Human Body Temperature Circadian Rhythm in Health and Disease

Abstract

Human body temperature continues to be of interest to researchers with the newest discovery that it had been steadily decreasing since the mid-1800s, thus affecting our definition of normothermia and the cutoff for fever. Further, body temperature constitutes an explicit manifestation of our circadian rhythm, with temperature trough occurring in early morning and peak in the evening in healthy individuals. On the other hand, human illness, as seen among patients ranging from stable hospitalized ones to the critically ill, was shown to correlate with disturbance or even complete disappearance of the body temperature circadian rhythm. Also, night shift work affects the rhythm and had been associated with increased risk for malignancies, gastroenterological and metabolic disorders. Importantly, quantification of the observed rhythm deviations appears to have diagnostic and prognostic value in medicine. This chapter reviews the determinants of body temperature and the body temperature circadian rhythm, discusses the most prominent published research on associations between the rhythm and human disease, and concludes by outlining possible new research avenues and promising clinical applications in the field of chronotherapy.

1. Introduction

The circadian rhythm of humans and other living beings had intrigued scientists and philosophers since antiquity. While its first known manifestation was the sleep-wake cycle, over the centuries additional body functions were identified as being controlled by the circadian rhythm. This chapter explores the relationship between human body temperature and our circadian rhythm, which turns out to be one of interdependence. The existing literature is reviewed with a particular emphasis on the health-related effects triggered by disruptions in the diurnal body temperature oscillations. The chapter concludes by offering possible future research avenues that could lead to the development of clinical tools such as mortality prediction models, sepsis early-warning systems and chronotherapy approaches to night shift work-associated disorders and psychiatric illnesses, all based on monitoring body temperature variations.

2. Human body temperature: An evolving story

Human body temperature had been of interest to ancient healers [1, 2, 3, 4]. In more recent times, the German physician and researcher Carl Reinhold August Wunderlich became known as the father of clinical thermometry for his pioneering application of a thermometer to measure a precise body temperature. In his 1868 seminal paper [5], Wunderlich used over a million axillary temperature readings from over 25,000 patients to established the first normothermia average point of 37°C, with the upper limit of normal being 38°C. To date, we still use these numbers as a reference standard. Since human body temperature continues to be regarded as an important screening and prognostic tool in modern medicine, further efforts had taken place to establish normothermia ranges and determine the factors that influence body temperature measurements, as was recently review by our group [6].

An important difference in normothermia exists between what are regarded as core body temperature measurement sites (e.g., rectal and transurethral) and the non-core sites such as oral, axillary, or tympanic. The former yield higher temperature measurements than the latter, likely due to heat-dissipating processes like convection occurring at the body surface. Figure 1 (adopted with modifications and permission from Geneva et al. [6]) illustrates this difference using data from 36 unique peer-reviewed studies. Further, age is a known major determinant of human body temperature, where a decline in temperature is observed as we get older, which is featured in Figure 2 (adopted with modifications and permission from Geneva et al. [6]). Some studies have shown that body temperature also depends on the subject’s sex due to the change in body temperature among pre-menopausal women based on when the measurement is taken with regards to their menstrual cycle [5, 7, 8, 9]. In addition, the seasonal environmental temperature itself appears to influence our body temperature – a large study of over 93,000 emergency department patients demonstrated that on average human body temperature is lower by 0.2°C (using temporal artery thermometers) in the winter compared with the summer [10]—a statistically significant difference albeit a small one. Certainly, medical illnesses such as infections, malignancies, thyroid disorders, among many others, can strongly affect our temperature as well.

Figure 1.

Human body temperature of healthy volunteers classified by measurement site. Adapted with modifications and with permission from Geneva et al. [6] Figure 1B.

Figure 2.

Human body temperature of healthy volunteers classified by age and measurement site. Adapted with modifications and with permission from Geneva et al. [6] Figure 1C.

