The Cortisol Awakening Response in Context

THE CORTISOL AWAKENING RESPONSE IN CONTEXT

Angela Clow
, Frank Hucklebridge†, and Lisa Thorn



†

Department of Psychology, University of Westminster, London W1B 2UW, UK Department of Human and Health Sciences, University of Westminster, London, W1W 6UW, UK

I. II. III. IV. V. VI. VII. VIII. IX.

Introduction History of the Investigation of the CAR Distinct Regulation of the CAR and Relationship with the SCN The CAR as an Awakening Process CAR and Cognitive Awakening CAR and Immunological Awakening CAR and Behavioral Awakening Measurement of the CAR Conclusions References

The cortisol awakening response (CAR) is a crucial point of reference within the healthy cortisol circadian rhythm, with cortisol secretion typically peaking between 30 and 45 min post awakening. This chapter reviews the history of investigation into the CAR and highlights evidence that its regulation is relatively distinct from cortisol secretion across the rest of the day. It is initiated by awakening, under the influence of the hypothalamic suprachiasmatic nucleus, and “fine tuned” by a direct neural input to the adrenal cortex by the sympathetic nervous system. This chapter also examples the CAR in relation to other awakening-induced processes, such as restoration of consciousness, attainment of full alertness, changes in other hor­ mones, changes in the balance of the immune system, and mobilization of the motor system, and speculates that there is a role for the CAR in these processes.

I. Introduction

The cortisol awakening response (CAR) is a period of increased cortisol secretory activity initiated by morning awakening and typically peaking between 30 and 45 min post awakening (Pruessner et al., 1997; Wilhelm INTERNATIONAL REVIEW OF NEUROBIOLOGY, VOL. 93 DOI: 10.1016/S0074-7742(10)93007-9

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et al., 2007). The CAR is recognized as a crucial point of reference within the healthy cortisol circadian rhythm but is generally studied in isolation from other awakening-induced processes (e.g., restoration of consciousness, attain­ ment of full alertness, changes in other hormones, changes in the balance of the immune system, and mobilization of the motor system). In psychobiolo­ gical research the CAR has frequently been used as a biomarker of hypotha­ lamic pituitary adrenal axis (HPA) status. However, evidence indicates that regulation of the CAR is relatively distinct from cortisol secretion across the rest of the day. The CAR is not a straightforward measure of HPA respon­ sivity (such as the Trier Social Stress Test), it is initiated by awakening, under the influence of the hypothalamic suprachiasmatic nucleus (SCN) and “fine tuned” by a direct neural input to the adrenal cortex by the sympa­ thetic nervous system (Buijs et al., 2003; Clow et al., 2010). Thus although different patterns of the CAR have been associated with different psycho­ pathologies, it is not entirely clear what these different patterns tell us about the underlying biological basis of the condition being studied. Furthermore as there is currently no clear understanding about the role of the CAR it is not clear what the downstream consequences of aberrant patterns of the CAR may be. It is becoming increasingly understood that circadian coordination via the central body clock is crucial for physical and mental flourishing and that disruption of circadian function is linked with multiple downstream negative physiological, psychological, and clinical consequences (Eismann et al., 2010). One of the main ways the SCN communicates with peripheral target tissues is via the neuroendocrine system and secretion of the hormones melatonin (at night) and cortisol (most prominent during the day). In this way the SCN coordinates peripheral cellular rhythms important for health. The dual SCN-mediated awakening-induced regulatory input to the CAR (i.e., via the HPA axis and the sympathetic nervous system) may make it a more accurate marker of the function of the central biological clock than examina­ tion of the HPA axis alone and account for its well-documented sensitivity to psychosocial and health variables. This chapter discusses the history and the use of the CAR as a biological marker of psychosocial status and health. Further, we aim to contextualize the CAR within the process of normal healthy awakening by exploring it in relation to other processes of awaken­ ing. The CAR is not an isolated response to awakening, rather it is part of a well-orchestrated physiology closely tuned to circadian cycles and essential for healthy functioning. Unhealthy states are often associated with poor circadian coordination and these can potentially be detected by exam­ ination of the CAR. Using this approach we hope to advance understanding of the CAR as well as potentially enlighten its physiological meaning and roles.

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II. History of the Investigation of the CAR

