in these regions for biopsychological consequences of chronic stress in daily life. The LawSTRESS project examined law students either in preparation for their first state examination (stress group [SG]) or in the mid-phase of their study program (control group [CG]) over 13 months. Ambulatory assessments comprising perceived stress measurements and the cortisol awakening response (CAR) were administered on six sampling points (t1 = − 1 year, t2 = − 3 months, t3 = − 1 week, t4 = exam, t5 = + 1 week, t6 = + 1 month). In a subsample of 124 participants (SG: 61; CG: 63), ScanSTRESS was applied at baseline. In the SG but not in the CG, amygdala, hippocampus, and (post-hoc analyzed) right mPFC activation changes during ScanSTRESS were significantly associated with the trajectory of perceived stress but not with the CAR. Consistent with our finding in the total LawSTRESS sample, a significant increase in perceived stress and a blunted CAR over time could be detected in the SG only. Our findings suggest that more pronounced activation decreases of amygdala, hippocampus, and mPFC in response to acute psychosocial stress at baseline were related to a more pronounced increase of stress in daily life over the following year.
... This response is characterized by a rapid increase in cortisol levels within the first 30-45 min after waking. In healthy individuals, this rise can range from 38% to 75%, with an average increase of about 50% [24]. The CAR is superimposed on the natural circadian rhythm of cortisol secretion, which typically peaks in the early morning hours before awakening and declines throughout the day. ...
Background/Objectives: Suicidal behaviors (SBs) and non-suicidal self-injury (NSSI) are significant mental health concerns in children and adolescents. The hypothalamic–pituitary–adrenal (HPA) axis, of which cortisol is a key hormone, has been implicated in these behaviors. This narrative review aims to explore whether cortisol levels play a role in SBs and NSSI in youth and to synthesize current evidence on this topic. Methods: A comprehensive literature search was conducted on studies published through November 2024, using PubMed, Web of Science, and Google Scholar databases. Studies were screened for eligibility, including only human studies published in English, with no animal models or studies excluding cortisol levels. A narrative synthesis approach was used due to the methodological diversity across studies. Due to limited adolescent-focused research, studies involving adults were also considered. Results: Findings indicate inconsistent cortisol patterns in relation to SBs and NSSI. Elevated cortisol levels are linked to SBs, with some studies suggesting they may predict future suicide attempts, though no definitive cause-and-effect relationship is established. Conversely, cortisol levels in relation to NSSI show mixed results, with some studies reporting no differences. Cortisol responses to stress, measured by saliva, blood, and hair, reveal complex interactions with psychological factors such as depression and impulsivity, influencing cortisol secretion. Discussion: Despite some evidence pointing to a role of cortisol dysregulation in SBs and NSSI, the relationship remains unclear due to study heterogeneity, including small sample sizes and methodological variations. Gender and the type of stressor used in studies also complicate the findings. Future research should prioritize longitudinal studies, better control for confounding factors, and utilize more diverse cortisol assessment methods to clarify these links. Conclusions: While cortisol may play a role in the pathophysiology of SBs and NSSI, further research is needed to establish clearer, more reliable patterns. Identifying alterations in cortisol levels may aid in early detection and targeted interventions for at-risk adolescents.
... Each individual had saliva samples collected on three days; here, we analyzed samples from two of these days chosen randomly. We aim to use these response data to record changes in the proteome profile related to the awakening response, which is thought to involve comprehensive molecular biological processes in the human body [5]. An overview of the collection and the structure of our data is given in Fig. 1a. ...
Understanding dynamics and co-regulatory patterns in the human proteome is a promising path for unraveling the molecular basis of health and disease. Nevertheless, there remains an open challenge in extracting concise information from high-throughput proteomic data that can effectively characterize and predict health. We develop novel statistical and computational pipelines to tackle this problem in a longitudinal saliva proteomics data set collected throughout the awakening response in six healthy controls and six subjects with severe mitochondrial disease (MitoD), a clinical condition caused by genetic mitochondrial defects that affects cellular energy transformation and alters multiple dimensions of health. We undertook three independent unsupervised approaches to characterize proteome dynamics and assessed their ability to separate MitoD individuals from controls. First, we designed a permutation test to detect the global difference in the proteomic co-regulation structure between healthy and unhealthy subjects. Second, we performed non-linear embedding and cluster analysis on elasticity to capture a more complicated relationship between health and the proteome. Third, we developed a machine learning algorithm to extract low-dimensional representations of the proteome dynamic and use them to cluster subjects into healthy and unhealthy groups without any knowledge of their true status. All three methods showed clear differences between MitoD individuals and controls. Our results revealed a significant and consistent association between MitoD status and the saliva proteome at multiple levels during the awakening response, including its dynamic change, co-regulation structure, and elasticity. This connection is not restricted to a few MitoD-specific proteins but spreads over a wide range of proteins from many body functions and pathways. Pipelines such as those shown here are the first step toward establishing interpretable and accurate prediction rules for health based on proteome dynamics.
... It is worth noting, however, that many of the educators self-reported illness at the post-intervention cortisol collection, so this may have impacted their cortisol levels. In comparison with our cortisol findings for students, some research indicates that a lack of improved cortisol may be a normal finding for adults [65][66][67][68][69][70], as noted by Galvan who asserted that "previous work has shown that, under identical stress conditions, teens show greater cortisol release than adults" [71]. Regarding heart rate variability, one potential explanation for this finding is that resting heart rate variability may be more entrained and difficult to change in such a short period of time. ...
(1) Background: Due to the mental health crisis that has spiraled since the onset of COVID-19, particularly among the nation’s youth, the purpose of this study was to examine the efficacy of a novel, school-based mental health intervention for high school students (ages 15–17 years). This project’s main aim was to determine which intervention modality was more effective with students across two school districts with varying degrees of rurality (in-person delivery vs. remote delivery). A secondary aim of this study was to determine the efficacy of a remotely delivered, concurrent intervention for educators across both school districts. This study took place in rural southwestern Montana. (2) Methods: Utilizing a 6-week, trauma-informed yoga intervention, comparisons of mental and physical health outcomes were performed using cohort data drawn from participants’ physiological data and validated mental health survey measures. (3) Results: While physiological results were mixed across experimental groups, mental health outcomes were overwhelmingly positive for all groups. Additionally, educators reported improvements in career satisfaction and burnout levels. (4) Conclusions: Findings indicate a great deal of promise with this intervention in improving mental health outcomes for both students and educators. Moreover, a face-to-face intervention for students showed dramatic improvement in physiological stress indicators.
... During sleep onset, HPA axis activity is suppressed, leading to a reduction in the secretion of ACTH and cortisol. Conversely, upon awakening, HPA axis activity increases, resulting in heightened plasma levels of ACTH and cortisol [23,24]. There is a bidirectional relationship between the HPA axis and insomnia: an activated HPA axis can lead to lighter sleep and more frequent nighttime awakenings, while insomniacs tend to have significantly higher 24 h plasma levels of ACTH and cortisol compared to healthy individuals [25]. ...
Insomnia poses considerable risks to both physical and mental health, leading to cognitive impairment, weakened immune function, metabolic dysfunction, cardiovascular issues, and reduced quality of life. Given the significant global increase in insomnia and the growing scientific evidence connecting gut microbiota to this disorder, targeting gut microbiota as an intervention for insomnia has gained popularity. In this review, we summarize current microbiome-based therapeutics for insomnia, including dietary modifications; probiotic, prebiotic, postbiotic, and synbiotic interventions; and fecal microbiota transplantation. Moreover, we assess the capabilities and weaknesses of these technologies to offer valuable insights for future studies.
... Delays may be due to non-conscientious participant behaviour, or participants not being aware of the exact timing of waking, likely caused by the immediate post awakening period being associated with a reduced state of cognitive and motor performance, resultant from sleep inertia [13]. This may increase the difficulty of accuracy to the saliva sampling protocol, even in the most painstaking and conscientious participants [14,15] These issues are important as even short delays between awakening and the commencement of sampling impact CAR measurement [11,12,16]. ...
Cortisol awakening response (CAR) research relies upon self-collected saliva sampling during the post-awakening period. It is unknown how the CAR protocol is perceived and how they may affect typical routines relevant to CAR methodology. CAR assessment is sensitive to state variables, suggesting that CAR measurement may be affected by research participation. This is the first qualitative study to explore motivation and experiences of participation in CAR research.
Interviews were conducted with a sample of 20 participants (males/females: 4/16) aged 46-82 years following their participation in CAR research in the domestic setting. Responses were transcribed verbatim and thematically analysed.
Participants were motivated to take part in CAR research for altruistic reasons and the apparent convenience of undertaking the study at home. Participants experienced the study as arduous describing apprehension and the cognitive burden it placed on them leading to disruptions to sleep and morning routines. Participants also struggled to identify the moment of awakening and there was uncertainty surrounding the timing of the first awakening sample. Disruptions were lessened with habituation to sampling on repeated study days.
There was apprehension about taking part in CAR research, affecting mood, cognition, and sleep; state variables known to influence the CAR. Findings inform ways to optimise CAR ‘ecological validity’ and obtain typical CAR characteristics. The ‘moment of awakening’, was not universally understood, leading to hesitancy in deciding when to collect saliva samples. Researchers need to include a specific discussion of the commonly experienced ambiguity surrounding awakening to increase awareness, lessen anxiety and highlight its importance.
... It is therefore possible that the overall effect size is even more negative than the non-significant result that was summarized, contrasting the HPA hyperactivity observed in the OAD at discrete timepoints throughout the day. Together, these findings further highlight how the CAR differs from other measures of cortisol in the natural environment, with stronger estimates of heritability and regulated by different brain circuits than daytime cortisol levels [16,82]. The absence of an effect for total daily cortisol output was surprising, as it was expected to parallel the finding for mean cortisol levels assessed at discrete time points. ...
Because the offspring of parents with an affective disorder (OAD) are at high risk for developing mental disorders, and persons with an affective disorder (AD) show dysfunctional hypothalamic–pituitary–adrenal (HPA) axis activity, changes in HPA functioning in OAD might be an etiological risk factor that precedes the development of ADs. The primary aim of the meta-analysis was to quantitatively summarize the existing data on different indices of diurnal cortisol in the OAD. The secondary aim was to explore potential moderators of this relation. Following PRISMA guidelines, we included 26 studies (3052 offspring) on diurnal cortisol in our meta-analysis after an initial screening of 3408 articles. Intercept-only and meta-regression models were computed using the robust variance estimation method. Analyses examining mean cortisol levels at discrete timepoints, total cortisol output, and the cortisol rise in response to awakening (CAR) were conducted separately. The results demonstrated that the OAD had higher mean levels of cortisol at different timepoints throughout the day compared to controls (Hedge’s g = 0.21). There was evidence of publication bias in studies examining CAR, such that effect sizes were positively biased. The present findings are consistent with a meta-analysis showing elevated cortisol in youth having an AD. Notable limitations across studies include the method of cortisol measurement and assessment of ADs. Altogether, these results highlight the fact that increased cortisol levels may act as a potential neuroendocrine antecedent and/or risk factor for the development of ADs among high risk youth.
