The Spit Report -- Salimetrics

Volume 3, Issue 3, June 2010 - Salimetrics

The Cortisol Awakening Response and Circadian Cortisol Regulation

Cortisol awakening response (CAR) graph

The cortisol awakening response (CAR) is a surge in cortisol production that occurs in most healthy people shortly after waking in the morning. The CAR has attracted a great deal of attention since its recognition in 1997, and in 2009-2010 alone nearly 300 papers have included some discussion of this physiological response. Dysregulation of cortisol levels has been proposed as a major factor that may be leading to an increased incidence of a broad range of disorders of the brain and body, and much of the research on the CAR has been devoted to its possible use as a biological marker of psychological and physical health status. This research has broadened our knowledge of some aspects of the CAR, but it remains difficult to understand the basic purpose of the CAR and its significance for human health.

In this issue of The Spit Report we present recent overview publications that explore the complex physiological factors that are involved in the regulation of the CAR, as well as the relationship of the CAR to the underlying circadian rhythm of cortisol. In addition, we include a newly-published study that re-examines the relationship between the CAR and health status, which may offer a way to explain the inconsistencies that have been observed to date in the CAR literature. In keeping with the belief that complex biological systems affect multiple analytes, we provide some background reading on melatonin, which is also involved in the body's transition from night to day. Finally, in our practical "Spit Tips" section, we present two valuable articles that offer advice on various strategies for saliva collection and data analysis that may be used to characterise cortisol production, including measurement of awakening levels, the CAR, area under the curve, and diurnal slope.


The Cortisol Awakening Response: More than a Measure of HPA Axis Function

Clow, A., Hucklebridge, F., Stalder, T., et al. (2009).  Neurosci Biobehav Rev, [epub ahead of print].

Interest in the CAR has been high since it was first described a little more than a decade ago, but many questions remain about the details of its regulation and the nature of its relationship to physical and mental health. In this overview of CAR research the authors discuss a number of interacting physiological influences that may be involved in the initiation and control of this cortisol peak. Where gaps in knowledge exist, they extrapolate and speculate, pointing out topics that will require further investigation.

Sub-Cortical Brain RegionsSpecial attention is given to the process of shifting from sleep to consciousness, which involves a rapid switching off of sub-cortical areas of the brain, such as the hippocampus, accompanied by switching on of cortical circuits. Because the CAR is superimposed on top of the normal circadian rhythm for cortisol production, these circadian influences must be considered as well. Control over the circadian cycle of cortisol production is largely maintained by the suprachiasmatic nucleus (SCN), which interacts with the hypothalamus over the course of the sleep period to gradually increase activity in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased secretion of ACTH and cortisol. In addition, associations between hippocampal function and the CAR and the existence of anatomical and functional pathways linking the hippocampus to the SCN suggest that the hippocampus plays an important role in the regulation of the CAR.

The authors review evidence that shows that the SCN is also involved in the control of the CAR via the sympathetic innervation of the adrenal gland. During the dark hours this extra-pituitary pathway-which is possibly modulated by pre-awakening activation of the hippocampus-appears to help keep rising cortisol levels in check by reducing the sensitivity of the adrenal glands to ACTH. At the point of awakening, rapid switching of brain circuits results in withdrawal of this suppressive mechanism, leading to a quick increase of cortisol production. The CAR is also clearly affected by light-mediated changes in SCN control, since awakening during the light period leads to heightened adrenal sensitivity to ACTH and a larger burst of cortisol production.

Control over the CAR is not only maintained by the SCN, however. The HPA system is also subject to negative feedback regulation, which has the ability to strongly inhibit the CAR. Individuals with PTSD, for example, have enhanced negative feedback, which reduces ACTH activity, resulting in the characteristic low and flat CAR observed with this condition. Other factors including gender and genotype are also thought to affect the CAR. There is also some speculation that the CAR may be related in some way to the gradual restoration of cerebral blood flow and the regaining of arousal during the first 15-60 minutes following awakening (i.e. overcoming sleep inertia). These links to restoration of brain function post awakening require further investigation.

The authors conclude that extra-pituitary input from the SCN appears to "fine tune" HPA axis function in both the pre- and post-awakening period, helping to initiate and shape the CAR. The CAR is a complicated phenomenon, however, and there are probably other regulatory influences that are also involved. Since cortisol has a wide range of effects on tissues in the body, it is likely that the CAR serves a variety of purposes, including recovery from sleep inertia, provision of an "energetic boost" for an anticipated busy day, elevation of cognitive function, and regulation of the immune system.

Angela Clow

Angela Clow is a distinguished faculty member at the University of Westminster, where she is a founding member of the interdisciplinary Psychophysiology and Stress Research Group.

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Additional Reading >


Assessing Salivary Cortisol in Large-Scale, Epidemiological Research

Adam, E.K., Kumari, M. (2009). PNEC, 34(10), 1423-36.

Large-scale social science and epidemiological studies are increasingly incorporating measurement of biomarkers such as salivary cortisol.  Ideally, researchers would be able to collect numerous samples, but in large studies this can result in prohibitively high costs.  This paper illustrates the use of several reduced-sampling protocols that provide adequate data points while keeping costs in check.  Other practical considerations such as obtaining consent, response rates, compliance with the protocol, saliva collection methods, and data analysis are also examined.

Abstract >

Two Formulas for Computation of the Area Under the Curve Represent Measures of Total Hormone Concentration Versus Time-Dependent Change

Pruessner, J.C., Kirschbaum, C., Meinlschmid, G., Hellhammer, D.H. (2003). PNEC, 28(7), 916-31.  

As discussed in the article by Adam and Kumari above, there are a number of ways to analyze salivary hormone data.  One method that is often used is the measurement of the area under the curve (AUC) over a certain time period.  Unfortunately, as noted here, differences in the way the AUC is computed can make it difficult to compare results between different research groups.  In this article the merits of two formulas for calculating the AUC are discussed.  Note also the correspondence that follows.

Abstract >

JUST IN . . .

Dr. Douglas Granger appointed to Johns Hopkins University

Douglas A. Granger, PhD, founder and Chief Scientific & Strategy Advisor for Salimetrics, has been appointed to the faculty of The Johns Hopkins University School of Nursing, where he will head the Center for Interdisciplinary Salivary Bioscience Research.  In his dual roles with Johns Hopkins and Salimetrics, Dr. Granger furthers the advancement of salivary research by exploring ideas that will demonstrate the ability of salivary analytes to make valuable contributions to the science of salivary research.

Dr. Granger served as president and scientific advisor of Salimetrics for the past eleven years and has directed Salimetrics through the development of assays for key biomarkers in saliva research.  Dr. Granger's current role as Chief Scientific & Strategy Advisor for Salimetrics accelerates the growth in development of salivary assays for new biomarkers of interest, as well as expands the development of salivary research applications for current biomarkers.

Salimetrics is dedicated to the advancement of salivary research through its support to the Center at Johns Hopkins University, sponsorships for salivary research in key areas of science, and training in the use of salivary biomarkers for research.

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