The circadian rhythm governs the biological cycle of most living things and can help to understand a series of events in our body.
The circadian rhythm (or circadian cycle) is the period of approximately 24 hours on which a biological cycle is based. In this way, a series of events in our organism are directly linked to them and external influences can have different consequences, also in our organism, according to the period of the circadian cycle in which they occur.
In this article, we will delve deeper into the topic, from its definition to its practical applications in the field of sleep medicine, work and other areas and understand how and why actigraphy is the best method for monitoring the circadian cycle.
Definition of circadian circle
The word “rhythm” could be succinctly defined as “any event that is repeated regularly”. Etymologically, the word rhythm comes from the Latin word rhythmus, which means regular movement. Several natural events have a steady rhythm over time, such as tidal rhythms, sunrise and sunset, as well as the phases of the moon.
These natural rhythms have existed for thousands of years and throughout the evolutionary process, several animals have adapted to these changes in the environment. In marine life, it is possible to notice several living beings that have adapted their behavior based on the ultradian cycles (less than 20 hours) of the tides, which last about 12 hours, and the infradian cycles (greater than 28 hours), both of which caused by the complete lunar cycle, which lasts about 28 days.
However, when it comes to biological rhythmicity, the phenomenon of stable rhythmicity most easily observed is day and night. The rotation of planet Earth, lasting approximately 24 hours, generates a temporal pattern in which dark and light phases follow one another. This regular succession of light and dark stages favored the evolution of endogenous oscillatory mechanisms, classified as timing systems (Panda et al., 2002).
The rhythms generated in these systems, which last approximately 24 hours, are known as circadian rhythms, a word originated from Latin (circa "about" + diem "day") (Marques and Menna-Barreto, 2003).
Circadian Rhythm and the interaction with living beings
The interaction of living beings with the environmental light-dark cycle has always been specialists’ object of study. There are records of observations of alterations in plant morphology dating from Ancient Greece. However, the first documentations on how this behavior is not based solely on exposure to environmental changes date from the 18th century and were reported by Jean-Jacques d’Ortous de Mairan. He observed that the mimosa plant still exhibited its characteristic leaf movement behavior even in a situation with no environmental information regarding day and night.
The term “circadian rhythms” was introduced by Halberg (1959) to describe the variations of processes in the organism. Said processes last approximately 24 hours and persist in the absence of time indications, but that can be altered by external stimuli such as the incidence of the light-dark cycle, feeding or daily activity.
The circadian rhythms initially observed in experimental studies in which the locomotor activity of animals kept in an environment with 12 hours of light phase and 12 hours of dark phase was evaluated, generating a light-dark cycle of 24 hours (Aschoff, 1965).
Important characteristics of circadian rhythms consist in:
Characterized by a specific moment in a cycle (either a specific point or a time frame of said cycle, such as, for example, the activity phase, the light phase or the feeding phase);
which is the difference between the maximum and minimum values of a biological rhythm
which is the duration of a biological cycle, such as sleep and wake cycles.
How to measure circadian rhythm
Several tools can be used in order to verify the presence of rhythm in these characteristics and to estimate their parameters (Marques and Menna-Barreto, 2003). A widely used analysis is the Cosinor method, which consists in adjusting a cosine curve of a time series of a rhythm and taking measurements of its acrophase (the highest value of the estimated curve), its batiphase (the lowest value of the estimated curve) and the duration of a complete cycle and its amplitude.
Mechanisms that generate circadian rhythmicity are present in all body cells as they are capable of marking an approximate 24-hour rhythm, which may suffer small oscillations. Although each cell performs said function, there is a structure in each individual located in the anterior hypothalamus, known as Suprachiasmatic Nuclei (SCN) (PANDA et al., 2002), which are capable of generating an endogenous rhythm based on environmental rhythmic information and signal to various internal oscillators that, in turn, promote oscillatory responses with an approximate period of 24 hours in various physiological factors.