... The diurnal cortisol slope, which represents the gradual drop in cortisol levels throughout the day, and the cortisol awakening response (CAR), which peaks soon after waking, are the two distinct components of the cortisol production pattern that occurs throughout the day [43][44][45][46]. Since cortisol is essential for the regulation of many biological systems, such as the immunological, inflammatory, and metabolic processes, irregularities in its circadian rhythm can have long-term negative effects on these systems as well as general health [47][48]. ...
... As an alternative to plethysmography an electrocardiogram can provide a more accurate measure of heart rate by directly quantifying cardiac activity (Berntson et al., 1997). Results may also be influenced by diurnal variation in testosterone and cortisol (Brownlee et al., 2005;Clow et al., 2010;Cumming, Quigley and Yen, 1983;Zhang et al., 2017). In order to account for diurnal variation studies often collect samples for hormone assays in either the morning or afternoon, though there are studies with wider data collection windows (e.g., Welker et al., 2014). ...
... Melatonin is a hormone known for its function in inducing sleep and is mainly produced in the pineal gland [19]. Cortisol is a hormone known for its function in response to stress, though it also plays a role in inducing wakefulness, and is produced in the adrenal glands [28]. Under physiological conditions, the body temperature drops, cortisol levels decrease, and melatonin levels increase to induce nocturnal sleep, and vice versa for wakefulness during the day [27]. ...
Alzheimer’s disease (AD) is the most common type of dementia, which is characterised by progressive memory loss and accumulation of hallmark markers amyloid-β (Aβ) and neurofibrillary tangles in the diseased brain. The current gold standard diagnostic methods have limitations of being invasive, costly, and not easily accessible. Thus, there is a need for new avenues, such as imaging the retina for early AD diagnosis. Sleep disruption is symptomatically frequent across preclinical and AD subjects. As circadian activity, such as the sleep-wake cycle, is linked to the retina, analysis of their association may be useful additions for achieving predictive AD diagnosis. In this narrative review, we provide an overview of human retina studies concerning the deposition of Aβ, the role of the retina in sleep-wake cycle, the disruption of sleep in AD, and to gather evidence for the associations between Aβ, the retina, and sleep. Understanding the mechanisms behind the associations between Aβ, retina, and sleep could assist in the interpretation of retinal changes accurately in AD.
... As a result of auricular acupuncture on the shenmen, kidney, liver, lung, and sympathetic areas of participants with major depressive symptoms, salivary cortisol decreased [33], supporting this study. However, cortisol is rapidly secreted approximately once an hour due to an ultra-radian rhythm, and significantly varies depending on individual personality characteristics [34]; thus, it is necessary to control psychological and environmental factors and check for differences in cortisol by shortening the time interval. Further, depressive symptoms decreased by 2.68 points in the experimental group, demonstrating that, when AA was applied only to the shenmen area for two weeks among the elderly living in a nursing home, depressive symptoms scores decreased from 8.71 to 5.35 points [15], supporting this study. ...
Purpose: This study investigated the effects of auricular acupressure on dry eye syndrome, stress, and depressive symptoms in older adults.Methods: This single-blind, randomized controlled trial was conducted among 42 people aged 65 years or older who experienced stress and had an Ocular Surface Disease Index score of 13 or higher. Auricular acupressure using vaccaria seeds was applied to both ears for 3 weeks at several acupoints, including the shenmen, liver, heart, endocrine system, eye, and anterior lobe areas. In the placebo group, blank patches were applied to the hip, lumbar vertebrae, shoulder, and cervical vertebrae points. The measures used were the Dry Eye Syndrome Scale, Perceived Stress Scale, salivary cortisol levels, electrodermal activity measured using a Fitbit device, and a depression scale.Results: Statistically significant differences were found between the groups for dry eye syndrome (t=3.442, p =.002), perceived stress (t=3.455, p =.001), salivary cortisol (z=-3.703, p <.001), and depressive symptoms (t=2.113, p =.043).Conclusion: Auricular acupressure improved in dry eye syndrome, perceived stress, salivary cortisol levels, and depressive symptoms in older adults. Therefore, it can be used as an alternative nursing intervention for dry eye syndrome, stress, and depressive symptoms.
... The association between depression and higher cortisol levels could reflect over-secretion of hormones at various points in the HPA axis or impaired glucocorticoid negative feedback (Hantsoo et al. 2023;Pariante & Lightman 2008). In addition, the diminished rise in CAR but steeper decline in cortisol across the day for women with greater depression could indicate a potential impairment in the circadian cortisol system (Clow et al. 2009;Dedovic & Ngiam 2015). The surge of cortisol reflected in the CAR is thought to prepare the body physiologically to deal with upcoming demands of the day (Smith et al. 2020). ...
Purpose
Women are at high risk of stress, anxiety, and depression during the postpartum but the ways in which these different types of psychological distress are related to cortisol regulation is not clear. We examined the distinct association of each type of distress with women’s average cortisol level, cortisol awakening response (CAR), cortisol decline across the day (diurnal slope), and overall amount of cortisol secretion across the day (AUCG).
Methods
At 6 months postpartum, a diverse group of 58 women completed measures of depression, anxiety, perceived stress, and life stressors. Each woman provided 4 salivary samples for cortisol assay from waking to bedtime on each of 2 consecutive days. Linear regressions were used to examine associations of stress, anxiety and depression to each of the 4 cortisol measures, controlling for number of stressful life events.
Results
Depressive symptoms were associated with less of a rise in the CAR (β = -.46, p = 0.01), steeper diurnal slope (β = .51, p = 0.006), and higher average cortisol level (β = .42, p = .01). Women who met the clinical cutoff for an anxiety disorder had lower overall cortisol output (β = -.29, p = 0.03). Stress was not related to any cortisol metric.
Conclusions
Findings suggest that stress is less associated with cortisol alterations in the postpartum than are more severe types of psychological distress. Anxiety and depression may have distinct and opposite profiles of cortisol dysregulation. Results indicate that mental health assessment is critical even in the later postpartum so that interventions can be initiated to reduce emotional suffering and the risk of impaired cortisol regulation.
... Upon awakening, the cortisol awakening response represents a normal surge in cortisol levels reaching maximal concentrations approximately 30 min after awakening (Pruessner et al., 1997). This surge is typically followed by a gradual diurnal decline in cortisol concentrations throughout the day with the lowest point or 'nadir' usually occurring at bedtime (Clow et al., 2010). A dynamic diurnal HPA-axis, like many other physiological parameters, is considered adaptive. ...
... Our findings may also suggest that confidence in oneself is more related to the average level of cortisol production across the day, reflected by the AUCg, compared with other distinct features of the cortisol diurnal rhythm, such as the CAR and DCS. In fact, the CAR is thought to play a role in regaining arousal upon waking or helping people meet the anticipated demands of their day (Clow et al., 2010) and then does not reflect the frequency and intensity of HPA axis activation during the day (Khoury et al., 2015;Starr et al., 2019). Further, given that the DCS is strictly dependent on the absolute levels of morning and evening cortisol, it may be interesting to disaggregate the relative contribution of morning and evening cortisol levels to DCS for reaching a better understanding of their potential associations with self-efficacy beliefs. ...
In the present ecological study, we analyzed the relations of a set of self-efficacy beliefs at work to parameters of diurnal cortisol variation. Specifically, using data collected during two consecutive working days from 166 workers, we tested a mediation model positing social and work-related self-efficacy beliefs as mediators of the relations between self-regulatory emotional self-efficacy beliefs in managing negative emotions and cortisol indicators. Results from the multilevel mediation analyses supported the proposed model for work-related self-efficacy, which resulted as a significant mediator of the relation between self-regulatory emotional self-efficacy beliefs in managing negative emotions and the overall cortisol daily production indexed by computing the area under the curve with respect to the ground. Findings suggest the importance of self-efficacy beliefs for workers' physiological adjustment. Theoretical and practical contributions of the findings are discussed.
Objective
To examine the psychophysiological effects of an 8-week expressive arts-based intervention (EABI) on young and pre-elderly stroke survivors.
Design
A parallel-group randomized controlled trial.
Setting
Public hospitals and community sites.
Participants
Community-dwelling participants (N=157) aged between 18 and 64 years who experienced a major stroke event in the past 10 years with mild to moderate post-stroke impairments (modified Rankin scale level=1-4).
Interventions
Participants were randomly assigned to an 8-week EABI group (N=75) once per week for 90 minutes or a treatment-as-usual waitlist control group (CG) (N=82).
Main Outcome Measures
Outcomes of psychophysiological functioning, including depression, anxiety, perceived social support, hope, self-esteem, generic and stroke-specific quality of life (QOL), and salivary cortisol, were measured at three assessment waves: baseline (T0), 2 months after baseline (T1), and 8 months after baseline (T2). The short-term (T0-T1) and long-term (T0-T2) effects of the EABI were analyzed by latent change analysis. Mediation analysis was conducted to explore the potential mechanisms of the short-term and long-term EABI effects.
Results
From T0 to T1, the EABI group showed significant improvements in perceived social support, hope, and self-esteem (Cohen d=0.32-0.48) compared with the CG. From T0 to T2, there were significant improvements in anxiety symptoms and self-esteem, physical QOLs, and wake-up cortisol (d=0.34-0.46). Short-term improvements in perceived social support and hope partially mediated the long-term EABI effects on physical QOLs. The beneficial effects of EABI showed heterogeneity across gender and stroke types.
Conclusions
This study found short-term effects for the EABI on perceived social support and hope and long-term effects on self-esteem and physiological functioning. Future research should develop tailored EABI as multifaceted support for rehabilitation practice for stroke survivors.
The hypothalamic‐pituitary‐adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH‐dependent and ACTH‐independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long‐term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary‐adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control. © 2014 American Physiological Society. Compr Physiol 4:739‐769, 2014.
Background
While the underlying mechanisms of agitation are not fully understood in people with Alzheimer's disease and related disorders, research suggests that dysregulated neuroendocrine processes, including the hypothalamic-pituitary-adrenal axis, may play a role.
Objective
This study aimed to explore the associations between salivary cortisol, melatonin at baseline, and agitation both at baseline and at post-intervention.
Methods
This study was a secondary analysis of a two-group, randomized, parallel designed clinical trial of 210 people living with cognitive impairment. Agitation, salivary cortisol, and salivary melatonin were measured at baseline and four weeks. Salivary cortisol and melatonin indicators were generated through three timepoints of cortisol and melatonin collection across the two consecutive days. Presence of agitation was measured using the Neuropsychiatric Inventory. Logistic regressions were conducted to achieve the aim.
Results
A significant association was found at baseline between diurnal cortisol slope and agitation (OR = 0.03, p = 0.029), there were no relationships between all other cortisol or melatonin indicators with agitation. Cortisol awaking response (OR = 0.16, p = 0.048), its percentage (OR = 0.27, p = 0.021) and its increase higher than 50% (OR = 0.09, p = 0.009), were significant with agitation at four weeks.