Glucocorticoids (cortisol in humans) are secreted in response to stress, affect multiple organ systems, and have a wide range of physiological and behavioral effects (Evanson et al., 2010; Sapolsky et al., 2000). Chronic stress and aging are associated with changes in the HPA axis and other glucocorticoid sensitive brain regions (e.g., the hippocampus) with consequent changes in the basal circadian pattern of cortisol secretion (Hsiao et al., 2010; Lightman, 2008). Aberrant basal patterns of cortisol secretion have been implicated in a range of psychological and somatic disease (Eismann et al., 2010; Minton et al., 2009; Sephton et al., 2000; Yehuda, 2001). Hence, there is a need for a thorough understanding of the components of the circadian pattern of cortisol secretion in order to develop meaningful biomarkers able to advance clinical and research studies involving this neuroendocrine system. A healthy basal pattern of cortisol secretion is characterized by a distinct circadian rhythm, largely controlled by the hypothalamic SCN, which influences adrenocortical activity via input to the paraventricular nuclei (PVN) of the hypothalamus (Buijs et al., 2003; Dickmeis, 2009; Kalsbeek et al., 2006; Krout et al., 2002). Under the influence of the SCN HPA axis activity gradually increases toward the end of nighttime sleep and gradually falls from a postawakening acrophase to a 24 h nadir in the early hours of sleep. This cyclical pattern of cortisol secretion can generate 14- to 15-fold changes in salivary free cortisol concentration across the day (e.g., Evans et al., 2007). Obviously the dynamic nature of the pattern of cortisol secretion makes it difficult to capture basal cortisol status accurately. Measures derived from a single blood sample taken in the early morning have been used frequently in assessment of adreno­ cortical status, particularly in clinical situations. However, these single point measures have low intra-individual stability (Schulz and Knabe, 1994), and hence limited utility. Twenty-four hour urinary measures of cortisol excretion provide a more reliable clinical index of overall cortisol secretion. However, this measure lacks subtlety in terms of the insight provided (different patterns of secretion could give identical results) as well as collection methodology (unplea­ sant and demanding on the participants). The adoption of saliva as the medium of choice for repeated measurement of cortisol across the day provided both a participant-friendly sample collection regime and the opportunity to look at dynamic change in cortisol secretion over the entire day and over short periods of time within the day (Kirschbaum and Hellhammer, 1994). As this approach was developed observations from multiple sleep research studies suggested that reported variability in cortisol levels stemmed from a stimulatory effect of awakening on HPA activity (Linkowski et al., 1993; Spathsch­ walbe et al., 1991, 1992; Vancauter et al., 1994; Weitzman et al., 1974). For

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example, Spath-Schwalbe et al. (1992) obtained polysomnographic recordings and 15 min blood sampling via forearm catheter from participants in a sleep laboratory. These authors revealed that the transition from sleep to wakefulness in the morning provoked brief elevations in plasma cortisol, a phenomenon later to be called the CAR (until recently also sometimes called the awakening cortisol response: ACR or even the cortisol awakening rise). However, it was Pruessner and colleagues (1995), then working at the Uni­ versity of Trier in Germany, who first brought the CAR into widespread notice. They reported that the concentration of salivary free cortisol showed a 50–100% increase within 30 min following awakening in healthy participants on five con­ secutive days. A more comprehensive account of the CAR was published by the same group two years later (Pruessner et al., 1997). This was the first paper to report intra-individual stability of the CAR over consecutive days and weeks in children, young, and older adults. In all three age groups the increase in salivary cortisol levels peaked at 30 min post awakening and the increase was relatively consistent, exhibiting good intra-individual stability. It was concluded that the CAR pro­ vided a reliable estimation of adrenocortical activity (Pruessner et al., 1997). Further evidence for intra-individual consistency, both in the overall levels of post-awakening cortisol secretion and the dynamic of the CAR, followed (Edwards et al., 2001a; Wuest et al., 2000b). Subsequent studies demonstrated that the CAR was not associated with postural change, sleep duration, or mode of awakening (see Clow et al., 2004). However, one noteworthy feature of the CAR to emerge from this early literature was that although overall cortisol secretion during the first 45 min follow­ ing awakening was representative of (i.e., correlated with) underlying diurnal cortisol secretory activity measured over the rest of the day the dynamic of the CAR did not, implying that they were in some way independent measures (Edwards et al., 2001a; Schmidt-Reinwald et al., 1999). Perhaps this was the first evidence that the CAR is a complex phenomenon, fine tuned by HPA-independent mechanisms, and therefore is not a simple index of HPA activity. This early evidence was supported by reports that the CAR was more closely associated with genetic variables than cortisol secretion across the rest of the day (Wuest et al., 2000a). This complex phenomenon has continued to be used as a simple biomarker of HPA axis activity in relation to health and psychosocial variables. Since the first papers concerning the CAR were published some 13 years ago, interest in this specific aspect of salivary cortisol secretion in humans has grown steadily, with a total of 280 outputs published up until the present, i.e., July 2010 (see Fig. 1). However, perhaps the full impact of work on the CAR can be best described from an analysis of the number of times each paper has been cited. There are a total of 4720 citations of the currently published 280 papers. This represents an impressive average citation count of 16.86 for each CAR paper. This means that

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Number of peer-reviewed publications

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Year FIG. 1. Peer-reviewed publications about the CAR in humans per year.

if all the CAR papers were published in the same journal it would have an impact factor of 16.86, which is in excess of Nature Neuroscience (which has an impact factor of just 14.345)! The conclusion from this analysis is that the findings from the relatively small set of CAR outputs are of interest to a wide range of people outside the area. The year by year increase in citations of the currently published CAR papers is shown in Fig. 2. Studies have examined the CAR in relation to a very diverse range of individual differences in psychosocial variables and health and there have been a multitude of interesting findings. However, the literature is by no means straightforward: there are inconsistent results about associations with different

Number of times cited

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9 19 7 9 19 8 9 20 9 0 20 0 01 20 0 20 2 0 20 3 0 20 4 0 20 5 0 20 6 0 20 7 0 20 8 09

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Year FIG. 2. Average citations per year for papers published on the CAR.