Interestingly, the 37°C normothermia average standard had been challenged by several research groups including Obermeyer et al. [11], Diamond et al. [12] and Corsi et al. [13], where a lower non-core average body temperature of 36.6°C, 36.1°C and 36.71°C were reported, respectively. While these findings were based on diverse cohorts and constituted only a point-in-time observation, Protsiv et al. [14] carried out a longitudinal study, where the measurements were adjusted for age, weight, height, and for some data sets for time of the day as well. By combining data from Civil War Union Army veterans covering 1860–1940, the National Health and Nutrition Examination Survey I covering 1971–1975, and the Stanford Translational Research Integrated Database Environment covering 2007–2017, Protsiv et al. discovered a curious trend of steady body temperature decrease at a rate of 0.03°C per birth cohort, leading to a difference of 0.56°C between males born in the 19th century and adult males today; for females, the total decrease was smaller — 0.32°C. Speculative explanations for this discovery centered around two major factors. First, there had been a decrease in metabolism as each new generation is believed to be significantly more sedentary than the prior and most homes are heated in winter and cooled in the summer, thus decreasing the human body basic metabolic rate expenditures. Second, the prevalence of fever in the human population induced by chronic inflammation had declined with the advent and widespread use of antibiotics, vaccines, and non-steroidal anti-inflammatory drugs.

In conclusion and knowing that we currently live in the era of personalized medicine, it is necessary to point out that ultimately, no matter what the population-wide average body temperature is, each person has their own baseline body temperature, which may be several standard deviations above or below the population average. This is illustrated by measured intrapersonal standard deviation of 0.32°C [12] and 0.39°C to 0.4°C [15] in healthy adults, while the range of measured interpersonal body temperatures in the same research studies spanned 2–3°C. This realization prompted several researchers to propose that “one size does not fit all” as it comes to normal body temperature [12, 13]. The definition of normothermia is further complicated by the fact that even within the same organism body temperature changes in a cyclic manner with a period of approximately 24 hours – the circadian rhythm of body temperature, which is the focus of the next chapter section.

3. Diurnal variation of human body temperature – A manifestation of our circadian rhythm

From unicellular organisms to complex mammals like humans, a circadian rhythm exists, whose role revolves around optimizing the function of the organism relative to an approximately 24-hour-long diurnal period [16, 17, 18, 19, 20]. While there are many bodily functions that appear to be governed by the circadian rhythm such as sleep, cardiovascular function, respiration, coagulation, and others, as detailed in other chapters of this book, body temperature is one of if not the most easily accessible manifestation of the circadian rhythm. Body temperature can be measured with both good accuracy [21] and at high frequency [22], thus allowing for relatively inexpensive experimental designs in the fields of circadian rhythm and chronotherapy research.

The relationship between body temperature diurnal oscillations and the circadian rhythm was first reported in the 1800s by Davy [23] and Ogle [24]. Currently, we know that in healthy humans the minimum body temperature (the bathyphase) occurs in the early morning about 2 hours before wakening (i.e., 5–7 AM) and the maximum body temperature (the acrophase) occurs in the evening about 2 hours before falling asleep (i.e., 8–10 PM) [25, 26, 27, 28]. The body temperature diurnal cycle can be approximated by a sinusoidal curve, whose amplitude is one-half of the total diurnal temperature change (acrophase minus bathyphase), and whose mesor is the rhythm-adjusted mean. The reader can refer to Figure 3 for an illustration of this cycle. In humans, the amplitude had been measured to be around 0.2–0.8°C [16, 26, 27, 29]. There appear to be certain sex-based differences in the diurnal body temperature cycle just like there were differences in average body temperature between the sexes, as was described in the previous section of this chapter. For instance, Cain et al. [27] showed that on average the bathyphase in healthy women occurred earlier (at 4:46 AM) compared with healthy males (at 6:11 AM). The same study also measured a statistically smaller diurnal amplitude among women (0.43°C) versus men (0.55°C). Mallette et al. [28] also found an earlier bathyphase for women (at 4:48 AM) compared with men (at 6:04 AM) and also measured a much later acrophase for women (at 10:49 PM) compared with men (at 8:49 PM). The authors of these studies hypothesized that the measured differences in the timing of acrophases and bathyphases could be related to the different timing of melatonin peak between the sexes. However, a highly controlled study by Gunn et al. [30] showed that although melatonin production and subsequently serum concentrations were higher in women, the circadian rhythm of melatonin, i.e., the timing of peak and trough, were statistically identical for both sexes. On the other hand, it was hypothesized that sex hormone-related differences could account for the lower diurnal change but not for the above detailed differences in acrophase and bathyphase timing [31, 32].