Conclusions
Given the potential link between cortisol and agitation, exploring cortisol-lowering interventions like minimizing environmental stressors, smoothing transitions to different situations, stress-reduction techniques, and behavioral therapies may aid in managing agitation in older adults with cognitive impairment.
Introduction
Adults with early life adversity (ELA) often exhibit stress system dysregulation and are prone to smoke for stress relief. This study, conducted as part of a larger project examining psychobiological stress responses in smokers, specifically focuses on the a priori research question of how ELA influences the cortisol awakening response (CAR) during acute tobacco withdrawal.
Aims and Methods
Using quasi-experimental design, adult daily (heavy) smokers were randomly assigned to either regular smoking (ad-lib) (N = 37) or 24-hour withdrawal (N = 55), and categorized into low or high ELA. Carbon monoxide levels verified smoking status, and CAR was assessed through salivary cortisol upon awakening and at 30 and 60 post-wakening. CAR was evaluated using mean cortisol levels, peak reactivity, and area under the curve with respect to increase (AUCi) and area under the curve with respect to ground while controlling for possible covariates. Self-reported measures of mood, craving, and withdrawal were also analyzed.
Results
Smoking status X ELA interaction on peak cortisol and AUCi. High ELA ad-lib smokers (versus high ELA withdrawal) had elevated peak and AUCi levels and were higher than low ELA ad-lib smokers with respect to peak (ps < .05). Withdrawal (versus ad-lib smokers) had lower positive affect and higher negative affect, craving, and withdrawal (ps < .05). Adult smokers with a history of ELA exhibit heightened stress response dysregulation, as evidenced by altered CAR, compared to those without ELA or in smoking withdrawal.
Conclusions
These findings demonstrate that ELA significantly exacerbates stress system dysregulation among adult smokers, as evidenced by alterations in the CAR.
Implications
Findings from this study suggest ELA not only leads to an earlier initiation of smoking but also worsens stress system dysregulation in adult smokers. These insights highlight the importance of developing early prevention strategies aimed at adolescents with ELA to prevent smoking initiation and reduce its impact on stress regulation. Additionally, the findings support the need for customized, trauma-informed smoking cessation programs for adults with ELA, emphasizing the necessity to address the distinct challenges related to stress regulation and nicotine withdrawal they face.
Emotion and cognition involve an intricate crosstalk of neural and endocrine systems that support dynamic reallocation of neural resources and optimal adaptation for upcoming challenges, an active process analogous to allostasis. As a hallmark of human endocrine activity, the cortisol awakening response (CAR) is recognized to play a critical role in proactively modulating emotional and executive functions. Yet, the underlying mechanisms of such proactive effects remain elusive. By leveraging pharmacological neuroimaging and hidden Markov modeling of brain state dynamics, we show that the CAR proactively modulates rapid spatiotemporal reconfigurations (state) of large-scale brain networks involved in emotional and executive functions. Behaviorally, suppression of CAR proactively impaired performance of emotional discrimination but not working memory (WM), while individuals with higher CAR exhibited better performance for both emotional and WM tasks. Neuronally, suppression of CAR led to a decrease in fractional occupancy and mean lifetime of task-related brain states dominant to emotional and WM processing. Further information-theoretic analyses on sequence complexity of state transitions revealed that a suppressed or lower CAR led to higher transition complexity among states primarily anchored in visual-sensory and salience networks during emotional task. Conversely, an opposite pattern of transition complexity was observed among states anchored in executive control and visuospatial networks during WM, indicating that CAR distinctly modulates neural resources allocated to emotional and WM processing. Our findings establish a causal link of CAR with brain network dynamics across emotional and executive functions, suggesting a neuroendocrine account for CAR proactive effects on human emotion and cognition.
In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30 to 45 minutes after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental, and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid nongenomic and slower genomic pathways (eg, affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological, and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences.
The current study explored associations between testosterone, cortisol, and both the Levenson Self-Report Psychopathy Scale (LSRPS) and the Inventory of Callous Unemotional (ICU) traits. Data were gathered from a relatively large sample of university students (n = 522) and analyses considered direct and interactive associations between hormones and psychopathic traits, as well as interactions between these associations and the time of day at which samples were gathered and the sex of participants. Baseline cortisol had a negative association with LSRPS primary psychopathy scores. In addition, baseline cortisol interacted with the time of day in association with LSRPS total scores. Simple slopes analyses indicated cortisol had a negative association with LSRPS total scores in the morning but not the afternoon. Interactions among hormone measures were not statistically significant. There was also no evidence for the moderation of associations between hormones and psychopathic traits by sex.
Light is essential in shaping human circadian rhythms, including that of the hormone cortisol. While cortisol is known to influence secretion of the cytokine IL-6, the influence of light itself on IL-6 remains unclear. Thus, this study investigated the effects of two light conditions – red and blue – on IL-6 concentrations and the cortisol awakening response in blood. The interplay between cortisol and IL-6 was explored as well. The between-subject experiment was conducted with 71 healthy adult men (aged Mred = 24.30, SD = 3.56; Mblue = 24.40, SD = 3.51) in a standardized sleep laboratory setting with 60-min light exposure post-awakening at 05:00 a.m. Two mixed models, with light condition and time across measurement points as factors, were calculated. In the one for cortisol, chronotype was introduced as a covariate. Mean cortisol concentrations did not differ between exposure to red vs. blue light (p = 0.443), but overall cortisol output (area under the curve with respect to ground; AUCG) and sensitivity (area under the curve with respect to increase; AUCI) were greater in the blue-light condition (p = 0.050 and p < 0.001, respectively). Additionally, chronotype significantly influenced cortisol concentrations (p = 0.035). As for IL-6, a main effect of time was obtained, with increasing concentrations over time (p = 0.002). Total IL-6 secretion was greater under blue-light exposure (p <. 001), but mean IL-6 concentrations (p = 0.230) and IL-6 sensitivity (p = 0.777) did not differ between the red- and blue-light condition. Mean and total cortisol and IL-6 concentrations were significantly negatively correlated (p = 0.021 and p < 0.001, respectively) during the red-light exposure. In the blue-light condition, cortisol sensitivity was significantly negatively correlated with IL-6 sensitivity (p = 0.034). Overall, blue light seemed to have exerted a greater influence on cortisol and IL-6. For cortisol, this effect might be moderated by chronotype. Additionally, cortisol and IL-6 seem to interact under light exposure. However, these effects were mixed and could not be found consistently across mean secretion, AUCg and AUCi.
We perceive color everywhere and on everything that we encounter in daily life. Color science has progressed to the point where a great deal is known about the mechanics, evolution, and development of color vision, but less is known about the relation between color vision and psychology. However, color psychology is now a burgeoning, exciting area and this Handbook provides comprehensive coverage of emerging theory and research. Top scholars in the field provide rigorous overviews of work on color categorization, color symbolism and association, color preference, reciprocal relations between color perception and psychological functioning, and variations and deficiencies in color perception. The Handbook of Color Psychology seeks to facilitate cross-fertilization among researchers, both within and across disciplines and areas of research, and is an essential resource for anyone interested in color psychology in both theoretical and applied areas of study.
Anxiety and depression are some of the most common mental disorders associated with a dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and elevated cortisol levels in the saliva. The aim of this scoping review was to synthesize all of the current information about the relationship between salivary cortisol and depression as well as address some of the shortcomings in prior research to explore its potential applications in diagnosing depression. In late July 2022, records from 2012-2022 were identified using Web of Science, PubMed, and Scopus. Unique abstracts were screened using the following criteria: (1) depression and saliva; (2) anxiety and saliva; (3) age and salivary cortisol and depression; (4) sex and salivary cortisol and depression. 4,869 records were identified across all three databases; resulting in 90 unique abstracts. 11 articles met all inclusion criteria. On balance, most studies associated the dysregulation of the HPA with depression and anxiety disorders, with a cofactor being the cortisol awakening response. Several studies also presented sex and age-related differences in salivary cortisol measures. However, there were several inconsistencies with some studies showing no age and/or sex-related differences. Furthermore, several studies also emphasized the importance of testing morning salivary cortisol as an effective method to diagnose depression and anxiety disorders. The oral microbiome may play a role in mental health disorders through changes in inflammation and cortisol levels in saliva. Our review contributes to the existing literature on the topic, highlighting gaps and strategizing the next steps.
The rapid shifts of society have brought about changes in human behavioral patterns, with increased evening activities, increased screen time, and postponed sleep schedules. As an explicit manifestation of circadian rhythms, chronotype is closely intertwined with both physical and mental health. Night owls often exhibit more unhealthy lifestyle habits, are more susceptible to mood disorders, and have poorer physical fitness. Although individual differences in chronotype yield varying consequences, their neurobiological underpinnings remain elusive. Here we carry out a pattern-learning analysis, and capitalize on a vast array of ~ 1,000 phenome-wide phenotypes with three brain-imaging modalities (region volume of gray matter, whiter-matter fiber tracts, and functional connectivity) in 27,030 UK Biobank participants. The resulting multi-level depicts of brain images converge on the basal ganglia, limbic system, hippocampus, as well as cerebellum vermis, thus implicating key nodes in habit formation, emotional regulation and reward processing. Complementary by comprehensive investigations of in-deep phenotypic collections, our population study offers evidence of behavioral pattern disparities linked to distinct chronotype-related behavioral tendencies in our societies.
Cortisol is a vital glucocorticoid hormone reflecting stress levels and related disease processes. We present an aptamer functionalized plasmonic nano-urchin (α-FeOOH@Au-aptamer) aided cortisol capturing and Surface-enhanced Raman spectroscopy (SERS) analysis...
The potential influence of pituitary-related hormones (including both pituitary gland and target gland hormones) on functional recovery after traumatic brain injury has been observed. However, the relationship between these hormones and the recovery of consciousness in patients with disorders of consciousness (DOC) remains unclear. In this retrospective and observational study, 208 patients with DOC were recruited. According to the Glasgow Outcome Scale (GOS) scores after 6 months, patients with DOC were categorized into two subgroups: a favorable prognosis subgroup (n = 38) comprising those who regained consciousness (GOS score ≥3), and a poor prognosis subgroup (n = 156) comprising those who remained in DOC (GOS score <3). Comparative analyses of pituitary-related hormone levels between the two subgroups were conducted. Further, a binary logistic regression analysis was conducted to assess the predictive value of pituitary-related hormones for the patients' prognosis. The favorable prognosis subgroup showed a significant increase in adrenocorticotropic hormone (ACTH) levels (p = 0.036). Moreover, higher ACTH levels and shorter days since injury were significantly associated with a better prognosis, with odds ratios (ORs) of 0.928 (95% confidence interval [CI] = 0.873-0.985, p = 0.014) and 1.015 (95% CI = 1.005-1.026, p = 0.005), respectively. A subsequent receiver operating characteristic (ROC) analysis demonstrated the potential to predict patients' prognosis with an area under the curve value of 0.78, an overall accuracy of 75.5%, a sensitivity of 77.5%, and a specificity of 66.7%. Our findings indicate that ACTH levels could serve as a clinically valuable and convenient predictor for patients' prognosis.