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patterns of the CAR. The confusion in the literature may stem from causes such as participant non-adherence to protocol; different experimental designs; differ­ ences in group demographics such as gender, age, and genotype; subtle difference in the psychosocial and health measures. Furthermore a full interpretation of the findings is not yet possible as the role or roles for the CAR has not yet been clarified. Indeed it is as if the role of the CAR is being deduced from these crosssectional studies (e.g., if the CAR is attenuated in condition X then it must be related to causes of condition X). This is a rather precarious approach and a more systematic analysis of the direct physiological correlates of the CAR, preferably in healthy participants in the first instance, would be helpful and inform cross-sectional studies more accurately. It is not the purpose if this chapter to fully review the disparate findings of studies examining between-subject differences in the CAR (reviewed in Chida and Steptoe, 2009; Clow et al., 2004; Fries et al., 2009). However, it is noteworthy that increasing age (Kudielka and Kirschbaum, 2003) as well as a range of conditions, e.g., cardiovascular disease, autoimmune conditions, slow wound healing, clinical depression, mild cognitive impairment, Alzheimer’s disease, and attachment anxiety, are associated with a high first waking sample and an attenuated dynamic increase following awakening (e.g., Arsenault-Lapierre et al., 2010; Buske-Kirschbaum et al., 2007; Ebrecht et al., 2004; Huber et al., 2006; Kudielka and Kirschbaum, 2003; Quirin et al., 2008). A notable and consistent exception to this pattern is post-traumatic stress disorder which is characteristically associated with an attenuated CAR with a low first waking sample (Fries et al., 2009). What is clear from the literature is that, despite early reports of individual day-to-day consistency, the CAR is not a simple trait measure as it is also prone to significant state influences (Hellhammer et al., 2007). It seems that healthy individuals can unknowingly modify their CAR in response to previous day’s experiences and in anticipation of the forthcoming day ahead (Adam et al., 2006; Dahlgren et al., 2009; Doane and Adam, 2010; Stalder et al., 2009). Indeed, anticipation of the time of awakening is known to impact upon the neuroendo­ crine system (Born et al., 1999) so it may not be surprising that anticipation of the day ahead can have similar effects. This corresponds to the reported weekday/ weekend differences in the CAR, where the CAR is typically reported to be attenuated at the weekend, when it is assumed that most people have fewer obligations (Kunz-Ebrecht et al., 2004; Schlotz et al., 2004). However, it has recently been reported that a better measure of positive psychosocial status is not the size of the CAR but rather greater day-to-day variation (Mikolajczak et al., 2010). In other words it is suggested that healthy functioning is associated with efficient anticipatory physiological responding that is flexible. It is also clear that the CAR is sensitive to non-psychological factors such as gender (Wright and Steptoe, 2005), time of awakening (Edwards et al., 2001b;

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Kudielka and Kirschbaum, 2003; Stalder et al., 2009), light (Scheer and Buijs, 1999; Thorn et al., 2004), hippocampal volume (e.g., Buchanan et al., 2004; Wolf et al., 2005), glucocorticoid receptor feedback (Pruessner et al., 1999), and genotype (van Leeuwen et al., 2010). These multiple factors again testify to the complexity of the CAR and the difficulty drawing meaningful conclusions about its role from cross-sectional studies in humans.

III. Distinct Regulation of the CAR and Relationship with the SCN

In a recent review the authors have argued that the CAR is subject to a complex range of physiological influences that facilitate the rapid increase in cortisol secretion initiated by awakening in healthy people (see Clow et al., 2010). In addition to awakening-induced SCN activation of the HPA axis (Wilhelm et al., 2007) direct sympathetic innervation from the SCN to the adrenal gland by the splanchnic nerve (Edwards and Jones, 1993; EhrhartBornstein et al., 1998; Engeland and Arnhold, 2005; Sage et al., 2002; UlrichLai et al., 2006) is implicated in the fine tuning of the CAR. In the immediate pre-awakening period there is evidence that this pathway induces reduced adrenal sensitivity to rising levels of adrenocorticotropic hormone (ACTH) (Bornstein et al., 2008; Buijs et al., 2003). The process of awakening is associated with “flip-flop” switching of regional brain activation (Braun et al., 1997; Lu et al., 2006; Saper et al., 2001; Sil’kis, 2009) which, it has been argued, initiates activation of the HPA axis. At the same time the SCN orchestrates a reversal of pre-awakening reduced adrenal sensitivity to ACTH (Bornstein et al., 2008; Buijs et al., 1997, 2003; Fehm et al., 1984). Indeed in the immediate post-awakening period adrenal sensitivity to ACTH is increased in response to light, a function again mediated by a SCN extrapituitary pathway (Buijs et al., 2003). Thus the SCN plays a pivotal role in the determination of the CAR by a combination of pre- and post-awakening influences operationalized via a dual control system: the HPA axis and the direct neural input to the adrenal cortex (see Fig. 3 for a diagrammatic representation of these pathways). One of the most consistent findings from the literature is that the hippocampus appears to play a permissive role in the regulation of the CAR (see Fries et al., 2009). This conclusion is derived from studies of clinical populations in which the hippocampus is impaired and the CAR attenuated (e.g., Buchanan et al., 2004; Wolf et al., 2005). In addition brain imaging studies have demonstrated positive associations between hippocam­ pal volume and the CAR (Bruehl et al., 2009; Pruessner et al., 2007). This