Figure 3.

Body temperature circadian rhythm schematic.

Further, age seems to be affecting the circadian rhythm as well. Czeisler et al. [29] showed that among healthy subjects the diurnal body temperature amplitude was significantly higher among younger individuals (average of 0.28°C) compared with older adults (average of 0.2°C). The authors proposed that there are age-related changes in the mammalian intrinsic pacemaker (the suprachiasmatic nucleus (SCN) in the hypothalamus) that could account for the smaller amplitudes among people and animals of advanced age. This is supported by the finding that other circadian rhythm indicators such as the sleep-wake cycle are also shorter in older people [33, 34]. Further, as humans age, the SCN decreases in size, likely due to age-related microvascular disease that leads to the overall shrinkage of the human brain with age, with the total number of SCN cells decreasing as well [35, 36]. Perhaps the most striking evidence stems from animal models using rodents, where the sleep-wake cycle period and the amplitude of the body temperature oscillation were shown to be directly proportional to the size of the remaining volume of the SCN in animals with partial lesions inflicted in that brain region [37, 38], with total loss of the circadian rhythm of body temperature upon complete surgical removal of the SCN [39]. However, it should be pointed out that traumatic brain injury in rats not involving the SCN specifically also had been shown to induce downregulation of circadian clock gene expression and associated animal behavioral changes [40], thus pointing to a more complex regulatory process of the mammalian circadian rhythm.

Although the complexity of body temperature regulation in man is great, ultimately a specific body temperature is the result of a balance between heat production via body metabolism and heat loss via processes such as heat radiation from and air convection at the body surface. Like we mentioned in the previous paragraph, the master pacemaker for all circadian cycles of the mammalian body, including body temperature, is believed to be located in the suprachiasmatic nucleus (SCN) of the hypothalamus, with abundant evidence thereof recently reviewed by Hastings et al. [41]. In a most simplistic description, body temperature information needs to be captured from the periphery, e.g., the extremities and the internal organs, then transported to the SCN, where it is processed, compared to the expected pre-set body temperature goal for the current location along the diurnal circadian cycle, then instructions for adjustments in heat production need to be sent from the SCN to the periphery and executed at the cellular level, with the ultimate result being a rise or fall in body temperature. To aid this temperature “normalization” process, there are also behavioral adaptations that animals exhibit such as seeking shade when the environment is too hot or moving to a warmer place when it is too cold. Certainly, the majority of modern humans have many more behavioral adaptations at their disposal compared with mammals living in the wild.