Objectives
The hypothalamic–pituitary–adrenal (HPA) axis and its primary end product, the glucocorticoid cortisol, are major components of the evolved human stress response. However, most studies have examined these systems among populations in high‐income settings, which differ from the high pathogen and limited resource contexts in which the HPA axis functioned for most of human evolution.
Methods
We investigated variability in diurnal salivary cortisol patterns among 298 Indigenous Shuar from Amazonian Ecuador (147 males, 151 females; age 2–86 years), focusing on the effects of age, biological sex, and body mass index (BMI) in shaping differences in diurnal cortisol production. Saliva samples were collected three times daily (waking, 30 minutes post‐waking, evening) for three consecutive days to measure key cortisol parameters: levels at waking, the cortisol awakening response, the diurnal slope, and total daily output.
Results
Age was positively associated with waking levels and total daily output, with Shuar juveniles and adolescents displaying significantly lower levels than adults ( p < .05). Sex was not a significant predictor of cortisol levels ( p > .05), as Shuar males and females displayed similar patterns of diurnal cortisol production across the life course. Moreover, age, sex, and BMI significantly interacted to moderate the rate of diurnal cortisol decline ( p = .027). Overall, Shuar demonstrated relatively lower cortisol concentrations than high‐income populations.
Conclusions
This study expands the documented range of global variation in HPA axis activity and diurnal cortisol production and provides important insights into the plasticity of human stress physiology across diverse developmental and socioecological settings.
Recently, the cortisol awakening response (CAR) has been focused as an index of chronic stress. Chronic, accumulated stress through burnout is known to result in uncontrollable HPA axis stress responses that cause abnormal CAR. However, the effects of burnout tendency on CAR in athletes remain unclear. This study examined the effect of burnout tendency on CAR in athletes. Participants were top-level female university athletes (N=45). Among them, the results of 40 participants were analyzed after excluding five participants that experienced measurement problems. The burnout tendency was evaluated using the Athletic Burnout Inventory (ABI). The participants were classified into the High BO group (N=12) with high burnout scores and the Low BO group (N=28) with low burnout scores. They were instructed to collect saliva at home, just after waking up, as well as 15 minutes, and 30 minutes later. The concentration of cortisol in saliva was estimated using the Enzyme-Linked Immuno-Sorbent Assay (ELISA). The results revealed higher CAR and AUCG tendencies in the High BO group compared to the Low BO group. However, this possibility has not been sufficiently supported statistically in the current study. We should revalidate these findings by ensuring an adequate number of samples estimated from the effect size. These findings indicate a new physiological index for assessing burnout tendency, which could contribute to better understanding the physiological mechanisms of burnout onset.
Objective
To explore the potential of a sitting reduction workplace intervention for improving stress and work-performance.
Methods
A cluster randomised controlled trial evaluated an intervention to reduce and break up occupational sitting in 12 clusters (n = 89 office workers) over eight weeks. Outcomes were physiological stress (cortisol concentrations), perceived stress and work-performance.
Results
Linear mixed model group x time interaction effects were non-significant. Exploratory analyses showed a trend, with a large effect, for lower cortisol concentrations over the day in the intervention group relative to controls at 8 weeks (-0.85; 95% CI -1.70, 0.03 nmol.L ⁻¹ ; p = 0.06; d = 0.79). The intervention group had higher vigour and cognitive liveliness at eight weeks relative to controls (p ≤ 0.05).
Conclusions
This exploratory study suggests there could be meaningful changes in physiological stress and work-related outcomes that should be investigated in future studies.
The biological clock, the suprachiasmatic nucleus (SCN), is essential for our daily well-being. It prepares us for the upcoming period of activity by an anticipatory rise in heart rate, glucose and cortisol. At the same time the 'hormone of the darkness', melatonin, decreases. Thus, the time-of-day message penetrates into all tissues, interestingly not only by means of hormones but also by a direct neuronal influence of the SCN on the organs of the body. The axis between the SCN and the paraventricular nucleus of the hypothalamus (PVN) is crucial for the organization/ synchronization of the neuroendocrine and autonomic nervous system with the time of day. This SCN– neuroendocrine PVN axis takes care of a timely hormonal secretion. At the same time, the SCN–autonomic PVN axis fine-tunes the organs by means of the autonomic nervous system for the reception of these hormones. Finally, the similar organization of the projections of the human SCN as compared with that in the rodent brain suggests that these basic principles of neuroendocrine autonomic interaction may also be true in the human. The physiological data collected in humans thus far seem to support this hypothesis, while pathological changes in the SCN of humans suffering from depression or hypertension indicate a role for the SCN in the etiology of these diseases.
Analysis of published data identifying different neurotransmitter concentrations in the brain in paradoxical sleep and waking and data on the influences of neurotransmitters on the efficiency of the synaptic inputs to hippocampal neurons led to the conclusion that increases in the acetylcholine, cortisol, and dopamine concentrations during paradoxical sleep, with simultaneous reductions in serotonin and noradrenaline levels, may lead synergistically to a significant depression of transmission efficiency in polysynaptic pathways running through the hippocampus (i.e., the perforant path to neurons of the dentate gyrus, the pathway from the dentate gyrus to field CA3, from field CA3 to field CA1, and from field CA1 to the subiculum) but also to potentiation of the efficiency of the perforant path to pyramidal neurons of fields CA1 and CA3 and increases in the efficiency of associative connections between neurons in field CA3. This pattern of changes in the functioning of the hippocampal formation circuit may underlie differences in remembering and extracting information from memory in paradoxical sleep as compared with waking.
Glucocorticoids, hormones produced by the adrenal gland cortex, perform numerous functions in body homeostasis and the response of the organism to external stressors. One striking feature of their regulation is a diurnal release pattern, with peak levels linked to the start of the activity phase. This release is under control of the circadian clock, an endogenous biological timekeeper that acts to prepare the organism for daily changes in its environment. Circadian control of glucocorticoid production and secretion involves a central pacemaker in the hypothalamus, the suprachiasmatic nucleus, as well as a circadian clock in the adrenal gland itself. Central circadian regulation is mediated via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, while the adrenal gland clock appears to control sensitivity of the gland to the adrenocorticopic hormone (ACTH). The rhythmically released glucocorticoids in turn might contribute to synchronisation of the cell-autonomous clocks in the body and interact with them to time physiological dynamics in their target tissues around the day.
To assess dynamic changes in brain function throughout the sleep-wake cycle, CBF was measured with H2(15)O and PET in 37 normal male volunteers: (i) while awake prior to sleep onset; (ii) during Stage 3-4 sleep, i.e. slow wave sleep (SWS); (iii) during rapid eye movement (REM) sleep; and (iv) upon waking following recovery sleep. Subjects were monitored polysomnographically and PET images were acquired throughout the course of a single night. Stage-specific contrasts were performed using statistical parametric mapping. Data were analysed in repeated measures fashion, examining within-subject differences between stages [pre-sleep wakefulness-SWS (n = 20 subjects); SWS-post-sleep wakefulness (n = 14); SWS-REM sleep (n = 7); pre-sleep wakefulness-REM sleep (n = 8); REM sleep-post-sleep wakefulness (n = 7); pre-sleep wakefulness-post-sleep wakefulness (n = 20)]. State dependent changes in the activity of centrencephalic regions, including the brainstem, thalamus and basal forebrain (profound deactivations during SWS and reactivations during REM sleep) are consistent with the idea that these areas are constituents of brain systems which mediate arousal. Shifts in the level of activity of the striatum suggested that the basal ganglia might be more integrally involved in the orchestration of the sleep-wake cycle than previously thought. State-dependent changes in the activity of limbic and paralimbic areas, including the insula, cingulate and mesial temporal cortices, paralleled those observed in centrencephalic structures during both REM sleep and SWS. A functional dissociation between activity in higher order, heteromodal association cortices in the frontal and parietal lobes and unimodal sensory areas of the occipital and temporal lobes appeared to be characteristic of both SWS and REM sleep. SWS was associated with selective deactivation of the heteromodal association areas, while activity in primary and secondary sensory cortices was preserved. SWS may not, as previously thought, represent a generalized decrease in neuronal activity. On the other hand, REM sleep was characterized by selective activation of certain post-rolandic sensory cortices, while activity in the frontoparietal association cortices remained depressed. REM sleep may be characterized by activation of widespread areas of the brain, including the centrencephalic, paralimbic and unimodal sensory regions, with the specific exclusion of areas which normally participate in the highest order analysis and integration of neural information. Deactivation of the heteromodal association areas (the orbital, dorsolateral prefrontal and inferior parietal cortices) constitutes the single feature common to both non-REM and REM sleep states, and may be a defining characteristic of sleep itself. The stages of sleep could also be distinguished by characteristic differences in the relationships between the basal ganglia, thalamic nuclei and neocortical regions of interest.
To determine whether human hypothalamo-pituitary-adrenal axis activity is related to the alertness level during wakefulness, 10 healthy young men were studied under resting conditions in the daytime (0900–1800 h) after an 8-h nighttime sleep (2300–0700 h). A serial 70-sec gaze fixation task was required every 10 min throughout the daytime experimental session. The corresponding waking electroencephalographic (EEG) segments were submitted to quantitative spectral analysis, from which EEG β activity (absolute power density in the 13–35 Hz frequency band), an index of central alertness, was computed. Blood was collected continuously through an indwelling venous catheter and sampled at 10-min intervals. Plasma cortisol concentrations were measured by RIA, and the corresponding secretory rates were determined by a deconvolution procedure.
Analysis of individual profiles demonstrated a declining tendency for EEG β activity and cortisol secretory rate, with an overall temporal relationship indicated by positive and significant cross-correlation coefficients between the two variables in all subjects (average r= 0.565, P < 0.001). Changes in cortisol secretion lagged behind fluctuations in EEG β activity, with an average delay of 10 min for all the subjects. On the average, 4.6 ± 0.4 cortisol secretory pulses and 4.9 ± 0.5 peaks in EEG β activity were identified by a detection algorithm. A significant, although not systematic, association between the episodes in the two variables was found: 44% of the peaks in EEG β activity (relative amplitude, near 125%; P < 0.001) occurred during an ascending phase of cortisol secretion, cortisol secretory rates increasing by 40% (P < 0.01) 10-min after peaks in EEG β activity. However, no significant change in EEG β activity was observed during the period from 50 min before to 50 min after pulses in cortisol secretion.
In conclusion, the present study describes a temporal coupling between cortisol release and central alertness, as reflected in the waking EEGβ activity. These findings suggest the existence of connections between the mechanisms involved in the control of hypothalamo-pituitary-adrenal activity and the activation processes of the brain, which undergoes varying degrees of alertness throughout daytime wakefulness.