Such oscillations, mediated by changes in the environment (light-dark cycle), result in two outputs of information for the organism:
a) humoral output, from SCN connections with the pineal gland, where physiological phenomena result in the production of melatonin – responsible for signaling the dark phase to the organism;
b) neural output, where the connection of the SCN culminates in the sympathetic autonomic output (SIMONNEAUX and RIBELAYGA, 2003; MORRIS et al., 2011). Both responses are responsible for generating and maintaining the synchronization of circadian rhythms in the body.
Alterações no ciclo circadiano
Many physiological variables show circadian oscillation, such as: body temperature, melatonin, cortisol and insulin secretion, blood glucose, blood pressure, heart rate, among others. Thus, it is possible to identify a sequential order of the circadian rhythms phases in several physiological variables throughout the day, characterizing an internal temporal organization in individuals. An example of that is the following pattern: the maximum body temperature is detected around 6 pm; followed by the beginning of sleep at around 11 pm; at 2 am, a peak of growth hormone secretion occurs, and immediately after that, at 4 am, a peak of melatonin secretion occurs; at 5 o’clock the minimum body temperature can be perceived and a few hours later, the individual wakens. The daily maintenance of this order and the intervals between the moments when the variables are expressed indicates that the individual is “synchronized”, reflecting a healthy state of the organism and a good quality of life (Marques and Menna-Barreto, 2003).
Circadian biological rhythms are the result of the interaction between endogenous biological oscillatory systems and the external environmental factors to which organisms are subjected. This process of adjusting organisms’ rhythms to environmental rhythms is called “entrainment”, and the environmental clues capable of promoting this action are called “synchronizing agents” (Marques and Menna-Barreto, 2003).
The events that can generate a change in the expression of circadian rhythmicity, called “synchronizing agents” (or entrainers) appear in different ways for humans:
✓ Environmental temperature;
✓ Social interactions;
✓ Food habits;
✓ Luminous information given by the day and night cycles.
The temporal relationships between physiological events and environmental events that are recognized for their ability to synchronize biological rhythms, as in the case of the light-dark cycle, characterize the external temporal organization (Menna-Barreto and Wey, 2007). Both processes – both the external temporal organization and the internal temporal organization – are mediated by circadian synchronization, which consists in the process responsible for maintaining stability in different rhythms, by means of entrainment or masking.
Marques and Menna-Barreto (2003) define entrainment as a temporal adjustment of a certain organic rhythm by another rhythm – either physiological, such as the secretion of a hormone, or environmental, such as the light-dark cycle. Masking, on the other hand, is defined as a process of modifying a biological rhythm through an event that increases or decreases its expression and can happen due to an event external to the individual, such as the suppression of the locomotor activity of rats when the ambient light is turned on. It can also be caused by an event in the individual’s body itself, such as facilitating the production of growth hormone during sleep
To determine the expression of circadian rhythmicity of physiological variables, laboratory protocols that aim to remove the masking conditions of the circadian rhythm are used, such as daily physical activity, food, temperature and light from the environment, among other conditions that may influence the endogenous biological rhythm (Marques and Menna-Barreto, 2003). To this end, there are the “constant routine” protocols, which use sleep deprivation, constant lighting and the provision of isocaloric meals at standardized times, and the “forced desynchronization” protocols, which use, in addition to the procedures described for the constant routine protocol, an alteration in the duration of the light-dark cycle to 20 or 28 hours, with the objective of preventing the synchronization of the timing system, obtaining a “pure” endogenous circadian rhythm, the free-running rhythm (Hofstra and De Weerd, 2008).
Using these protocols, which allow individuals to express their rhythm freely, Daan and Pittendrigh (1976) observed that animals exhibit different behaviors in response to the same light stimulus, when it is presented at different times, so that it is possible to perform the construction of Phase-Dependent Response Curves (PRC). Thus, when pulses of light are applied at the beginning of the subjective night (sleep phase, regardless of the time it happens) there is a delay in the rhythm phase, but when they are applied at the end of the subjective night, there is an advance in the rhythm phase of the animal. However, stimuli applied at intermediate periods between these extremes cause little or no displacement of the rhythm (Marques and Menna-Barreto, 2003).