The specific mechanisms for some of these steps are well understood while others are still being investigated, with several recently published reviews available in the literature [17, 41, 42]. In mammals, including humans, temperature is sensed by TRP (transient receptor potential) family of ion channels [43, 44, 45]. The TRPs are expressed in sensory neurons throughout the body, with the biggest contributors to the signal being the skin, spinal cord, abdominal viscera, and the brain [46]. Different subtypes of TRPs are activated at different temperature thresholds [47] and the temperature information from the various sources is believed to be collected and processed by the SCN [48]. The SCN then communicates with the neurons in the preoptic area of the hypothalamus, which initiate the downstream signaling to achieve a “correction” in the organism’s body temperature via the physiologic effectors that control thermogenesis, shivering, skin blood flow, and evaporative cooling as well as via thermoregulatory behaviors [49, 50]. The details regarding the various signaling cascades involved in the downstream signaling are still an area of active research. How the master pacemaker in the SCN operates is also being debated. There is some evidence pointing toward synchronization (a.k.a., entrainment) of the SCN by the ambient day-night lightening pattern [51, 52, 53]. Other studies provide evidence for hormonal regulation via melatonin feedback loops [54, 55] and via fluctuations in the serum serotonin levels [56, 57].

Regarding the circadian clock signaling mechanisms on the cellular level of multicellular organisms, these are being detailed in other chapters of this book. But briefly, in nearly all cells, including the SCN neurons, there is a clock-like mechanism in the form of an auto-regulatory transcriptional negative feedback loop as follows: The proteins CLOCK and BMAL1 (brain and muscle Arnt-like protein-1) form a dimer, which serves as a transcription factor and activates the transcription of the period and cryptochrome genes, which are then translated into the PER and CRY proteins. The PER and CRY proteins then interact with CLOCK and BMAL1, preventing them from further activating the period and cryptochrome genes’ transcription. The CLOCK:BMAL1 transcription factor had been shown to also facilitate the expression of the clock-controlled genes (Ccgs), which are believed to control about 30% of the mammalian genome expression, thus controlling physiologic functions involved in metabolism, immunity, and many others [58]. To offer an example relevant to the circadian rhythm of body temperature, one of the downstream effects of this transcription loop involves the generation of oscillations in the mitochondrial oxidative capacity in mice via rhythmic changes of NAD+ biosynthesis [59]. These oscillations lead to changes in metabolic rate on the cellular level, which could potentially lead to a change in body temperature on the organismal level. All in all, at the current stage of scientific knowledge, the mechanisms that link the metabolic circadian rhythm at the cellular level to the circadian rhythm on the organismal level remain largely uncertain. What is curious however is the finding that even though an organism’s body temperature diurnal cycling is governed by the circadian rhythm generated by the SCN, the diurnal temperature cycling itself is sufficient to sustain peripheral circadian clocks. This had been demonstrated by Brown et al. [60] in experiments where peripheral tissues from mammals were cultured ex vivo. The authors showed that by simulating the in vivo body temperature cycling inside the incubator, the tissues were able to maintain the proper circadian gene expression patterns. This points toward the existence of interdependence between the master clock in the SCN and body temperature. Beyond doubt, more research needs to be carried out before we can have a complete mechanistic picture for the maintenance of our body temperature. In parallel, knowledge regarding the clinical implications of disturbance in the body temperature diurnal rhythmicity had been accumulating and is explored in the next chapter section.

4. Fever, hypothermia, and other disruptions to the human body temperature circadian rhythm

Numerous studies had been carried out to demonstrate how disruption in the circadian rhythm of body temperature can affect human health. Perhaps the most extreme situations are those where fever or hypothermia completely obliterate the circadian rhythm balance. To better understand the clinical implications of these disruptions, we need to define fever and hypothermia. It had been known for a long time that a pyrogen (such as bacteria, viruses, toxins, and others) triggers “fever” by causing the release of prostaglandin E2, which acts on the preoptic area of the hypothalamus (a.k.a., the mammalian thermostat) to make it raise the temperature set point [61]. A higher temperature set-point results in a systemic body response attempting to raise the peripheral body temperature via active heat generation and by heat retention. Fever (pyrexia) in humans is associated with high inflammatory states such as sepsis and trauma [62]. Elevation of body temperature promotes the activation and trafficking of immune cells— in the case of T-lymphocytes, cell mobilization is achieved via a thermal sensory pathway involving alpha4 integrins and heat shock protein 90 [63]. On the other hand, hypothermia is a state of lower-than-normal hypothalamic setpoint. It occurs in settings such as severe debility due to illness leading to the inability to raise the body temperature; brain injury involving the preoptic area including age-related microvascular brain damage, stroke, and traumatic brain injury; congenital malformation of the preoptic area; seizure disorders, and likely others [64]. Hypothermia is associated with the inability to mount a strong inflammatory reaction and this is the reason why induced hypothermia had been used in some patients of cardiac arrest, where inflammation needs to be suppressed in order to allow time for the cardiac tissues to recover from the ischemic injury [65].