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Hippocampus Retina Light

PVN Negative feedback by cortisol

SCN

CRH Anterior pituitary

Dual SCN-mediated regulatory input to the CAR

ACTH Cortisol secretion

Adrenal cortex

FIG. 3. Simplified diagrammatic representation of some proposed regulatory inputs to the CAR. The hypothalamic suprachiasmatic nucleus (SCN) influences the secretion of cortisol via input to the paraventricular nucleus (PVN) and the HPA axis cascade (CRH and ACTH). In addition the SCN has a direct neural input to the adrenal cortex via the splanchnic nerve of the sympathetic nervous system; a pathway that may also be modulated by activity of the hippocampus (see text). Upon awakening the SCN enhances cortisol secretion in response to light.

evidence, although not extensive, suggests a causal linkage between func­ tional integrity of the hippocampus and the CAR. This is a feasible hypoth­ esis as there are anatomical and functional pathways linking the hippocampus to the SCN (Krout et al., 2002; Pace-Schott and Hobson, 2002; Stranahan et al., 2008). However, the hippocampus is known to have inhibitory effects on HPA axis activity (Herman and Cullinan, 1997; Herman et al., 2005). Thus the ambiguity as to why the hippocampus is permissive for the CAR has yet to be adequately explained. It has been argued (see Clow et al., 2010) that the role of the hippocampus in the regulation of the CAR occurs prior to awakening. This possibility is consistent with the fact that rapid eye movement (REM) sleep (typically dominant in the later stages of sleep and immediately pre-awakening) is associated with marked hippocampal activation which provides inhibitory tone on cortisol secretion, whereas awakening is associated with switching off of hippocampal activation (Balkin et al., 2002; Braun et al., 1997). It is speculated that pre-awakening activation of the hippocampus restrains pre-awakening cortisol secretion. Again it is possible that this regulation may be related to the SCN-mediated extrapituitary fine tuning of adrenal sensitivity to ACTH in the pre-awakening period, as described above. Although speculative there is sufficient circum­ stantial evidence to merit further investigation of these relationships in their role in the determination of the CAR.

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IV. The CAR as an Awakening Process

As its name suggests the CAR is a response to awakening. Although awakening corresponds to the transition between sleep and wakefulness, i.e., a clear disconti­ nuity of an ongoing sleep episode (Salzarulo et al., 2002), the physiological data available clearly show that the sleep-to-wake transition is not a rapid shift from one state of consciousness to another, but a complex process that takes some time to be completed. Awakening initiates the CAR, but the CAR may play a role in this transition from sleep to full alertness, awakening both the mind and the body in preparation for daytime activity. Cortisol is one of the most potent hormones of human physiology; virtually all of the body’s cells are potential targets for cortisol. It provides one of the means by which the circadian message from the SCN is transmitted to peripheral tissues. The peak of cortisol following awakening may play a particular part in synchronizing the body to both the sleep–wake and light–dark cycles via a range of nongenomic actions (Evanson et al., 2010). Further, it is becoming increasingly understood that circadian rhythms, particularly that of cortisol, transcribe the time of day message to the immune system. Circadian coordination is crucial for healthy physical and mental flourishing and disruption of circadian function is linked with multiple downstream negative physiological, psychological, and clinical consequences (Eismann et al., 2010). As detailed above, however, the CAR has generally been studied as an isolated phenomenon; it has rarely been considered as one of the physiological processes involved in the complex process of awakening. In fact, the CAR literature is characterized by an absence of a discourse on its role in the awaken­ ing process. Therefore, there is a need to re-contextualize the CAR as part of the awakening process. Here we are concerned with spontaneous morning awaken­ ing at the end of nocturnal sleep, leading to long-lasting and consistent awakening representing the termination of a full nocturnal sleep episode and a new beha­ vioral state. Other chapters in this volume (see Moul from Chapter 5 and Voss from Chapter 8) describe the difficulties in defining and identifying awakening. Voss proposes that as well as physiological markers, an awakening is accompa­ nied by behavioral responsiveness and the ability to think and the capacity for rational decision making and reflective awareness. Interestingly, these criteria for awakening are fully met in the measurement of the CAR which requires selfcollection of saliva samples. Participants are usually instructed to take the first sample as soon as they are conscious of being awake, which involves a cognitive component (“I am awake”) and a behavioral component (taking the saliva sample). Indeed difficulty in determining the precise time of awakening and delays in attainment of behavioral responsiveness may contribute to inaccuracies in its measurement and variation in the CAR literature. Below we review the potential role of the CAR in cognitive, immune, and also behavioral awakening.