Some people can quite accurately time the end of their night's sleep at will, without using an alarm clock, demonstrating that it is possible to voluntarily control a state of consciousness that is characterized by a loss of volition and attentional guidance. Here we show that the expectation that sleep will come to an end at a certain time induces a marked increase in the concentration of the hormone adrenocorticotropin in the blood one hour before waking. The regulation of adrenocorticotropin release during nocturnal sleep is therefore not confined to daily rhythms; it also reflects a preparatory process in anticipation of the end of sleep.
The effect of light on the morning-cortisol peak in humans was investigated in fourteen healthy men by exposing them to darkness and to light of 800 lux during a 1-h period on two subsequent mornings. In the early morning, we demonstrated a temporary increase of salivary cortisol levels after awakening, while light exposure resulted in a +/- 35% further increase in cortisol levels. Cortisol levels 20 and 40 min after waking were significantly higher during 800 lux exposure than during darkness. In order to investigate the time-dependency, the experiment was repeated in the late evening. In the evening, light had no effect on cortisol levels. These results demonstrate that light conditions in the early morning have a strong impact on the morning-cortisol peak, but that evening cortisol levels are unaffected by light. The possible role of the circadian pacemaker as mediator of the light effect on cortisol level is discussed.
The only well documented effect of light exposure on endocrine function is the suppression of nocturnal melatonin. Bright light exposure has behavioral effects, including the alleviation of sleepiness during nocturnal sleep deprivation. The present study examines the effects of bright light on the profiles of hormones known to be affected by sleep deprivation (TSH) or involved in behavioral activation (cortisol). Eight healthy men participated each in three studies involving 36 h of continuous wakefulness. In one study, the subjects were exposed to constant dim light (baseline). In the two other studies, dim light exposure was interrupted by a 3-h period of bright light exposure either from 0500-0800 h (early morning study) or from 1300-1600 h (afternoon study). Blood samples were obtained every 15 min for 24 h to determine melatonin, cortisol, and TSH concentrations. Alertness was estimated by the number of lapses on two computerized vigilance-sensitive performance tasks. The early morning transition from dim to bright light suppressed melatonin secretion, induced an immediate, greater than 50% elevation of cortisol levels, and limited the deterioration of alertness normally associated with overnight sleep deprivation. No effect was detected on TSH profiles. Afternoon exposure to bright light did not have any effect on either hormonal or behavioral parameters. The data unambiguously demonstrate an effect of light on the corticotropic axis that is dependent on time of day.
More than 70 years ago, von Economo predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting region in the preoptic area. Recent studies have dramatically confirmed these predictions. The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior lateral hypothalamus contains orexin/hypocretin neurons that are crucial for maintaining normal wakefulness. A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Disruption of wake- or sleep-promoting pathways results in behavioral state instability.
To appreciate the neural underpinnings of sleep, it is important to view this universal mammalian behaviour at multiple levels of its biological organization. Molecularly, the circadian rhythm of sleep involves interlocking positive- and negative-feedback mechanisms of circadian genes and their protein products in cells of the suprachiasmatic nucleus that are entrained to ambient conditions by light. Circadian information is integrated with information on homeostatic sleep need in nuclei of the anterior hypothalamus. These nuclei interact with arousal systems in the posterior hypothalamus, basal forebrain and brainstem to control sleep onset. During sleep, an ultradian oscillator in the mesopontine junction controls the regular alternation of rapid eye movement (REM) and non-REM sleep. Sleep cycles are accompanied by neuromodulatory influences on forebrain structures that influence behaviour, consciousness and cognition.
Awakening from sleep entails rapid re-establishment of consciousness followed by the relatively slow (20-30 min later) re-establishment of alertness--a temporal dissociation that facilitates specification of the physiological underpinnings of each of these facets of the awakening process. H(2)(15)O PET was used to assess changes in regional cerebral blood flow (rCBF) upon awakening from stage 2 sleep. Cerebral blood flow (CBF) was most rapidly re-established in centrencephalic regions (e.g. brainstem and thalamus), suggesting that the reactivation of these regions underlies the re-establishment of conscious awareness. Across the ensuing 15 min of wakefulness, further increases in CBF were evident primarily in anterior cortical regions, suggesting that the dissipation of sleep inertia effects (post-awakening performance and alertness deficits) is effected by reactivation of these regions. Concomitant shifts in correlation patterns of regional brain activity across the post-awakening period [in particular, a waning negative correlation between prefrontal cortex and mesencephalic reticular formation (RF) activity, and a waxing positive correlation between prefrontal cortex and ventromedial caudate nucleus (CAUD) activity] suggest that the post-awakening reversal of sleep inertia effects may be mediated by more than mere reactivation--it may also involve the functional reorganization of brain activity. Conversely, stable post-awakening correlations--such as those found between the anterior cingulate cortex (ACC) and most other brain regions--may denote the pattern of functional connectivity that underlies consciousness itself.
The dynamics of cerebral blood flow velocity during sleep were measured in the right and left middle cerebral artery of 12 and 10 healthy male volunteers, respectively. A computer-assisted pulsed (2-MHz) Doppler ultrasonography system was modified for continuous long-term and on-line recording of cerebral hemodynamics in combination with polysomnography. Mean flow velocity (MFV) decreased steadily during deepening nonrapid eye movement (NREM) sleep and increased suddenly during rapid eye movement sleep, corresponding to changes in brain function. However, spontaneous or provoked changes in sleep stage patterns as well as awakenings from NREM sleep were not regularly accompanied by corresponding changes in MFV. Differing values for MFV in subsequent sleep cycles could be shown for several sleep stages. Furthermore, MFV values in sleep stage II at the end of an NREM-sleep period were lower than in preceding slow-wave sleep. After application of short acoustic signals the electroencephalogram frequency rose, indicating an arousal, whereas MFV rapidly decreased for several seconds and then gradually returned to the prior level. These results imply an uncoupling between cerebral electrical activity and cerebral perfusion during sleep and support a dissociation in the activity of central regulatory mechanisms. In light of the proposal that cortical energy consumption can be accounted for by cerebral electrical activity, the concept that cerebral perfusion during sleep is regulated solely by the metabolic rate must be reconsidered.
A distinct rise in cortisol levels that occurs after morning awakening is increasingly used as an indicator of adrenocortical activity which is associated with different pathologies. Although it was previously assumed that the transition from sleep to wake is essential for the occurrence of the cortisol morning rise, this has never been tested. Here, we examined 16 healthy young men (20–33 yrs) between 2300 and 0800 h under sleep laboratory conditions. Serum cortisol and plasma adrenocorticotropin (ACTH) as well as salivary cortisol levels (after subjects were woken up at 0700 h) were repeatedly assessed. In a supplementary study condition, salivary cortisol levels in the first hour after awakening were measured at the subjects’ home on two consecutive days. Comparison of pre- and post awakening measurements revealed significantly steeper increases in cortisol and ACTH after awakening. The rise in cortisol upon awakening under laboratory conditions did not significantly differ from that observed at home. We conclude that the cortisol increase after awakening is a response to morning awakening that is distinct from the circadian rise in hypothalamo-pituitary-adrenal (HPA) activity in the morning hours. Although the cortisol awakening response is modulated by circadian influences, it primarily reflects phasic psychophysiological processes specific to the sleep–wake transition.
Summary Awakening from sleep entails rapid re-establishment of consciousness followed by the relatively slow (20‐30 min later) re-establishment of alertness—a temporal dissociation that facilitates specification of the physiological underpinnings of each of these facets of the awakening process. H2 15 O PET was used to assess changes in regional cerebral blood flow (rCBF) upon awakening from stage 2 sleep. Cerebral blood flow (CBF) was most rapidly re-established in centrencephalic regions (e.g. brainstem and thalamus), suggesting that the reactivation of these regions underlies the reestablishment of conscious awareness. Across the ensuing 15 min of wakefulness, further increases in CBF were evident primarily in anterior cortical regions, suggesting that the dissipation of sleep inertia effects (postawakening performance and alertness deficits) is effected by reactivation of these regions. Concomitant shifts in correlation patterns of regional brain activity across the post-awakening period [in particular, a waning negative correlation between prefrontal cortex and mesencephalic reticular formation (RF) activity, and a waxing positive correlation between prefrontal cortex and ventromedial caudate nucleus (CAUD) activity] suggest that the post-awakening reversal of sleep inertia effects may be mediated by more than mere reactivation—it may also involve the functional reorganization of brain activity. Conversely, stable post-awakening correlations—such as those found between the anterior cingulate cortex (ACC) and most other brain regions— may denote the pattern of functional connectivity that underlies consciousness itself.
The present study examined the effects of sleep inertia on arousal level and frontal lobe function after a normal night's sleep. Nine undergraduate and graduate students slept for two consecutive nights (adaptation and experimental). The bedtime and waking times were fixed as the times that were usual for the participants in their daily life. A switching task that reflects frontal lobe functioning and a simple auditory reaction time task that reflects general arousal level were conducted for 15 min before bedtime and for 60 min immediately after waking. In comparison with 15 min before bedtime, the arousal level was lowered for 15 min and subjective sleepiness deteriorated for 1 h after awakening, whereas performance on the switching task was not reduced after awakening. These results suggest that sleep inertia occurring after a normal night's sleep affects arousal level but does not have an appreciable effect on frontal lobe functions.
Our previous findings have demonstrated that individuals with post-traumatic stress disorder (PTSD) show lower basal cortisol levels, a larger number of lymphocyte glucocorticoid receptors, and an enhanced suppression of cortisol following the administration of dexamethasone compared to normals and patients with major depression. We have previously suggested that these alterations reflect an enhanced negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD. However, in the absence of direct knowledge of pituitary capability in this disorder, it has been equally likely that the alterations observed reflected either pituitary or adrenal insufficiency. In the present study, we examined ACTH release from the pituitary gland in PTSD following the administration of metyrapone. Metyrapone resulted in a significantly greater increase of ACTH and 11-deoxycortisol in combat veterans with PTSD (n = 11) compared with normal male volunteers (n = 8). When seen in the context of other abnormalities observed in PTSD, the present demonstration of increased pituitary activity in the absence of negative feedback provides unequivocal support for the hypothesis of enhanced negative feedback.
Integration of the hypothalamo–pituitary–adrenal stress response occurs by way of interactions between stress-sensitive brain circuitry and neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN). Stressors involving an immediate physiologic threat (`systemic' stressors) are relayed directly to the PVN, probably via brainstem catecholaminergic projections. By contrast, stressors requiring interpretation by higher brain structures (`processive' stressors) appear to be channeled through limbic forebrain circuits. Forebrain limbic sites connect with the PVN via interactions with GABA-containing neurons in the bed nucleus of the stria terminalis, preoptic area and hypothalamus. Thus, final elaboration of processive stress responses is likely to involve modulation of PVN GABAergic tone. The functional and neuroanatomical data obtained suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways.
