Relationship between post-awakening salivary cortisol and melatonin secretion in healthy participants.

We report the relationship between patterns of post-awakening salivary melatonin and cortisol secretion in healthy participants (n = 51; mean age 21.6 ± 5.0 years). Saliva samples were collected within the domestic setting, at 0-, 15-, 30-, and 45-min post-awakening on 2 consecutive typical weekdays. Analyses were undertaken on data with electronically verified sample timing accuracy (<5-min delay between awakening and the start of saliva sampling). Melatonin secretion declined linearly by an average of 29% within the first 45-min post-awakening. In contrast, there was a marked 112% surge in cortisol, characteristic of the cortisol awakening response. No day differences in melatonin or cortisol secretion were observed but melatonin concentrations were lower with later awakening. Despite contrasting post-awakening changes in these hormones, there was a lack of relationship between overall levels or patterns of melatonin and cortisol during this period.

Use of Salivary Diurnal Cortisol as an Outcome Measure in Randomised Controlled Trials: a Systematic Review.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with diverse adverse health outcomes, making it an important therapeutic target. Measurement of the diurnal rhythm of cortisol secretion provides a window into this system. At present, no guidelines exist for the optimal use of this biomarker within randomised controlled trials (RCTs). PURPOSE: The aim of this study is to describe the ways in which salivary diurnal cortisol has been measured within RCTs of health or behavioural interventions in adults. METHODS: Six electronic databases (up to May 21, 2015) were systematically searched for RCTs which used salivary diurnal cortisol as an outcome measure to evaluate health or behavioural interventions in adults. A narrative synthesis was undertaken of the findings in relation to salivary cortisol methodology and outcomes. RESULTS: From 78 studies that fulfilled the inclusion criteria, 30 included healthy participants (38.5 %), 27 included patients with physical disease (34.6 %) and 21 included patients with psychiatric disease (26.9 %). Psychological therapies were most commonly evaluated (n = 33, 42.3 %). There was substantial heterogeneity across studies in relation to saliva collection protocols and reported cortisol parameters. Only 39 studies (50 %) calculated a rhythm parameter such as the diurnal slope or the cortisol awakening response (CAR). Patterns of change in cortisol parameters were inconsistent both within and across studies and there was low agreement with clinical findings. CONCLUSIONS: Salivary diurnal cortisol is measured inconsistently across RCTs, which is limiting the interpretation of findings within and across studies. This indicates a need for more validation work, along with consensus guidelines.

The cortisol awakening response predicts same morning executive function: results from a 50-day case study.

A relationship between individual differences in trait estimates of the cortisol-awakening response (CAR) and indices of executive function (EF) has been reported. However, it is difficult to determine causality from such studies. The aim of the present study was to capitalise upon state variation in both variables to seek stronger support for causality by examining daily co-variation. A 50 days researcher-participant case study was employed, ensuring careful adherence to the sampling protocol. A 24-year-old healthy male collected saliva samples and completed an attention-switching index of EF on the morning of each study day. Subsidiary control measures included wake time, sleep duration, morning fatigue, and amount of prior day exercise and alcohol consumption. As the CAR preceded daily measurement of EF, we hypothesised that, over time, a greater than average CAR would predict better than average EF. This was confirmed by mixed regression modelling of variation in cortisol concentrations, which indicated that the greater the increase in cortisol concentrations from 0 to 30 min post-awakening (CAR) the better was subsequent EF performance at 45 min post-awakening (t = 2.29, p = 0.024). This effect was independent of all potential confounding measures. Results are discussed in terms of implications for the understanding of the relationship between the CAR and the cognitive function, and the previously suggested role of the CAR in "boosting" an individual's performance for the day ahead.

Anxious attachment style predicts an enhanced cortisol response to group psychosocial stress.