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V. CAR and Cognitive Awakening

Hormones other than cortisol show a distinct circadian rhythm, most notably melatonin (Benloucif et al., 2005), which along with core body temperature, is a classic circadian rhythm marker. Melatonin has sleep-promoting effects in humans (Pandi-Perumal et al., 2008). The timing of melatonin secretion is closely associated with the timing of sleep propensity and it also coincides with decreases in core body temperature, alertness, and performance. Exogenous melatonin administered during the day has soporific effects; it lowers body temperature, induces fatigue, and generates a brain activation pattern resembling that which occurs during sleep (see Cajochen, this volume). In humans, melatonin secretion increases soon after the onset of darkness, peaks in the middle of the night (between 2 and 4 a.m.), and gradually falls during the second half of the night. In other words it has the opposing rhythm to that of cortisol, with melatonin promoting sleep and cortisol promoting wakefulness. At awakening, when cortisol levels rise, melatonin levels are falling. Although studies have observed that administration of melatonin alters the timing of circadian rhythms including that of cortisol (Arendt and Skene, 2005), no study to date has explored the explicit relationship between the rise in cortisol following awakening and the decline in melatonin. As both these hormones are regulated by the SCN and are controlled by the same underlying mechanism, an inverse relationship could be hypothesized. The attainment of consciousness following sleep constitutes cortical arousal/ activation. Switching of brain circuitry associated with the transition between sleep and consciousness may be associated with initiation of the CAR as such switching is known to be actively initiated by the process of awakening (Spathschwalbe et al., 1992; Vancauter et al., 1994; Wilhelm et al., 2007). Studies of brain activity support the notion that brain activation levels upon awakening largely differ from those characterizing wakefulness, and that awakening is a process. Both EEG and brain imaging studies have revealed that although awakening from sleep comprises rapid reestablishment of consciousness, the reestablishment of alertness is relatively slow. For example, Ferrara et al. (2006) demonstrated that visual evoked potentials (VEP) recorded upon awakening have decreased amplitude and increased latency of 100–300 ms components relative to the pre-sleep waking state. The sleep–wake transition is characterized by an EEG pattern of decreased beta power and of increased power in the delta-theta-lower alpha range for the first 10 min following awakening. Balkin et al. (2002) used positron emission tomography (PET) methodology to examine changes in regional cerebral blood flow during the transition to wakefulness and full alertness revealing that upon awakening reactivation in the brainstem, thalamus, basal ganglia, and anterior cingulate cortex was rapid, for example, the reactivation of the thalamus was complete at 5 min post awakening. Taken together these studies confirm that a

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state of cortical hypoarousal characterizes the early awakening. As detailed else­ where in this volume, this period between regaining consciousness (i.e., awakening) but before attainment of full alertness is described as “sleep inertia”: a transitory period of impaired arousal and behavioral performance lasting between 15 and 60 min (Ferrara et al., 2006; Ikeda and Hayashi, 2008). It seems that the initiation of the CAR is temporally associated with the attainment of consciousness and that the dynamic of the CAR closely parallels that of reactivation of the prefrontal cortex and attainment of full alertness. This temporal association could be considered simply as two parallel processes linked by the same underlying mechanism. However, there is some evidence indicating that the CAR may indeed play a role in the attainment of alertness following awakening. Indirect support is provided by the relatively consistent finding that acute bursts of cortisol have a stimulatory influence on psychological arousal and lead to a reduction of fatigue. This effect has been confirmed using self-report measures (Tops et al., 2006), arousal ratings in response to non-arousing stimuli (Abercrombie et al., 2005), as well as electro­ encephalographic (EEG) indicators of central alertness (Chapotot et al., 1998). Additionally, in sleep-deprived individuals early morning exposure to bright light induced an immediate elevation of cortisol levels, suppressed melatonin secretion, and limited the deterioration of alertness assessed by computerized vigilancesensitive performance tasks (Leproult et al., 2001). Few studies have directly tested the hypothesis that the CAR is associated with state arousal or levels of physiological activation. However, the results available to date have been supportive of a role for the CAR in the regaining of arousal, suggesting a positive association between state arousal at 45 min post awakening and post-awakening cortisol levels (Thorn et al., 2004) as well as the dynamic of the CAR (Thorn et al., 2009). This finding is also in general agree­ ment with results of Adam et al. (2006) showing an association between a larger mean CAR and lower average fatigue levels over a 3-day period. State arousal/ anticipations of a busy day ahead at 45 min post awakening have also been shown to relate positively with the CAR (Stalder et al., 2009). In addition high levels of sleepiness were associated with lower levels of cortisol 15 min after awakening in healthy office workers (Dahlgren et al., 2009). In summary the proposition for causal linkages between the CAR and recovery from sleep inertia, although speculative, certainly deserve further investigation. As well as general effects on alertness a further role for the CAR in awakening cognition can be discerned through its effects on memory retrieval. Rimmele et al. (2010) suppressed the CAR via administration of the cortisol synthesis inhibitor metyrapone. Participants were asked to recall emotional and neutral texts and pictures learned 3 days prior at 30 min following awakening. The metyraponeinduced cortisol suppression significantly impaired free recall in comparison to placebo. This finding corresponds to the view that memory-related processes are

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of importance for the CAR. Wilhelm et al. (2007) speculate that the CAR may play a role in the “booting” of memory representations in the organization of personality, identity, and the self, as well as of representations that have remained preactivated from more acute experiences. This idea is endorsed by research showing that the CAR is attenuated in patients with hippocampal damagerelated memory disorders (Buchanan et al., 2004; Wolf et al., 2005).