In aged and pathological populations, reduced hippocampal volume is frequently described in association with impairment of hippocampus-dependent cognitive processes and chronically elevated cortisol levels. Recent studies in young healthy subjects show a negative association between hippocampal volume and memory. The aim of the present study was to investigate the associations among hippocampal volume, cortisol levels and memory performance in a group of healthy young men. Hippocampal volume was determined by manual segmentation of high-resolution 3D Magnetic Resonance Images from 13 subjects. Stress-induced cortisol levels in response to the "Trier Social Stress Test" (TSST) as well as the cortisol response to awakening (CRA) over four weeks were assessed. Declarative memory performance was tested before and after exposure to the TSST. The results show that larger hippocampal volume was associated with a significantly stronger cortisol increase in response to the TSST and a significantly greater CRA. Moreover, larger hippocampal volume was associated with significantly lower memory performance before the TSST. Our results challenge the direction of the frequently observed relationships among hippocampal volume, cortisol reactivity and memory performance and question the relevance of findings in clinical and aged subjects for young healthy populations.
Dreaming has fascinated and mystified humankind for ages: the bizarre and evanescent qualities of dreams have invited boundless speculation about their origin, meaning and purpose. For most of the twentieth century, scientific dream theories were mainly psychological. Since the discovery of rapid eye movement (REM) sleep, the neural underpinnings of dreaming have become increasingly well understood, and it is now possible to complement the details of these brain mechanisms with a theory of consciousness that is derived from the study of dreaming. The theory advanced here emphasizes data that suggest that REM sleep may constitute a protoconscious state, providing a virtual reality model of the world that is of functional use to the development and maintenance of waking consciousness.
In attempts to understand the social determinants of health, strong associations have been found between measures of loneliness, physiological stress processes, and physical and mental health outcomes. Feelings of loneliness are hypothesized to have implications for physiological stress processes, including activity of the hypothalamic-pituitary-adrenal (HPA) axis. In a community sample of young adults, multilevel modeling was used to examine whether trait and state feelings of loneliness were related to changes in levels of the stress-sensitive hormone cortisol, and whether the associations between loneliness and cortisol were mediated or moderated by the presence of concurrent depression or high levels of chronic life stress. Results indicated that trait loneliness was associated with a flattening of the diurnal cortisol rhythm. In addition, both daily and momentary state variations in loneliness were related to cortisol. Prior day feelings of loneliness were associated with an increased cortisol awakening response the next morning and momentary experiences of loneliness during the day were associated with momentary increases in cortisol among youth who also had high chronic interpersonal stress. Results were significant after covarying current depression, both chronic and momentary reports of stress, and medical and lifestyle covariates. This study expanded on prior work by investigating and revealing three different time courses of association between loneliness and HPA axis activity in young adults: trait, daily and momentary.
Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and results in the secretion of corticosteroids, which facilitate behavioral adaptation and promote the termination of the stress response. These actions exerted by cortisol are mediated by two brain corticosteroid receptor types: the high affinity mineralocorticoid (MR) and the low affinity glucocorticoid receptor (GR). Dexamethasone is a potent GR agonist with affinity to MR. Administration of dexamethasone in the evening results in a significant suppression of the morning cortisol awakening response (CAR). Here we tested the involvement of MR variants in this effect of dexamethasone in 218 young healthy subjects (125 females, all using oral contraceptives). For this purpose we determined two single nucleotide polymorphisms (SNPs) in the MR gene, the previously described MRI180V (rs5522) and the MR-2G/C (rs2070951), which both affect in vitro the transactivational capacity of the MR in response to either cortisol or dexamethasone. Administration of a low dose dexamethasone (0.25mg) at 2300h resulted in a significant suppression of the cortisol awakening response (CAR). Both SNPs modulated the suppression of the CAR after dexamethasone significantly and in a sex specific manner. Suppression of the CAR was highest in the female MR-2G/C GG subjects while in male GG subjects the dexamethasone suppression of the CAR was attenuated compared to the MR-2G/C GC and CC groups. For the MRI180V, male AA subjects showed after dexamethasone a higher CAR than AG subjects while this effect was not observed in females. The SNPs had no significant influence on the CAR without prior dexamethasone treatment. The association of the CAR with functional MR gene variants only in dexamethasone treated subjects suggests the involvement of MR in dexamethasone induced suppression of morning cortisol.
The objective was to examine the day-to-day variation in cortisol among healthy individuals and its relation to the time of saliva sampling, work, stress and fatigue. During 4 consecutive weeks, 14 office workers provided saliva samples (at awakening, 15 min after awakening and at bedtime) and made diary ratings for each day. Results showed a variation in cortisol values between participants but also within individuals. After controlling for the individual differences, results showed that low cortisol levels in the morning were associated with sleepiness at awakening and anxiety, exhaustion, and poor health the day before. High evening levels of cortisol were associated with symptoms of stress and poor self-rated health. Further analysis of the cortisol awakening response (CAR) showed that all participants had a mixture of both a positive and negative responses. During mornings with a negative response participants stayed in bed for a longer time after the initial awakening, which might be a sign of snoozing, thus missing the awakening response.
Cortisol levels are increasingly often assessed in large-scale psychosomatic research. Although determinants of different salivary cortisol indicators have been described, they have not yet been systematically studied within the same study with a large sample size. Sociodemographic, health and sampling-related determinants of salivary cortisol levels were examined in a sample without potential disturbances because of psychopathology.
Using 491 respondents (mean age=43.0 years, 59.5% female) without lifetime psychiatric disorders from the Netherlands Study of Depression and Anxiety (NESDA), sociodemographic, sampling and health determinants of salivary cortisol levels were examined. Respondents collected seven salivary cortisol samples providing information about 1-h awakening cortisol, diurnal slope, evening cortisol and a dexamethasone (0.5mg) suppression test (DST).
Higher overall morning cortisol values were found for smokers, physically active persons, persons without cardiovascular disease, sampling on a working day or in a month with less daylight. In addition, the cortisol awakening response was significantly flattened for males, persons with cardiovascular disease, those with late awakening times and those with longer sleep duration. Diurnal slope was steeper in men, physically active persons, late awakeners, working persons, and season with less daylight. A higher evening cortisol level was associated with older age, smoking and season with more daylight. Cortisol suppression after dexamethasone ingestion was found to be less pronounced in smokers, less active persons and sampling on a weekday.
Sociodemographic variables (sex, age), sampling factors (awakening time, working day, sampling month, sleep duration) and health indicators (smoking, physical activity, cardiovascular disease) were shown to influence different features of salivary cortisol levels. Smoking had the most consistent effect on all cortisol variables. These factors should be considered in psychoneuroendocrinology research.
A key regulator of serotonergic neurotransmission is the serotonin transporter (5-HTT) and a common 5HTT gene promoter polymorphism, termed 5HTTLPR, is associated with phenotypes related to anxiety and depression. Furthermore, the serotonergic system influences hypothalamus-pituitary-adrenal (HPA) axis activity, which, in turn, is related to psychiatric diseases.
To explore the association between the 5-HTTLPR and HPA axis regulation we performed a detailed endophenotyping in 216 healthy subjects (all 126 females used oral contraceptives).
While ACTH and cortisol responses to an established psychosocial stress paradigm (Trier Social Stress Test) were not found to be related to the 5-HTTLPR, we observed a significant and sex-specific association with the cortisol awakening response, which is a reliable marker of basal cortisol secretion, and with ACTH levels after dexamethasone administration. The supplementary inclusion of a 5-HTT A/G polymorphism (rs25531) in the analyses did not substantially modify our results.
These findings support the view that the 5-HTTLPR is associated with a major neuroendocrine stress system. It could be speculated that the sex-specific nature of this association contributes to the distinct gender differences in the vulnerability for depression.
There is emerging evidence from healthy individuals, as well as direct and indirect evidence from psychiatric and neurological patients with disease-related hippocampal atrophy, linking the cortisol awakening response (CAR) to hippocampal volume. Type 2 diabetes mellitus (T2DM) is a metabolic disease that is also accompanied by hippocampal atrophy, and therefore can serve as a model for ascertaining the relationship between CAR and hippocampal volume. We contrasted a group of 18 individuals with T2DM with 12 matched controls on MRI-based hippocampal volume and salivary diurnal cortisol profile including CAR. Individuals with T2DM had smaller hippocampal volumes and exhibited a blunting of the CAR relative to controls, while diurnal cortisol was not affected. Across all subjects, fasting insulin and hippocampal volume were associated with the CAR, independent of diagnosis. Our findings support the hypothesis that hippocampal integrity is an important predictor of the CAR.
The aim of this study was to investigate the relationship between the cortisol awakening response (CAR) and two key state variables (morning stress and arousal) and the trait-like variable of seasonality as recent evidence suggests that the CAR is subject to both state and trait influences. The CAR was examined across two consecutive winter days in 50 healthy participants. Participants collected saliva samples in the domestic setting immediately on awakening, then at 15, 30 and 45min post-awakening on the two study days. Concomitant trait and state measures were examined, notably seasonal changeability in mood as a trait, and self-reported stress and arousal as state measures. Although there was correlational stability for measures of the CAR across days, there was a significant difference in the magnitude of the increase in cortisol levels following awakening between the two study days, being greater on the first sampling day. This reduction in the magnitude of cortisol increase was significantly associated with an observed reduction across the 2 days in self-reported arousal assessed at 45min following awakening. Participants reported greater arousal (more alert, active, energetic and stimulated, less drowsy, tired and sluggish) on the first study day than the second. Average CAR across days was associated with seasonality score, greater propensity for seasonal changes in mood being associated with smaller average CAR. High seasonality scorers were also more likely as a group to show a strong association between daily changes in state arousal and CAR. This study supports the view that the CAR is, in part, susceptible to short-term changes in state variables, notably perceived arousal, while observing a novel link between CAR and the trait variable of perceived seasonality. Finally a tentative finding suggests the importance of examining for possible interaction between trait and state effects, evidenced by a significantly greater association between state arousal changes and cortisol response changes in those with high (trait) seasonality.
Salivary cortisol is frequently used as a biomarker of psychological stress. However, psychobiological mechanisms, which trigger the hypothalamus-pituitary-adrenal axis (HPAA) can only indirectly be assessed by salivary cortisol measures. The different instances that control HPAA reactivity (hippocampus, hypothalamus, pituitary, adrenals) and their respective modulators, receptors, or binding proteins, may all affect salivary cortisol measures. Thus, a linear relationship with measures of plasma ACTH and cortisol in blood or urine does not necessarily exist. This is particularly true under response conditions. The present paper addresses several psychological and biological variables, which may account for such dissociations, and aims to help researchers to rate the validity and psychobiological significance of salivary cortisol as an HPAA biomarker of stress in their experiments.