Deviations from normothermia among critically ill patients had been extensively studied. These deviations manifest in most such patients and appear to carry a prognostic value. For instance, a study by Sunden-Cullberg et al. [66] demonstrated that the ability among critically ill septic patients to mount fever while in the emergency department, i.e., before their admission to the ICU, was associated with lower in-hospital mortality and shorter hospital length of stay. On the other hand, Kiekkas et al. [67] showed that among the 239 ICU patients without cerebral damage such as stroke or neurosurgery in their study, fever was not associated with mortality but there was statistically significant increase in mortality with each 1°C increase in sustained maximal body temperature, indicating too much of a good thing (fever and the associated heightened immunity levels) can be harmful. Further, Peres Bota et al. [68] studied 439 ICU patients, not excluding any patients such as those with cerebral damage or those undergoing hypothermia protocols e.g., following cardiac arrest. These researchers found that both fever and hypothermia were associated with increased morbidity and mortality but those with hypothermia had a worse survival rate than the febrile patients. A potential confounding factor there was the fact that the hypothermic patients were significantly older compared with the patients with fever and it is common sense that older age is associate with less favorable clinical outcomes. In the case of patients with cerebral injury, studying 251 hospitalized subjects Schwartz et al. [69] demonstrated worse outcomes for patients with persistent fever and intracerebral hemorrhage, while Bao et al. [70] found similar results among their 355 patents with traumatic brain injury.

Regarding alterations in the body temperature circadian rhythms, these had been shown to occur in a variety of ways among the critically ill, including erratic acrophases, bathyphases, amplitudes, even complete abolishment of the cycling pattern [71, 72, 73, 74]. Specifically, Tweedie et al. [71] showed that among the 15 intensive care unit (ICU) patients in their study, the acrophases varied by several hours from day to day both between patients and within the same individual patients over the study period of at least 8 ICU days per patient. Nuttall et al. [72] evaluated 149 ICU patients and reported that nearly all lacked a circadian rhythmicity of body temperature with the bathyphases distributed randomly throughout each 24-hour period. Paul et al. [73] studied 48 ICU patients and demonstrated major disturbance and often complete abolishment of the circadian rhythm as given by body temperature, melatonin and cortisol levels, blood pressure, heart rate, and spontaneous motor activity, all of which are known to be cycling with a 24-hour period in healthy individuals. Pina et al. [74] evaluated 8 patients managed in the burn ICU for 30 days and demonstrated the lack of circadian rhythm based on body temperature, melatonin, and cortisol levels for all patients during the entire hospitalization, although the authors noted a trend toward normalization of the body temperature diurnal cycle for some of the patients during the later stages of hospitalization. The latter two studies described above were prospective in design, thus providing more frequent data points, which may correspond to higher reliability but the overall conclusion based on all research findings is that critical illness is associated with major disturbance in the circadian rhythm of human body temperature.