Insecure attachment style is associated with poor health outcomes. A proposed pathway implicates the hypothalamic-pituitary-adrenal axis (HPA-axis), dysregulation of which is associated with a wide range of mental and physical ill-health. However, data on stress reactivity in relation to attachment style is contradictory. This relationship was examined using the novel Trier Social Stress Test for groups (TSST-G): a group-based acute psychosocial stressor. Each participant, in the presence of other group members, individually performed public speaking and mental arithmetic tasks. Seventy-eight healthy young females (20.2 ± 3.2 years), in groups of up to six participants completed demographic information and the Vulnerable Attachment Style Questionnaire (VASQ), and were then exposed to the TSST-G. Physiological stress reactivity was assessed using salivary cortisol concentrations, measured on seven occasions at 10-min intervals. Vulnerable attachment predicted greater cortisol reactivity independent of age, smoking status, menstrual phase and body mass index. Supplementary analysis indicated that insecure anxious attachment style (high scores on the insecurity and proximity-seeking sub-scales of the VASQ) showed greater cortisol reactivity than participants with secure attachment style. Avoidant attachment style (high scores for insecurity and low scores for proximity seeking) was not significantly different from the secure attachment style. Attachment style was not associated with the timing of the cortisol peak or post-stress recovery in cortisol concentrations. These findings in healthy young females indicate subtle underlying changes in HPA axis function in relation to attachment style and may be important for future mental health and well-being.

Reduced memory skills and increased hair cortisol levels in recent Ecstasy/MDMA users: significant but independent neurocognitive and neurohormonal deficits.

OBJECTIVES: The goals of this study were to measure the neurocognitive performance of recent users of recreational Ecstasy and investigate whether it was associated with the stress hormone cortisol. METHODS: The 101 participants included 27 recent light users of Ecstasy (one to four times in the last 3 months), 23 recent heavier Ecstasy users (five or more times) and 51 non-users. Rivermead paragraph recall provided an objective measure for immediate and delayed recall. The prospective and retrospective memory questionnaire provided a subjective index of memory deficits. Cortisol levels were taken from near-scalp 3-month hair samples. RESULTS: Cortisol was significantly raised in recent heavy Ecstasy users compared with controls, whereas hair cortisol in light Ecstasy users was not raised. Both Ecstasy groups were significantly impaired on the Rivermead delayed word recall, and both groups reported significantly more retrospective and prospective memory problems. Stepwise regression confirmed that lifetime Ecstasy predicted the extent of these memory deficits. CONCLUSIONS: Recreational Ecstasy is associated with increased levels of the bio-energetic stress hormone cortisol and significant memory impairments. No significant relationship between cortisol and the cognitive deficits was observed. Ecstasy users did display evidence of a metacognitive deficit, with the strength of the correlations between objective and subjective memory performances being significantly lower in the Ecstasy users.

Exercise Increases the Dynamics of Diurnal Cortisol Secretion and Executive Function in People With Amnestic Mild Cognitive Impairment.

Regular physical activity is protective against, and beneficial for, mild cognitive impairment (MCI), dementia, and Alzheimer's disease. The mechanisms underlying these benefits remain unknown although it has been suggested that exercise-induced changes in the circadian pattern of cortisol secretion may be implicated. Fitness, salivary cortisol levels (0 and 30 min postawakening, midday, 5 p.m., and 9 p.m.), and cognitive function were determined in a group of amnestic MCI patients (n = 39) before and after a three-month exercise program (n = 19) or usual care (n = 20). At baseline, fitness measures were positively correlated with peak levels of cortisol and a greater fall in cortisol concentration from peak levels to midday. The exercise intervention successfully increased fitness and resulted in a greater fall in cortisol concentration from peak to midday, compared with the control group. The exercise intervention enhanced indices of executive function, although memory, mood, and functionality were not affected.

Biological stress regulation in female adolescents: a key role for confiding.