Recent evidence suggests that the cortisol awakening response (CAR) on any single day is determined by a combination of trait and state factors; however, the nature of such state associations remains largely unexplored. In this study we examined day-to-day changes in the CAR and their covariance with simultaneous changes in sleep-related variables, alcohol consumption, and motility levels. We employed a novel approach to this field of research in the form of a detailed case study of a 27-year-old healthy male (TS) over 50 measurement days, occurring at 3-day intervals. On each measurement day, salivary free cortisol was determined at 0, 15, 30, and 45min post-awakening and sleep-related variables, alcohol consumption on the previous evening, and post-awakening motility were measured. Our findings show considerable day-to-day variability in the CAR, particularly the dynamic increase, which averaged 17.2nmol/l and ranged from 3.6 to 39.0nmol/l (max-min values). We also report a strong relationship between changes in awakening time and changes in the first waking sample (explaining approximately 38% of its variability) such that later awakening was associated with a higher first waking sample. This relationship was found to be stronger on days when awakening time was earlier in the morning than on days when it was later. Our findings also provide a preliminary indication for an inverse association between alcohol consumption on the evening before a sampling day and the dynamic of the AUC(I), while no associations between sleep quality, post-awakening motility levels, and mode of awakening and measures of the CAR were found.
In humans, the secretion of cortisol from the adrenal glands follows a diurnal cycle with a profound increase after awakening. This increase after awakening, a phenomenon termed the cortisol awakening response (CAR), appears to be a distinct feature of the hypothalamus-pituitary-adrenal (HPA) axis, superimposing the circadian rhythmicity of cortisol secretion. Several studies point towards an important role of the hippocampus and, additionally, other brain structures (e. g. amygdala, prefrontal cortex, suprachiasmatic nucleus) in the regulation of the CAR. There is increasing knowledge that the CAR is influenced by a variety of factors such as gender, health status, and health behavior or stress perception. However, the exact function of the profound cortisol increase after awakening is still not clarified. We hypothesize that the anticipation of the upcoming day is of major relevance for the magnitude of the CAR. The present paper reviews the current knowledge on the neural regulation of the CAR and factors influencing this phenomenon and considerations are addressed concerning the exact function of the CAR.
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Dysregulations of the hypothalamus-pituitary-adrenal (HPA) axis, as a physiological substrate of stress, have been observed in patients with different stress-related and chronic pain disorders. In this study, we investigated possible dysregulations of the HPA axis in patients with masticatory muscles pain. In 20 patients with myogenous facial pain and 20 healthy controls, awakening cortisol responses, i.e.cortisol rise in the first hour after awakening, as well as a short circadian free cortisol profile, i.e. four cortisol samples over 12h during the day, were assessed before and after administration of 0.5mg dexamethasone.
Results:
In comparison to controls, chronic myogenous facial pain patients showed enhanced and prolonged suppression of cortisol after the administration of 0.5mg dexamethasone. Unstimulated cortisol response (before dexamethasone-intake) to awakening and cortisol levels during the day did not differ between the groups. Dysregulation in terms of enhanced negative feedback suppression exists in chronic myogenous facial pain. These results are in line with a multifactorial etiology of chronic facial pain, shifting the perspective away from a local towards a more central etiology with dysregulations in the stress and pain modulating system.
Previous studies found higher cortisol levels in Alzheimer's disease (AD) compared to normal elderly controls (NCs). However, studies on individuals with mild cognitive impairment (MCI), who are at risk to progress to AD, are contentious. In this study, we examined whether seasonal variations in cortisol secretion in NCs, MCI individuals and AD patients might mask group differences in cortisol secretion. We found significant seasonal differences in salivary cortisol levels in all three groups. Moreover, by testing everyone in the same seasons, we found lower salivary cortisol levels in NCs compared to MCI individuals and AD patients. This suggests that controlling for the season of sampling may help elucidate subtle effects of normal and pathological aging on basal cortisol secretion.
It is still discussed controversially to what extent the nocturnal activity of the hypothalamus-pituitary-adrenocortical system depends on sleep and awakening in the morning. Therefore, we investigated the association of plasma ACTH and cortisol levels with undisturbed nocturnal sleep and spontaneous awakening in 14 healthy male subjects (between 2300 h and 1100 h). Between sleep onset and 476.9 min after sleep onset mean plasma cortisol level was significantly (P < 0.01) higher (210 +/- 15 vs. 155 +/- 9 nmol/L) in the group with a shorter (476.9 +/- 15.0 min; n = 7; mean +/- SEM) than in the group with a longer total sleep time (596.9 +/- 14.4 min; n = 7). Spontaneous awakening in the morning was not linked to the presence of any specific sleep stage or to rising plasma ACTH and cortisol levels. However, spontaneous awakening was followed by a brief rise in plasma ACTH and cortisol in both groups. Thereafter, during wakefulness plasma ACTH and cortisol abruptly declined in all subjects irrespective of the time of awakening. The slope of the plasma ACTH and cortisol curves differed significantly (ACTH: P < 0.001; cortisol: P < 0.002, for all subjects) comparing the time after awakening (until 1100 h) with a time interval of identical length before awakening. We conclude that the duration of sleep and nocturnal ACTH and cortisol secretion are interrelated. Furthermore, the data suggest that the endogenous early morning activation of the hypothalamus-pituitary-adrenocortical system is terminated by mechanisms closely associated with awakening.
Noradrenergic innervation of the human adrenal cortex was investigated using immunohistochemistry directed at dopamine-beta-hydroxylase. Nerves were present as slender trunks and individual varicose fibres in the capsule and all cortical zones except the inner zona reticularis. Some fibres were located adjacent to blood vessels and in the muscular tunics of arterioles; others were apparently adjacent to parenchymal cells. These results in the human confirm and extend previous animal studies and suggest a possible anatomical substrate for regulation of adrenal blood flow, and also for the direct action of noradrenaline on zona fasciculata cells to stimulate glucocorticoid secretion via beta-1-adrenoceptors.
There is considerable, although not entirely consistent, evidence that the hippocampus inhibits most aspects of HPA activity, including basal (circadian nadir) and circadian peak secretion as well as the onset and termination of responses to stress. Although much of the evidence for these effects rests only on the measurement of corticosteroids, recent lesion and implant studies indicate that the hippocampus regulates adrenocortical activity at the hypothalamic level, via the expression and secretion of ACTH secretagogues. Such inhibition results largely from the mediation of corticosteroid feedback, although more work is required to determine whether the hippocampus supplies a tonic inhibitory input in the absence of corticosteroids. It must be noted that the hippocampus is not the only feedback site in the adrenocortical system, since removal of its input only reduces, but does not abolish, the efficacy of corticosteroid inhibition, and since other elements of the axis appear eventually to compensate for deficits in feedback regulation. The importance of other feedback sites is further suggested not only by the presence of corticosteroid receptors in other parts of the brain and pituitary, but also by the improved prediction of CRF levels by combined hypothalamic and hippocampal receptor occupancy. The likelihood of feedback mediated by nonhippocampal sites underscores the need for future work to characterize hippocampal influence on HPA activity in the absence of changes in corticosteroid secretion. However, despite the fact that the hippocampus is not the only feedback site, it is distinguished from most potential feedback sites, including the hypothalamus and pituitary, by its high content of both type I and II corticosteroid receptors. The hippocampus is therefore capable of mediating inhibition over a wide range of steroid levels. The low end of this range is represented by corticosteroid inhibition of basal (circadian nadir) HPA activity. The apparent type I receptor specificity of this inhibition and the elevation of trough corticosteroid levels after hippocampal damage support a role for hippocampal type I receptors in regulating basal HPA activity. It is possible that basal activity is controlled in part through hippocampal inhibition of vasopressin, since the inhibition of portal blood vasopressin correlates with lower levels of hippocampal receptor occupancy, and the expression of vasopressin by some CRF neurons is sensitive to very low corticosteroid levels. At the high end of the physiological range, stress-induced or circadian peak corticosteroid secretion correlates strongly with occupancy of the lower affinity hippocampal type II receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
To further characterize diurnal changes in the rhythm in adrenal responsiveness to ACTH, we have measured ACTH distribution volume, MCR, and t 1/2. These do not change between morning and evening in groups of untreated, dexamethasone-pretreated, or hypophysectomized female rats. To characterize the nature of the change in adrenal responsiveness to ACTH, dexamethasone-pretreated rats were infused for 2 h with a variety of doses of ACTH in the morning and evening. The adrenal response to an infusion rate of ACTH that maximally stimulated the adrenals (200 pg/100 g BW.min) was the same in the morning and evening, showing that adrenal capacity does not change. However, infusion of ACTH at lower rates (50-100 pg/100 g BW.min) revealed that the slope of the steroid response curve increased between morning and evening, demonstrating a diurnal change in adrenal sensitivity to ACTH. These results together with previous data showing that the magnitude and time course of the adrenal cAMP response to ACTH changes diurnally strongly suggest that ACTH receptor affinity or coupling with adenylate cyclase changes diurnally. In other experiments, plasma ACTH and corticosterone levels were determined in groups of young and adult male and adult female untreated rats killed at 4-h intervals around the clock. Peak sensitivity to ACTH was found at lights-out, and trough sensitivity was found at lights-on, suggesting that the experimentally demonstrated rhythm occurs normally.
There is evidence for the existence of ACTH unrelated mechanisms in the regulation of cortisol secretion in man. This study was designed to elucidate the interrelationship between plasma ACTH and cortisol levels during the increase in cortisol levels, which occurs during morning hours. The results were compared with those of an artificial cortisol peak induced by administration of small amounts of ACTH, and with ACTH and cortisol values during insulin-induced hypoglycemia. In these control groups, the increase in cortisol levels was preceded by a large increase in ACTH levels; in the case of the physiological morning peak there was no adequate rise in mean ACTH levels. Thus, the spontaneously occurring increments in individual ACTH levels appear to be inappropriate for the increases in cortisol. This conclusion was corroborated by the finding that oscillations of plasma cortisol concentrations, comparable to the physiological morning peak, were demonstrable in ACTH-deficient patients when they were supplied with subthreshold amounts of exogenous ACTH. These findings argue against the classic concept that the adrenal cortex is invariably linked to immediately preceding episodes of pituitary ACTH secretion.
To define the chronobiology of glucose tolerance and insulin secretion in obesity, nine obese men and nine lean men were studied during constant glucose infusion for 53 h, including 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples were collected at 20-min intervals to assay glucose, insulin, C-peptide, cortisol, and GH. Sleep was polygraphically monitored. Abnormal temporal profiles of glucose regulation were observed during wakefulness and sleep in obese subjects. During daytime hours, the normal profile of glucose tolerance was reversed, as an improvement, rather than a deterioration, was observed from morning to late evening. This reversal of the daytime pattern appeared to be caused by a dual defect in glucose regulation during the previous night. Indeed, during early sleep, GH secretion was markedly reduced, and the nocturnal rises of glucose and insulin secretion were dampened. During late sleep, obese subjects failed to suppress insulin secretion and plasma glucose, resulting in high morning levels. Comparisons of metabolic and hormonal patterns during nocturnal and daytime sleep suggest that the failure to suppress insulin secretion in late sleep may reflect a relative insensitivity of the beta-cell to acute inhibitory effects of cortisol in addition to insulin resistance.