VI. CAR and Immunological Awakening

According to Dimitrov et al. (2009) circadian rhythms have been underinvestigated in relation to the processes underlying the regulation of the immune system. Evidence indicates that both enumerative and functional immune mea­ sures exhibit circadian rhythmicity and these rhythms seem to be closely asso­ ciated with the circadian rhythm of cortisol (Kronfol et al., 1997). Hence, disruption of circadian endocrine rhythms has been found to be associated with many disease states, including cancer. In fact evidence points toward circadian disruption as a risk factor for tumor initiation and accelerated progression (Eismann et al., 2010). The relationship between cortisol and the immune system is complex. Corti­ sol and melatonin appear to counter-regulate the Th1/Th2 balance by inhibiting Th1 and promoting Th2 immune responses (Cutolo et al., 2006). There is a bias toward Th1 responses during the night and Th2 responses during the day. The circadian rhythm of cortisol may play an important role in regulating the diurnal rhythmicity of Th1 and Th2 immunity. In particular it has been suggested that a primary role of the increase in free cortisol in response to awakening may be to switch the immune system from nighttime Th1 to daytime Th2 domination (Hucklebridge et al., 1999). In support of this hypothesis there is evidence that the Th1 cytokine profile during nocturnal sleep is switched to a Th2 cytokine profile on awakening (Petrovsky and Harrison, 1997). Furthermore these authors reported that the degree of switch correlated with cortisol levels measured at the time the cytokine switch was detected. This immune-switching hypothesis has yet to be investigated in any systematic way. However, in a more recent study Dimitrov et al. (2009) demonstrated that the regulation of circadian rhythms in T cell populations is tightly controlled by the rhythms of cortisol and catecholamines. Interestingly, epinephrine appears also to exhibit a response to awakening. Dodt et al. (1997) observed that during REM–NONREM sleep both epinephrine and norepinephrine were significantly lower than earlier sleep stages. On morning awakening epinephrine concentrations gradually began to increase, whereas norepinephrine levels were not affected by

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awakening, but were enhanced by change to an upright body position. Dimitrov et al. (2009) report similar findings with both epinephrine and norepinephrine reaching peak levels following awakening in the morning. Furthermore in this study, administration of both cortisol and epinephrine at low doses, purportedly mimicking the endogenous morning increase in these hormones, produced mark­ edly differential effects on the T cell subpopulations. For example cortisol infusion decreased naive T cell counts by approximately 40%, whereas administration of epinephrine produced an increase in circulating effector CD8þ T cells. Further investigation is warranted to explore the relationship between the shift in two major hormones following awakening in the morning and also their effect on immune parameters, particularly in relation to day and nighttime immunity.

VII. CAR and Behavioral Awakening

One of the functions of awakening (planned or otherwise) is to be able to respond to environmental cues by initiation of appropriate behavioral responses. Behavior requires coordinated and efficient motor function. This section pro­ poses a potential role for the CAR on the facilitation of voluntary motor function. Sleep states (especially REM sleep) are associated with inhibition of motor function called “sleep atonia.” This paralysis of most skeletal muscles is essential to ensure physical passivity during the periods of dynamic brain activation associated with dream states. Muscle atonia during sleep results from descending inhibitory projections to the spinal motor neurons from the caudal dorsolateral pontine tegmentum (Jones, 1991). Interestingly, an inability to initiate muscle atonia during REM sleep is increasingly being interpreted as an early sign of a range of neurodegenerative conditions (Boeve et al., 2001). As described earlier the process of awakening, in healthy individuals, involves the rapid switching off of these inhibitory pathways to restore the full waking state including voluntary motor function (Hobson, 2009). It is possible that the CAR may play a supplementary role in the reactivation of motor function post awakening as acute bursts of cortisol administration (similar in time course to the CAR) in humans have been shown to increase the excitability of the motor cortex as well as increase variability in motor cortex excitability (Milani et al., 2010). In their study Milani and colleagues examined motor-evoked potentials (MEPs) in the thumb in response to transcranial magnetic stimulation of the appropriate part of the motor cortex. Participants were assessed before and after either an injection of 20 mg of hydro­ cortisone or saline solution. Mean plasma cortisol levels rose rapidly and peaked around 10 min after hydrocortisone injection, at which time the mean MEP ampli­ tude and mean standard deviation of MEPs were significantly greater than pre­