The clinical prognostication value of human body temperature circadian rhythm variations is remarkable as well. Blume et al. [75] demonstrated that among their 18 patients with severe brain injury leading to loss of consciousness, preservation of the body temperature diurnal cycling was associated with increased chance for recovering from their comatose state. Further, Tweedie et al. [71] found that among their 15 ICU patients, there was a bigger circadian rhythm amplitude during periods of unconsciousness compared with when patients were conscious and the amplitudes were also bigger among the patients who died compared to those who survived. In a larger study of 248 patients with severe trauma admitted to the ICU and excluding any patients who had undergone targeted hypothermia protocol following cardiac arrest, Culver et al. [76] found that disruption in the body temperature circadian rhythm with mesor <36.9°C and amplitude >0.6°C were associated with higher 28-day-all-cause mortality. They also showed that the association was more pronounced among patients with head trauma compared with those with non-head trauma. Among the general ICU patient population comprising of 21 patients, Gazendam et al. [77] documented an acrophase shift in 81% of the studied patients and also found that the severity of illness, as given by the APACHE III (Acute Physiology and Chronic Health Evaluation) score, was predictive of the magnitude of circadian misplacement. Importantly, it was demonstrated by Drewry et al. [78] how in the ICU setting one can monitor the diurnal body temperature oscillations and look for specific disruptions in the rhythm that had been associated with the early development of sepsis, thus providing an early sepsis warning before the traditional sepsis criterial are met, which in turn would allow for an earlier intervention with antibiotics. Given all the clinical data, it is fair to conclude that disruption of the circadian rhythm and deviation from normothermia among the critically ill likely facilitates a mal-adaptive and hyperactive (in the case of fever) or hypoactive (in the case of hypothermia) inflammatory responses that can lead to organismal failure and death.

The importance of the circadian rhythm has also been demonstrated in non-critically ill hospitalized patients. For instance, our group [79] found that among the 16,245 hospitalized patients included in the study, the circadian rhythm was disrupted in 80%. Further, we reported an age-dependent shift in the circadian pattern, with the body temperature bathyphase of older people shifted to 12 pm in the afternoon (compared with 8 am for young adults) but with the acrophase among the old remaining at 8 pm, similar to the younger patient cohort. (Figure 4, adopted with modifications and permission from Geneva et al. [79]). After considering other theories, we had concluded that the most likely explanation for the circadian body temperature disruption during hospitalization was the disturbance in the patients’ day-night light cycles caused by frequent awaking at night for procedures, vital signs measurements, and the associated exposure to light during the night. Several other studies with human subjects have also supported the role of diurnal light levels in resetting the human circadian clock [80, 81, 82, 83, 84]. Similar to the ICU patients, body temperature measurements from non-critically ill patients appear to carry prognostic value as demonstrated by Obermeyer et al. [11]. The authors studied the body temperature of over 35,000 hospitalized patients, who were not diagnosed with infection and did not receive antibiotics; they showed that after adjustment for age and comorbidities that could affect body temperature (e.g., hypothyroidism is associated with lower body temperature, active cancer is associated with higher body temperature), there was correlation between deviation from the expected normothermia range and the one-year mortality.

Figure 4.

Diurnal body temperature variation of hospitalized patients classified by age. Adapted with modifications and with permission from Geneva et al. [79] Figure 2A.