Attachment behaviors play a critical role in regulating emotion within the context of close relationships, and attachment theory is currently used to inform evidence-based practice in the areas of adolescent health and social care. This study investigated the association between female adolescents' interview-based attachment behaviors and two markers of hypothalamic-pituitary-adrenal axis activity: cortisol and dehydroepiandrosterone (DHEA). Unlike the classic stress hormone cortisol, there is very limited investigation of DHEA-a quintessential developmental hormone-in relation to attachment, especially in adolescents. Fifty-five healthy females mean age 14.36 (±2.41) years participated in the attachment style interview. A smaller cortisol awakening response was related to anxious attachment attitudes, including more fear of rejection, whereas greater morning basal DHEA secretion was only predicted by lower levels of reported confiding in one's mother. These attachment-hormone relationships may be developmental markers in females, as they were independent of menarche status. These findings highlight that the normative shifts occurring in attachment to caregivers around adolescence are reflected in adolescents' biological stress regulation. We discuss how studying these shifts can be informed by evolutionary-developmental theory.

Day differences in the cortisol awakening response predict day differences in synaptic plasticity in the brain.

The cortisol awakening response (CAR) is the most prominent, dynamic and variable part of the circadian pattern of cortisol secretion. Despite this, its precise purpose is unknown. Aberrant patterns of the CAR are associated with impaired physical and mental health and reduced cognitive function, suggesting that it may have a pervasive role or roles. It has been suggested that the CAR primes the brain for the expected demands of the day but the mechanisms underlying this process are unknown. We examined temporal covariation of the CAR and rapid transcranial magnetic stimulation (rTMS)-induced long term depression (LTD)-like responses in the motor cortex. Plasticity was evaluated across 180 measures from five time points on four sessions across nine healthy researcher participants, mean age 25 ± 2.5 years. Plasticity estimates were obtained in the afternoon after measurement of the CAR on 4 days, at least 3 days apart. As both CAR magnitude and rTMS-induced responses are variable across days, we hypothesized that days with larger than individual average CARs would be associated with a greater than individual average plasticity response. This was confirmed by mixed regression modelling where variation in the CAR predicted variation in rTMS-induced responses (df: 1, 148.24; F: 10.41; p = 0.002). As the magnitude of the CAR is regulated by the "master" circadian CLOCK, and synaptic plasticity is known to be modulated by peripheral "slave" CLOCK genes, we suggest that the CAR may be a mediator between the master and peripheral circadian systems to entrain daily levels of synaptic plasticity.

The cortisol awakening response: regulation and functional significance.

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 30-45 min 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 non-genomic and slower genomic pathways (e.g., 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.

Physiological evidence consistent with reduced neuroplasticity in human adolescents born preterm.

Preterm-born children commonly experience motor, cognitive, and learning difficulties that may be accompanied by altered brain microstructure, connectivity, and neurochemistry. However, the mechanisms linking the altered neurophysiology with the behavioral outcomes are unknown. Here we provide the first physiological evidence that human adolescents born preterm at or before 37 weeks of completed gestation have a significantly reduced capacity for cortical neuroplasticity, the key overall mechanism underlying learning and memory. We examined motor cortex neuroplasticity in three groups of adolescents who were born after gestations of ≤32 completed weeks (early preterm), 33-37 weeks (late preterm), and 38-41 weeks (term) using a noninvasive transcranial magnetic brain stimulation technique to induce long-term depression (LTD)-like neuroplasticity. Compared with term-born adolescents, both early and late preterm adolescents had reduced LTD-like neuroplasticity in response to brain stimulation that was also associated with low salivary cortisol levels. We also compared neuroplasticity in term-born adolescents with that in term-born young adults, finding that the motor cortex retains a relatively enhanced neuroplastic capacity in adolescence. These findings provide a possible mechanistic link between the altered brain physiology of preterm birth and the subsequent associated behavioral deficits, particularly in learning and memory. They also suggest that altered hypothalamic-pituitary-adrenal axis function due to preterm birth may be a significant modulator of this altered neuroplasticity. This latter finding may offer options in the development of possible therapeutic interventions.

State variation in the cortisol awakening response.