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injection levels. Thus, although this study does not examine the CAR per se it does demonstrate that an equivalent acute burst in cortisol can have marked effects on the excitability of the motor cortex, effects that would facilitate voluntary movement. Currently the full significance of cortisol-induced increases in the variability of the excitability of the motor cortex is not fully understood. However, it is plausible that this state would facilitate appropriate motor responses to novel patterns of behavior, i.e., the capacity to explore and try out new motor skills. There is some supportive evidence for this theory showing that acute, physiologically relevant, corticosterone administration to rats rapidly increased exploratory locomotor activity when the animals were placed into a new activity cage but that the same dose of corticosterone failed to increase locomotion when administered to rats that had been previously exposed to the activity cage (Sandi et al., 1996). It has been suggested that this increase in locomotor activity may relate to risk-assessment behavior, which is also rapidly increased after treatment with corticosterone, without any change in anxi­ ety-like behavior or general locomotion in rats (Mikics et al., 2005). In contrast to its effects on motor cortical excitability, reported above, it is known that cortisol inhibits neural plasticity in the human motor cortex. Motor plasticity is associated with consolidation of learnt skills and the efficiency of plasticity is lowest in the morning and inhibited by acute bursts of cortisol administration (Sale et al., 2008). It is possible, and speculated here, that explora­ tory behavior (associated with increased motor cortical excitability and variabil­ ity) is facilitated by cortisol secretion in the morning, whereas consolidation of these actions (associated with neural plasticity) is facilitated later in the day when cortisol levels are low and in a steady state. Thus it seems plausible that the CAR may play a part in rapidly inducing specific behavioral adjustments to meet the immediate requirements set by the challenge of awakening. These speculations resonate with the observation that the dynamic of the CAR has been shown to be greater with more anticipated obligations in the day ahead: the CAR may play a role in literally “preparing for action.” Of course a role for the CAR in this type of motor function, although plausible, is speculative. It would be interesting to test this hypothesis by examin­ ing the impact of overnight cortisol synthesis inhibition (which abolishes the CAR) upon post-awakening motor cortical excitability in healthy participants.

VIII. Measurement of the CAR

Within the literature the CAR is most frequently derived from saliva samples taken by the participants themselves, within the domestic setting. This confers ecological validity but also lacks rigor in terms of reassurance that the sampling

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Awakening

regime is strictly adhered to (especially problematic due to the occurrence cogni­ tive deficits immediately post awakening). Instructions are typically given to collect samples on awakening and at a number of subsequent time points, e.g., 15, 30, and 45 (sometimes even 60) min post awakening. Due to the difficulties in accurately capturing this dynamic aspect of cortisol secretion within the domestic setting it is advisable to collect samples from each participant on more than one day as this allows for examination of day-to-day consistency, which should always be reported. Furthermore measures to assess and take account of participant adher­ ence to protocol, a notorious problem with this area of research (Broderick et al., 2004; Kudielka et al., 2003; Kupper et al., 2005) should be employed. The CAR is sometimes used as an umbrella term to describe both overall levels of cortisol secretion as well as the dynamic change in cortisol post awakening; these different elements are illustrated in Fig. 4. The area under the curve with reference to ground: AUCG (sample 2 þ s3 þ (s1 þ s4)/2) gives a good measure of overall cortisol secreted whereas the area under the curve with reference to the first waking sample: AUCI (sample 2 þ s3 – (2 * s1) þ ((s4 – s2)/2)) or the mean increase: MnInc (sample 2 þ s3 þ s4)/3 – s1) provide closely correlated measures of the dynamic change in cortisol following awakening. (The dynamic change in post waking cortisol is also sometimes calculated as levels 30 min post awakening minus the waking value, or the maximum concentration minus the first waking sample.) We would argue that the CAR is by its very nature a “response” to awakening and thus should always be presented as the change in concentration from the first waking sample rather than the overall AUCG. The main reason for this is that identical measures of AUCG can be derived from completely different, indeed even oppo­ site patterns of secretion, e.g., a high first sample and low last sample would equate

AUCI AUCG

S1 AUCB

Time FIG. 4. Graphical representation of the area under the curve with reference to increase (AUCI) and the first sample on awakening (S1). The area under the curve with reference to ground (AUCG) is the sum of the AUCi and the area under the curve with reference to base (AUCB).