Circadian rhythm in humans
In the graph above, it is possible to observe how the response of circadian expression occurs to different light stimuli, as well as to a chronobiotic drug, in this case, melatonin – which is responsible for signaling the dark phase of a day. It is possible to notice that, depending on the time when individuals are submitted to light or to the administration of melatonin, a different adaptation of circadian rhythm expression occurs. The incidence of light, bright or dim, close to the time of sleep onset, might delay the rhythm, that is, delay the onset of the sleep phase. Conversely, when light is administered in the final hours of the sleep phase, it is possible to see an advance in rhythm, that is, an earlier awakening is observed. It is interesting to note that the response to ambient light generates an adaptation of advances and delays of a greater magnitude than that observed by the administration of melatonin.
At times when individuals are usually active (the middle of the day), exposure to light does not cause any adjustment in the circadian timing system. In other words, trying to drastically and quickly change sleep and wake-up schedules by using light exposure periods will not generate a response in the circadian timing system. Another aspect that must be taken into account is that this graph is a generalized model, not considering the variability of the preference of the subjects’ habits.
Human beings are a diurnal species, meaning individuals are active most of the day and asleep most of the night. However, as previously mentioned, there are individual differences regarding the execution of daily activities, as well as sleep and wake-up schedules. Considering the preferences for certain times for performing activities and for sleeping and waking up, it is possible to classify individuals in different groups, called “chronotypes” in Chronobiology: people who prefer to sleep and wake up earlier, are classified as having morningness characteristics; those who prefer to sleep and wake up later have eveningness characteristics; those with preferences between these two extremes have indifferent chronotype characteristics (Roenneberg et al., 2003). These characteristics of daily preferences change throughout life. However, some studies claim that there is a genetic component involved in individual preferences for performing activities.
Chronotypes are basically identified through questionnaires. The most used questionnaire is that of Horne and Ötsberg (HO) (1976), a questionnaire with the main objective of assessing whether the preferences in the execution of an individual’s daily tasks occur in the morning, afternoon or at an intermediate time.
This study showed that the peak state of alertness is associated with the maximum values of central temperature: morningness chronotype individuals showed the peak temperature at earlier times than eveningness chronotype individuals, and indifferent chronotype individuals recorded temperature peaks between the values obtained for morningness and eveningness chronotypes (Horne and Ostberg, 1976).
More recently, another questionnaire has been introduced for the identification of chronotypes: the Munich Questionnaire (MCTQ) (Roenneberg et al., 2003), which has been widely used. This questionnaire has questions about sleeping and waking hours during both work days and free days (weekends, for example), allowing the identification of the individual’s average sleep duration by calculating the weighted average of sleep duration in both work days and free days. Except for individuals with extreme morningness chronotypes, there is a significant difference in individual sleep times between work days and free days, with most subjects accumulating sleep debt during work days.
The difference in daily habits that characterize morningness and eveningness chronotype individuals, including sleeping and waking habits, also results in different ways of responding to the temporal adjustments in these groups. Morningness chronotype individuals find it easier to wake up earlier than usual than an eveningness chronotype person, but have a greater difficulty in extending the duration of the activity, that is, sleeping later, which leads to different adjustments in circadian synchronization mediated by the light-dark cycle information.
Thus, when establishing strategies for the use of therapies involving the manipulation of environmental information or drugs that can alter the circadian timing system, it is initially necessary to have knowledge of people’s daily habits, whether through the use of activity diaries, or by the use of devices from which it is possible to obtain information on the expression of individuals’ circadian rhythmicity. Therefore, by better understanding people’s habits, it is possible to plan an intervention in order to ensure a more effective adaptation of the individual to the strategies proposed by the treatment.