The cortisol awakening response (CAR) is a much studied but poorly understood aspect of the circadian pattern of cortisol secretion. A Scopus search of "cortisol" and "awakening" reveals 666 publications in this area since 1997 when it was first identified by Pruessner and colleagues as a "reliable biomarker of adrenocortical activity". The primary focus of the majority of these studies is centered on its utility as a biomarker associated with a range of psychosocial, physical and mental health variables. Such studies typically examine differences in the CAR (studied on 1 or 2 days) between healthy participants and other comparator groups of interest. Fewer studies (25 in our estimation) have examined correlates of day-to-day variation in the CAR in healthy participants, informing its role and regulation within the healthy circadian pattern of cortisol secretion. This is the first review to examine these studies which, although limited in number, offer a relatively coherent emerging story about state factors that influence the CAR and the impact of the CAR on daily functioning. Greater understanding of these issues helps illuminate the utility of the CAR as a promising biomarker in psychophysiological and epidemiological research. The review also highlights areas that require greater clarification and points to potentially fruitful areas of further research.

Targeting neuroendocrine abnormalities in Parkinson's disease with exercise.

Parkinson's Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones - cortisol, melatonin, insulin, klotho, and vitamin D - that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease.

Diurnal patterns of salivary cortisol and DHEA in adolescent anorexia nervosa.

Although there is well-documented evidence for hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis function in anorexia nervosa (AN), there has been little research into secretory patterns of salivary cortisol and dehydroepiandrosterone (DHEA) in this condition. The cortisol awakening response (CAR), a prominent and discrete feature of the cortisol cycle, has not been extensively explored in adolescent AN. Saliva samples were collected at awakening, 30 min and 12 h post-awakening on two consecutive weekdays from eight female adolescents with clinically diagnosed AN and 41 healthy control (HC) age-matched females. Adolescent AN patients had greater salivary cortisol and DHEA concentrations than HC girls at all points. Increased hormone secretion was unrelated to body mass index. However, despite hypersecretion of both hormones, the circadian pattern including the CAR paralleled that of the HC group. Findings from this preliminary study confirm dysregulation of HPA axis function in adolescent AN as evidenced by hypersecretion of both cortisol and DHEA, which share the common secretagogue adrenocorticotropic hormone. However, the parallel diurnal profiles for AN and HC participants, including the CAR, may indicate hypersecretion per se rather than differential regulation of the diurnal pattern of these two adrenal steroids in AN.

The Interrelated Multifactorial Actions of Cortisol and Klotho: Potential Implications in the Pathogenesis of Parkinson's Disease.

The pathogenesis of Parkinson's disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD.

Evaluation and update of the expert consensus guidelines for the assessment of the cortisol awakening response (CAR).

The cortisol awakening response (CAR) is frequently assessed in psychobiological (stress) research. Obtaining reliable CAR data, however, requires careful attention to methodological detail. To promote best practice, expert consensus guidelines on the assessment of the CAR were published (Stalder et al., 2016, PNEC). However, it is unclear whether these highly cited guidelines have resulted in actual methodological improvements. To explore this, the PNEC editorial board invited the present authors to conduct a critical evaluation and update of current CAR methodology, which is reported here. (i) A quantitative evaluation of methodological quality of CAR research published in PNEC before and after the guidelines (2013-2015 vs. 2018-2020) was conducted. Disappointingly, results reveal little improvement in the implementation of central recommendations (especially objective time verification) in recent research. (ii) To enable an update of guidelines, evidence on recent developments in CAR assessment is reviewed, which mostly confirms the accuracy of the majority of the original guidelines. Moreover, recent technological advances, particularly regarding methods for the verification of awakening and sampling times, have emerged and may help to reduce costs in future research. (iii) To aid researchers and increase accessibility, an updated and streamlined version of the CAR consensus guidelines is presented. (iv) Finally, the response of the PNEC editorial board to the present results is described: potential authors of future CAR research to be published in PNEC will be required to submit a methodological checklist (based on the current guidelines) alongside their article. This will increase transparency and enable reviewers to readily assess the quality of the respective CAR data. Combined, it is hoped that these steps will assist researchers and reviewers in assuring higher quality CAR assessments in future research, thus yielding more reliable and reproducible results and helping to further advance this field of study.