On the outpatient basis, the disruption of the natural circadian rhythm emerged as an important player in disease pathogenesis via epidemiologic studies in the 1990s that linked it to the development of cancers among night shift workers. Specifically, higher levels of breast cancer were noted among Norwegian radio and telegraph operators [85]. Further research also demonstrated increased incidence of colorectal and prostate cancers as well as metabolic and gastrointestinal disorders among people working night shifts [86, 87, 88]. In this population of workers, various circadian rhythm markers such as melatonin and cortisol blood levels as well as the diurnal cycling of body temperature were shown to be disturbed [89, 90, 91, 92]. The situation was further aggravated by the realization that these circadian abnormalities persist for years after retirement from night shift work jobs [92, 93]. It should be mentioned that not all research had been supportive of these associations; namely a recent meta-analysis by Dun et al. [94] evaluated 57 observational studies and concluded that there was no association between any exposure to night shift work during subjects’ lifetime and increased risk for several common solid cancers, albeit there were several major caveats regarding the data heterogeneity. Notwithstanding the meta-analysis results, researchers theorized that light exposure at night facilitates the carcinogenesis via disruption of the natural melatonin cycle in humans. Melatonin is believed to have a second function, in addition to neuro-hormonal signaling, where it acts as a scavenger of reactive oxygen species [95]. As melatonin production occurs at night and it is suppressed by light, exposure to light during night shift-work leads to less melatonin production and supposedly accumulation of oxygen radicals, which constitute a known risk for the development of malignancies [96]. In support of this theory, it was demonstrated that women with complete blindness (no light perception) had significantly lower prevalence of breast cancer compared with blind women with preserved light perception [97]. Research with mice had provided more specific evidence, where melatonin knockout animals prone to breast cancer development (p53(R270H/+)WAPCre conditional mutant mice) suffer from faster tumor growth in shift work simulation experiments as compared to animals with the same breast cancer predisposition but with normal melatonin production [98]. Over the years, sufficient evidence had accumulated from epidemiological studies and animal model research to prompt the Agency for Research on Cancer to classify shift work involving circadian rhythm disruption as likely carcinogenic [99]. This is a good place to point out that in the current era of technological advance, a large portion of Earth’s population is living in conditions akin to night shift workers’ due to the extensive use of digital devices (cell phones, tablets, TV, etc.) late into the night, thus leading to the so called social jetlag and likely circadian misalignment [100, 101].

It is well established that a weakened immune system is a predisposition to the growth of malignancies, with cancer immunotherapy currently being a hot area of research [102]. As such, the above-described associations between circadian rhythm disruption and cancer may stem from the effect of circadian rhythm abnormality on the immune system, which was previously reviewed by Logan et al. [103], Comas et al. [104], and Coiffard et al. [105]. While most research had been done in animal models, human studies did show that disruption of the circadian rhythm (induced with a sleep desynchronization protocol) negatively affects the human transcriptome [106]. Namely, the authors found a reduction in the normal diurnally-guided rhythmic transcription from a baseline of 6.4% to 1.0%. Many of the genes affected by this transcription reduction are known to play important roles in immune pathways, including cytokine and NFκB signaling [106, 107]. The effect of the circadian rhythmicity on one’s immunity could also explain the observation from mice animal models where disease severity was higher if a pulmonary infection with Streptococcus pneumoniae was induced during the resting phase of the animals (when their body temperature is lower) compared with infecting them during their active phase (when their body temperature is higher) [108].

In addition to associations with cancer and immunologic dysfunction, night shift-work-related circadian rhythm disturbance had been linked to cardiovascular risk factors such as decrease in insulin sensitivity and decrease in leptin (the satiety hormone) blood levels [109, 110, 111, 112, 113, 114]. Other published reports have demonstrated links to cognitive and psychiatric disorders as reviewed by Karatsoreos et al. [115]. These include decreased reaction time, increased error rate, and temporal lobe atrophy among flight attendants serving on frequent trans-Atlantic flights leading to jet-lag-induced circadian rhythm desynchronization [116]; correlation between the intensity of major depression attacks with the size of delays in the circadian pacemaker as regards the timing of sleep onset [117]; reduction in the self-reported mood and wellbeing level among healthy volunteers who were subjected to a sleep-wake circadian rhythm disruption experimental protocol [118]. Even the gut microbiota was shown to be altered upon disruption of the circadian rhythm based on light-dark cycling in animal models using mice [119] and Drosophila [120]. It should be noted that the experimental findings detailed in this paragraph do not directly link disruption in the body temperature circadian rhythm to the identified behavioral or physical health conditions and deficits. Still, body temperature is the most easily measured indicator of circadian rhythm preservation or disruption. As such, its application in the design of experimental paradigms and tests for the effects of medical interventions is expected to be of great benefit to future research, which is the focus of the next chapter section.