Recent studies of adrenal function in conscious calves are reviewed. These have involved collecting the whole of the adrenal effluent blood from the right adrenal gland at intervals and, where necessary, prior functional hypophysectomy by destruction of the pituitary stalk under general halothane anaesthesia 3 d previously. The adrenal medulla was found to release numerous neuropeptides, in addition to catecholamines, in response to stimulation of the peripheral end of the right splanchnic nerve, which was carried out below behavioural threshold. Many of these responses were enhanced by stimulating intermittently at a relatively high frequency. Intra-aortic infusions of a relatively low dose of acetylcholine (4.5 nmol min-1 kg-1) elicited similar responses. In the adrenal cortex, agonists which either potentiated the steroidogenic response to ACTH or exerted a direct steroidogenic action included VIP, CGRP, CRF and ACh acting via muscarinic receptors. Stimulation of the peripheral end of the right splanchnic nerve strongly potentiated the steroidogenic response to ACTH and there is compelling evidence that the innervation normally plays an important part in cortisol secretion.
Circadian rhythms are major features of adaptation to our environment. In mammals, circadian rhythms are generated and regulated by a circadian timing system. This system consists of entertainment pathways, pacemakers, and pace-maker output to effector systems that are under circadian control. The primary entertainment pathway is the retinohypothalamic tract, which terminates in the circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The output of the suprachiasmatic nuclei is principally to the hypothalamus, the midline thalamus, and the basal forebrain. This provides a temporal organization to the sleep-wake cycle, to many physiological and endocrine functions, and to psychomotor performance functions. Disorders of circadian timing primarily affect entertainment and pacemaker functions. The pineal hormone, melatonin, appears to be promising agent for therapy of some circadian timing disorders.
Basal plasma ACTH and corticosterone levels are controlled by the suprachiasmatic nucleus (SCN), the site of the circadian pacemaker, resulting in a daily peak in plasma corticosterone and ACTH. The present study was carried out to investigate the mechanisms employed by the biological clock to control these hormones. Novel environment induced changes in plasma ACTH and corticosterone in intact and SCN-lesioned animals were employed as experimental approach. Placing intact animals in a new environment results in different plasma corticosterone and ACTH responses depending on the clock time of the stimulus. (1) Novel environment (2 h after onset of darkness (ZT14)) results in a fast decrease followed by an increase in corticosterone. This changing pattern in corticosterone secretion was not accompanied by any change in plasma ACTH, suggesting a direct neuronal control of the adrenal cortex. (2) In contrast, novel environment at 2 h after light onset (ZT2) results in a rapid increase in plasma ACTH. Regression analysis of the relation ACTH-corticosterone before and after stress shows a changed pattern at ZT2, although at that time still no significant correlation between ACTH and corticosterone was detected. AT ZT14 this correlation was only present after stress. (3) SCN lesioning results in low basal ACTH at all circadian times combined with elevated corticosterone levels. Here, a new environment results in an immediate increase in corticosterone without inhibition; ACTH also increases rapidly, but attains lower levels than at ZT2 in intact animals. (4) The present results therefore demonstrate SCN modulating corticosterone secretion by affecting ACTH secretion and changing the sensitivity of the adrenal cortex by means of a neuronal input.
In three independent studies, free cortisol levels after morning awakening were repeatedly measured in children, adults and elderly subjects (total n=152). Cortisol was assessed by sampling saliva at 10 or 15 minute intervals for 30-60 minutes, beginning at the time of awakening for two days (Study 1 and 2) or one (Study 3) day, respectively. In all three studies, free cortisol levels increased by 50-75% within the first 30 minutes after awakening in both sexes on all days. Premenopausal women consistently showed a stronger increase with a delayed peak after awakening compared to men on all days. In Study 2, there was a tendency for lower early morning free cortisol levels for women taking oral contraceptives (p=.10). Stability of the area under the curve (AUC) of the early morning free cortisol levels over the three (Study 1 and 2) or two (Study 3) days ranged between r=.39 and r=.67 (p<.001). Neither age, weight, nor smoking showed an effect on baseline or peak cortisol levels. Sleep duration, time of awakening and alcohol consumption also appeared to be unrelated to early morning free cortisol levels. From these data we conclude that in contrast to single assessments at fixed times, early morning cortisol levels can be a reliable biological marker for the individual's adrenocortical activity when measured repeatedly with strict reference to the time of awakening.
The present study investigated the dynamic regulation of the hypothalamo-pituitary-adrenal axis and its significance to acute stress responsiveness in the female rat. An automated, frequent blood-sampling technique allowed the circadian rhythm of corticosterone to be resolved into a series of pulses. These were equally distributed (mean interval, 50.9 +/- 3.7 min) throughout the 24-h cycle, but their magnitude varied significantly, being higher between 1800-2200 h (137 +/- 9 ng/ml) than between 0600-1000 h (75 +/- 17 ng/ml). This pattern of release indicates continuous, but variable, activity of the axis throughout the day. The pulsatile ultradian rhythm suggested alternate periods of secretion and inhibition, which were found to have a profound effect on the corticosterone responses to acute stress. Noise stress (10 min, 114 decibels) evoked a transient increase in corticosterone, which reached a maximum (377 +/- 87 ng/ml) 20 min after onset. However, within this group (n = 26) the response varied depending on the underlying basal activity. When stress coincided with a rising (secretory) phase of a pulse, corticosterone concentrations rose to 602 +/- 150% of mean basal concentrations (P < 0.001). In contrast, when stress coincided with a falling (nonsecretory) phase of a pulse, a significantly smaller response, no greater than a basal pulse, was evoked. Thus, the alternate periods of secretion and inhibition generating basal hypothalamo-pituitary-adrenal activity are an important determinant of responses to acute stress.
The effects of burnout and perceived stress on early morning free cortisol levels after awakening were investigated in a group of teachers. Previous studies revealed that cortisol levels show a significant increase after awakening, with high intraindividual stability.
Sixty-six teachers from local public schools (42 women and 24 men, mean age 42+/-5 years) were asked to sample saliva for cortisol analysis on 3 consecutive days. On each day, cortisol levels were measured at the time of awakening and 15, 30, and 60 minutes thereafter. On the night before the third day, subjects took 0.5 mg dexamethasone orally for testing glucocorticoid feedback inhibition. Burnout and perceived stress were measured by three different questionnaires.
Perceived stress correlated with increases of cortisol levels during the first hour after awakening after dexamethasone pretreatment. In addition, teachers scoring high on burnout showed lower overall cortisol secretion on all sampling days, and a higher suppression of cortisol secretion after dexamethasone administration. In the subgroup of teachers with both high levels of perceived stress and high levels of burnout, a lower overall cortisol secretion was observed on the first 2 days, with stronger increases during the first hour after awakening after dexamethasone suppression. This subgroup also showed the lowest self-esteem, the highest external locus of control, and the highest number of somatic complaints.
These results demonstrate differential effects of burnout and perceived stress on hypothalamic-pituitary-adrenal axis regulation.
A 12-hour diurnal profile of salivary free cortisol was measured in healthy adults (n=40) on two consecutive days. Samples were collected at timed intervals synchronised to awakening. The mean profile is characterised by a marked increase in cortisol concentration following awakening, peaking after about 30 min, and a subsequent decline over the remainder of the day. Thus two components of the diurnal cycle were examined: a) the first 45 min post-awakening (the awakening cortisol response) and b) the underlying 12 h profile from immediately until 12 h post awakening (but without the awakening response). Both of these components were analysed in two ways such as to provide an indication of overall cortisol concentration and the degree of change in cortisol concentration, i.e. the rise for the awakening response and the diurnal decline. Both components of the cortisol diurnal profile were negatively correlated with awakening time. Thus, those subjects who awoke earliest had higher levels of cortisol over the 45 min following awakening as well as throughout the rest of the day. They also displayed a more marked diurnal decline to be convergent with late awakeners at the end of diurnal measurement, 12 h following awakening. Hence the diurnal cortisol cycle, which is synchronised to awakening, is significantly related to awakening time. These findings support the notion of a close association between suprachiasmatic nucleus (SCN) control of both awakening and cortisol secretory activity.
We investigated the effects of ablation of the suprachiasmatic nucleus (SCN) on corticosterone (CORT) responses to synthetic ACTH given in either the morning or evening. After dexamethasone treatment, evening ACTH injections in intact rats produced a significantly larger increase in plasma CORT compared with morning ones. In rats with SCN lesions, the ACTH-induced CORT secretion was independent of time of day, providing direct evidence for a driving influence of the SCN on the diurnal rhythm of adrenal sensitivity to ACTH. In the absence of dexamethasone treatment, the SCN-lesioned rats were selected for morning-like (ML) or evening-like (EL) basal levels of CORT. Responses to ACTH were not different in ML rats compared with sham-lesioned morning controls. In contrast, EL rats compared with sham-lesioned evening controls showed an approximately 60% decrease in increment of CORT levels within the first 15 min postinjection. These results indicate that the SCN upregulates ACTH sensitivity of the adrenal cortex during the ascending phase of the daily CORT secretion and point to a critical role of glucocorticoids in determining SCN action.
The neural circuits that modulate the suprachiasmatic nucleus (SCN) of the rat were studied with the retrograde transneuronal tracer – pseudorabies virus. First-order afferents were also identified using cholera toxin β subunit. Olfactory processing regions (viz., main olfactory bulb, anterior olfactory nucleus, taenia tecta, endopiriform nucleus, medial amygdaloid nucleus, piriform cortex, and posteriomedial cortical amygdaloid nucleus) were virally labeled. The subfornical organ directly innervates SCN; two other circumventricular organs: organum vasculosum of the lamina terminalis and area postrema provide multisynaptic inputs. Direct limbic afferents arise from lateral septum, bed nucleus of the stria terminalis, amygdalohippocampal zone, and ventral subiculum; multineuronal connections come from the basolateral and basomedial amygdaloid nuclei, ventral hippocampus, amygdalopiriform area, as well as lateral entorhinal, perirhinal, and ectorhinal cortices. Most preoptic regions project directly to SCN. Multisynaptic inputs come from the lateral preoptic region. Hypothalamic inputs originate from the anterior, arcuate, dorsal, dorsomedial, lateral, paraventricular, posterior, periventricular posterior, retrochiasmatic, subparaventricular, ventromedial and tuberomammillary nuclei. Paraventricular thalamic nucleus, intergeniculate leaflet and zona incerta directly innervate SCN. Polyneuronal inputs arise from the subparafascicular parvicellular thalamic nucleus. Brainstem afferents originate from the pretectum, superior colliculus, periaqueductal gray matter, parabrachial nucleus, pedunculopontine nucleus, raphe system, locus coeruleus, nucleus incertus and reticular formation. Nucleus tractus solitarius, C3 catecholamine region, rostral ventrolateral medulla and spinal trigeminal nucleus provide indirect inputs.