Anxious attachment style and salivary cortisol dysregulation in healthy female children and adolescents.

BACKGROUND: Attachment style has been linked with basal cortisol secretion in healthy adult women. We investigated whether dysregulation in basal cortisol secretion may be evident in younger healthy females. METHODS: Sixty healthy females aged 9-18 years (mean 14.16, SD ± 2.63 years) participated in the Attachment Style Interview (ASI). Eight saliva samples, synchronised to awakening, were collected per day on two consecutive weekdays to examine the cortisol awakening response (CAR) and the subsequent diurnal decline. RESULTS: Participants exhibiting an anxious attachment style had higher cortisol levels on awakening, in contrast to those who were securely attached. The anxious insecure group also showed an attenuated CAR compared to all other participants. Attachment style groups did not differ in cortisol secretion over the remainder of the day. CONCLUSIONS: These findings indicate that the same pattern of cortisol dysregulation associated with disorder in adulthood manifests as a function of anxious (but not avoidant) insecure attachment style in females during healthy childhood and adolescence.

Smaller Cortisol Awakening Responses Are Associated with Greater Visual Dependence in Postural Control.

There are known links between the hypothalamic-pituitary-adrenal (HPA) axis and systems responsible for regulating posture. Our aim was to explore directly, for the first time, whether an aspect of circadian HPA axis activity (the cortisol awakening response: CAR) was associated with greater visual dependency in postural control. For measurement of the CAR, electronically monitored saliva samples were collected by participants following morning awakening in their home environment. On the afternoons of the same days, postural sway was measured in the laboratory by exposing participants to static (control) and moving visual stimuli whilst standing still and upright on a force platform. Visual dependence was assessed as the increase in postural sway (path length) during exposure to the moving compared with the static condition. The 44 measurement days were derived from four days for each of eleven healthy participants (mean ± SD age: 51.18 ± 3.3 years). As expected, postural sway was greater when exposed to moving versus static cues. Mixed regression modelling showed that participants with smaller four day average CARs had greater deterioration in postural sway when presented with moving stimuli. These data are the first to document associations between the CAR and visual dependency in postural sway.

Salivary cortisol as a non-invasive window on the brain.

The validation of accurate and meaningful assessment of cortisol in saliva samples has proved revolutionary in stress research. Its many advantages have expanded the scope of investigation from traditional laboratory and clinical settings to include multidisciplinary and community-based research. These developments have given rise to a wealth insight into the links between stress and health. Here we highlight the potential of salivary cortisol as both a product and mediator of brain function, instrumental in disturbing brain health. However, the subtleties of salivary cortisol as a measure can be underestimated, leading to misinterpretation of findings. These issues are explored, with a particular emphasis on necessary methodological rigor. Notwithstanding great promise, there is undeniably more to learn so we conclude by making recommendations for future research including use of salivary cortisol in the development of integrative predictive models of stress-related risk factors and resilience across the life course.

Stress, the cortisol awakening response and cognitive function.

There is evidence that stress-induced disruption of the circadian rhythm of cortisol secretion, has negative consequences for brain health. The cortisol awakening response (CAR) is the most prominent and dynamic aspect of this rhythm. It has complex regulatory mechanisms making it distinct from the rest of the cortisol circadian rhythm, and is frequently investigated as a biomarker of stress and potential intermediary between stress and impaired brain function. Despite this, the precise function of the CAR within the healthy cortisol circadian rhythm remains poorly understood. Cortisol is a powerful hormone known to influence cognition in multiple and complex ways. Studies of the CAR and cognitive function have used varied methodological approaches which have produced similarly varied findings. The present review considers the accumulating evidence linking stress, attenuation of the CAR and reduced cognitive function, and seeks to contextualize the many findings to study populations, cognitive measures, and CAR methodologies employed. Associations between the CAR and both memory and executive functions are discussed in relation to its potential role as a neuroendocrine time of day signal that synchronizes peripheral clocks throughout the brain to enable optimum function, and recommendations for future research are provided.