5. Future directions in body temperature and chronotherapy research

The last two centuries saw a great advancement in our knowledge of the circadian rhythm of living organisms. Yet, much remains to be discovered as relates to both molecular pathways and clinical applications to improve human health. In particular, at the current stage of scientific knowledge, the mechanism that links the circadian rhythm at the cellular level to the circadian rhythm of body temperature on the organismal level remains unknown. Also, there is a significant heterogeneity among human studies, thus making the confirmation of specific associations between disruption in the circadian rhythm and human disease challenging. Further, the clinical interventions currently in use are at best crude and not optimized to reach their full potential. One example is the use of a melatonin pill in the evening to fight insomnia, where research regarding the dose or time of intake remains inconclusive and the effects are modest, as detailed in a metanalysis by Ferracioli-Oda et al. [121]. Another example would be the use of very bright light (7000 to 12,000 lux with the associated possible light damage to the retina) instead of the ordinary 150 lux during night shifts, which was shown to lead to circadian rhythm adaptation to shift work after 4 days of treatment as evidenced by the delay in the body temperature nadir from 3:30 AM to 2:50 PM and improvement in cognitive performance and alertness among healthy volunteers [122]. It should also be pointed out that a big portion of the existing knowledge stems from animal model research and needs validation in humans before wide-spread application in clinical settings could be attempted. What is perhaps most relevant to this book chapter is the fact that the vast majority of circadian rhythm research uses the day-night wake-sleep pattern and measurements of serum biomarkers such as melatonin. Measuring body temperature as the human circadian rhythm marker would be a much less resource-heavy and less invasive approach in research designs. Thanks to the recent advances in electronics, the monitoring of human body temperature can be done at high frequency (collecting several measurements per minute) using relatively inexpensive equipment for data collection with wearable devices that allow for research to be carried out even outside hospitals and research centers. An important requirement for all research involving body temperature would be accurate temperature measurement via careful device calibration and by ensuring the temperature collection site is not significantly influenced by environmental temperature fluctuations or alternatively devising an algorithm to correct for any external variables.

Many of the experiments that so far involved animal models can be repeated in humans using body temperature as the main circadian rhythm measure. For instance, using the Gibbs et al. encouraging pre-clinical results regarding bacterial infections in mice [108], a human challenge model experimental protocol could be built as follows. One could inflict skin cuts on one arm of healthy volunteers during the day (near the body temperature acrophase) and on the other arm during the night (near the body temperature bathyphase). Then, one would quantify the inflammatory response and the evolution of the infection of each cut, where each person serves as their own internal control. If there is significant difference in the infection severity and healing times akin to the difference observed in mice, then this experiment could inform the timing of surgical procedures based on each patient’s specific circadian rhythm. Such an approach would constitute another step toward personalized medicine.

As detailed earlier in this chapter, disruption in the body temperature diurnal cycling pattern can be used as a predictor of events such as early sepsis, it can serve as a predictor of patient outcome among the critically ill, it can monitor the success (or lack thereof) of circadian adaptation in night shift workers, and the list goes on. But if any of these applications are to be used as standard of care tools, we would need well-controlled multi-institutional studies to validate the potential early warning system and clinical prediction models. In order to improve model validity, data from body temperature oscillations will likely have to be combined with other types of information such as the non-temperature vital signs, comorbidities, age, race, environmental specifications such as level of lightning, etc. Similar considerations apply to interventional studies such as light therapy to re-establish the circadian rhythm in night shift workers and people with psychiatric illnesses. Research aiming to identify the most optimal time along the circadian cycle for chemotherapy [123] or antibiotics [124] delivery constitutes yet another promising avenue open for exploration. Given the complexity of the involved models, the field of chronotherapy could prove an opportunity for the application of artificial intelligence to optimize the various model variables.

In conclusion, ours are exciting times for circadian rhythm research and the circadian rhythm of human body temperature provides an easily accessible tool for the development of clinically relevant applications.