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with low fist sample and high last sample. While AUCG may be informative under some circumstances, e.g., overall low as compared to overall high levels of cortisol secretion; it does little to enlighten knowledge of patterns of post-awakening cortisol secretion. We recommend that the most meaningful data to present from studies of the CAR are both the fist waking sample (S1) plus a measure of the change in cortisol secretion following awakening: AUCI or MnInc (the com­ posites from which the AUCG are derived). It is interesting to note that high levels of cortisol in S1 are sometimes associated with an attenuated CAR (Adam et al., 2006; Dahlgren et al., 2009; Stalder et al., 2009; Vreeburg et al., 2009; Wilhelm et al., 2007). However, this inverse association is not always the case (e.g., Evans et al., 2007) implying that the relationship between S1 and the AUCI is not fixed. Indeed it has been argued that S1 (if collected correctly) represents a measure of pre-awakening cortisol secretion, whereas AUCI or MnInc are post-awakening measures of cortisol secretion (Clow et al., 2010). As pre- and post-awakening cortisol secretions are under different types of regulatory control (see earlier) it is possible that dysfunc­ tion in either or both of these regulatory systems could affect the pattern of the CAR. For example a high first sample could implicate hypofunctioning of the hippocampus and/or SCN pathways to the adrenal (e.g., inefficient pre-awaken­ ing inhibition of adrenal sensitivity to ACTH). If S1 is in normative range but the AUCI is attenuated this could implicate a role for post-awakening processes (e.g., a role for light and the SCN). If both the S1 and the AUCI are affected then this might imply a role for the HPA axis more generally (e.g., low availability of ACTH and consequent low cortisol secretion). In order to help determine which of the CAR pathways are implicated in any particular pattern of post-awakening cortisol secretion, it would be helpful to have additional measures of cortisol from across the day. If the CAR is aberrant yet the rest of the diurnal pattern is not (e.g., Evans et al., 2007; Oskis et al., 2010) then this would imply that a CAR-specific mechanism is implicated, rather than HPA axis more generally. If, however, both the CAR and the rest of the diurnal cycle are aberrant then this might implicate a more general HPA axis-related phenomenon. It may also be useful to look at post-awakening patterns of salivary dehydroepiandrosterone (DHEA) (note that DHEA sticks to some types of saliv­ ettes, so care is required in choice of saliva collection methodology). DHEA does not mount an awakening response (Hucklebridge et al., 2005). This has been attributed to the fact that cortisol is synthesized predominantly in the adrenal zona fasciculata, whereas DHEA is synthesized in the zona reticularis only. In contrast to the reticularis, the zona fasciculata is subject to sympathetic innerva­ tion, a pathway that might form the light-sensitive extra-pituitary input to the adrenal cortex that contributes to the CAR (discussed earlier; see Fig. 3). As a consequence levels of post-awakening DHEA are a “cleaner” index of ACTH availability than the more complex CAR.

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More recently it has been suggested that the best way to capture individual differences in the CAR is to assess day-to-day variability, i.e., a measure of the flexibility of the CAR (Mikolajczak, 2010). This may be a promising new approach although work along these lines is in the early stages of verification. If adopting this strategy it is still necessary to ensure accurate measures of S1 and AUCI. It will be interesting to see how different degrees of variability in the CAR are related to different patterns of CAR. We would hypothesize that those with the most advantageous psychosocial profiles would typically present with a moderate S1 followed by a responsive AUCI and would also be capable of the most day-to-day variability, i.e., generate appropriate CARs in response to anticipation of the forthcoming demands of the day.

IX. Conclusions

Awakening from sleep can be a “hazy” phenomenon. Recently, when we asked people to recall and describe their first waking thoughts they said things like: I experienced a flow of disconnected thoughts; A woolly awareness; My thoughts were incoherent and jumpy. Indeed many of those asked to recall their first waking thoughts were unable to do so. This haziness belies the range of dynamic physiological activities that accompany the process of awakening and the restora­ tion of full waking alertness and function. In this chapter we have attempted to review the status of the CAR within the field of psychobiological research, summarize some of its distinctive regulatory characteristics, and contextualize it in relation to other post-awakening changes. There can be little doubt that the CAR holds great promise as a biomarker, but it represents more than an index of HPA axis function. Evidence is presented for dual control links with the hypothalamic SCN nucleus. It is increasingly apparent that physical and psychological flourishing is associated with close coordination of physiological functioning around the 24-h day (Eismann et al., 2010). It is argued that the CAR is part of a SCN-synchronized response to morning awakening in healthy participants. We propose that the CAR may play a part in the restoration of alertness and cognitive function, immune system balance, and voluntary motor function following nighttime sleep. Indeed evi­ dence is presented that the CAR can vary within an individual in response to the anticipated demands of the forthcoming day in order to meet those demands, both physically and mentally. Evidence is presented that individual differences in psychological and physi­ cal status (e.g., chronic stress, aging, and gender) are associated with the pattern of the CAR in distinct ways. These effects could be mediated by any of the

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regulatory pathways that affect the CAR, e.g., ACTH availability via the HPA axis, SCN-related mechanisms, hippocampal function, and provide a window into the brain that is broader than examination of the HPA axis alone. The relative ease by which the CAR can be measured in salivary samples enables large-scale population studies and can provide useful insight into risk factors. However, such work needs to pay attention to the particular issues associated with self-collection of saliva immediately upon awakening, to ensure that data collection is as free from non-adherence to protocol as possible. In addition due to the complex regulation of the CAR it is recommended that all studies should present data on the first waking sample (as a measure of pre-awakening cortisol secretion) and the dynamic of the cortisol rise post awakening. These measures are the two key determinants of the CAR and different states and regulatory pathways may be associated with either or both of these measures. Research on the CAR is making a wide impact upon the psychobiological research community and its significance and use is set to increase. We hope that in the near future greater clarification on the regulation and roles of the CAR in healthy participants will emerge. It is plausible that it plays a part in a range of functions as discussed in this chapter. These hypotheses are yet to be fully tested, but once we have a clearer view of its regulation and roles this biomarker will surely become even more significant. For example, in the future, it is possible that distinct patterns or characteristics of the CAR will be recognized biomarkers for different patterns of functioning associated with distinct brain system and neuroendocrine dysfunction (e.g., SCN-related mechanisms, hippocampal function, as well as of the HPA axis) and also point to downstream consequences in relation to health, cogni­ tion, and function. If this is the case then the measurement of the CAR will prove to be an increasingly valuable tool in the armory of researchers and clinicians alike.

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