**5. Chronobiological terminology**

The terminology accepted and approved in the field of chronobiology by The American Association of Medical Chronobiology and Chronotherapeutics describes aspects of biological rhythms that are often used in chronobiological texts, and for which no alternative terminology is suitable. This nomenclature was presented at the fourth Postgraduate Course of Medical Chronobiology and its Applications, held in Nevşehir [4]. As with other medical disciplines, the following terms must be introduced and should be accepted by specialists in this field. However, chronobiology is a rapidly evolving discipline, and, moreover, many of the established terms in the field of chronobiology remain unknown to many scientists and physicians who can benefit from applying chronobiological principles to their work.

**Biological clocks**: self-sustained oscillators that generate biological rhythms in the absence of external periodic input (e.g., at the gene level in cells).

**Pacemaker**: the functional unit capable of self-sustaining oscillations, which synchronize other rhythms or internal mechanisms, which sets the period and phase of the endogenous rhythm. They are oscillators (biological o'clock), which generate biological rhythms in the absence of external periodic inputs (e.g., at the gene level in individual cells). The hypothalamic suprachiasmatic nuclei are the dominant pacemaker of many circadian rhythms in mammals.

**Synchronization**: the state of a system when two or more variables exhibit periodicity with the same frequency, acrophase, and phasic relation. It refers to the adjustment of endogenous rhythm to external periodic influences. This influence is mediated by the synchronizer (**zeitgeber**)—the environmental periodicity determining the temporal placement of a biological rhythm along an appropriate time scale.

Human synchronizers can be:


**Desynchronization (internal)**: a state in which two or more previously synchronized variables within the same organism (endogenous rhythms) cease to exhibit different time relations.

**Desynchronization (external)**: desynchronization of biological (endogenous) rhythm from an environmental cycle.

**Free-running rhythms**: endogenous rhythms with their own periods, which also persist under conditions in which the periodicity of the external environment is modified or eliminated.

**Phase shifts**: if the period or timing of a dominant synchronizer changes, endogenous circadian rhythms, but synchronized with environment, follow a shift of their synchronizer and display phase advances or phase delays. The rhythms adapt to this new condition in a time—re-entrainment.

**7**

*Introductory Chapter: Chronobiology - The Science of Biological Time Structure*

energy and is able to continue to oscillate without outside energy input.

variable (e.g., episodic secretion of certain hormones).

**Phase advance and phase delay**: involves the earlier or later occurrence of a

**Entrainment**: coupling of two rhythms of the same frequency to one of them (the entraining agent or synchronizer) determining the phase of the other. It is coupling of endogenous rhythms to an environmental oscillator of the same frequency or determination of the phase of biological rhythms by an internal pacemaker. **Self-sustained oscillation**: a system that can make use of a constant source of

**Episodic variation**: apparently irregular (nonrhythmic) variation of a biological

**Reference rhythm and marker rhythm**: is the rhythm of one variable used as a

After the discovery of the mechanism of circadian rhythm, functioning did not last long, and numerous studies were carried out describing their impact on the etiopathogenesis of diseases as well as the possibility of their application in therapy. Even in the 3–6 weeks after birth, the internal clocks are gradually synchronized with 24-h period. In the greatest extent, the influence of lighting shares on this synchronization, but the role of melatonin, which is found in breast milk only at night, is also discussed. However, circadian rhythms also occur in the blind people,

and even 50–75% blind people indicate that they suffer by sleep disorders.

Periodic phenomena are encountered in many studies investigating various diseases. Very often, many symptoms or significant remissions exhibit a cyclic course. The time structure of living organisms is the source of these phenomena: accurate intermodulation over time, changing biological variables, and similar. If the harmony between and among biological rhythms is disrupted or disordered, the subjects themselves detect susceptibility to the disease or the disease itself. It is necessary to capture these different situations by monitoring the biological phenomenon during the day and to estimate the periodicity of the system using precise

*DOI: http://dx.doi.org/10.5772/intechopen.88583*

rhythm's phase, usually acrophase.

time reference for other rhythms.

statistical methods.

**6. Clinical medicine: chronomedicine**

*Introductory Chapter: Chronobiology - The Science of Biological Time Structure DOI: http://dx.doi.org/10.5772/intechopen.88583*

**Phase advance and phase delay**: involves the earlier or later occurrence of a rhythm's phase, usually acrophase.

**Entrainment**: coupling of two rhythms of the same frequency to one of them (the entraining agent or synchronizer) determining the phase of the other. It is coupling of endogenous rhythms to an environmental oscillator of the same frequency or determination of the phase of biological rhythms by an internal pacemaker.

**Self-sustained oscillation**: a system that can make use of a constant source of energy and is able to continue to oscillate without outside energy input.

**Episodic variation**: apparently irregular (nonrhythmic) variation of a biological variable (e.g., episodic secretion of certain hormones).

**Reference rhythm and marker rhythm**: is the rhythm of one variable used as a time reference for other rhythms.

### **6. Clinical medicine: chronomedicine**

*Chronobiology - The Science of Biological Time Structure*

The terminology accepted and approved in the field of chronobiology by The American Association of Medical Chronobiology and Chronotherapeutics describes aspects of biological rhythms that are often used in chronobiological texts, and for which no alternative terminology is suitable. This nomenclature was presented at the fourth Postgraduate Course of Medical Chronobiology and its Applications, held in Nevşehir [4]. As with other medical disciplines, the following terms must be introduced and should be accepted by specialists in this field. However, chronobiology is a rapidly evolving discipline, and, moreover, many of the established terms in the field of chronobiology remain unknown to many scientists and physicians who can benefit from applying chronobiological prin-

**Biological clocks**: self-sustained oscillators that generate biological rhythms in

**Pacemaker**: the functional unit capable of self-sustaining oscillations, which synchronize other rhythms or internal mechanisms, which sets the period and phase of the endogenous rhythm. They are oscillators (biological o'clock), which generate biological rhythms in the absence of external periodic inputs (e.g., at the gene level in individual cells). The hypothalamic suprachiasmatic nuclei are the

**Synchronization**: the state of a system when two or more variables exhibit periodicity with the same frequency, acrophase, and phasic relation. It refers to the adjustment of endogenous rhythm to external periodic influences. This influence is mediated by the synchronizer (**zeitgeber**)—the environmental periodicity determining the temporal placement of a biological rhythm along an appropriate time scale.

the absence of external periodic input (e.g., at the gene level in cells).

dominant pacemaker of many circadian rhythms in mammals.

• electromagnetic field, gravitational field, and cosmic radiation

**Desynchronization (internal)**: a state in which two or more previously synchronized variables within the same organism (endogenous rhythms) cease to

**Desynchronization (external)**: desynchronization of biological (endogenous)

**Free-running rhythms**: endogenous rhythms with their own periods, which also persist under conditions in which the periodicity of the external environment is

**Phase shifts**: if the period or timing of a dominant synchronizer changes, endogenous circadian rhythms, but synchronized with environment, follow a shift of their synchronizer and display phase advances or phase delays. The rhythms

**5. Chronobiological terminology**

Human synchronizers can be:

• knowledge of the time of day

• light-dark cycle

• social contacts

• sleep-wake cycle

exhibit different time relations.

modified or eliminated.

rhythm from an environmental cycle.

adapt to this new condition in a time—re-entrainment.

• time of eating

ciples to their work.

**6**

After the discovery of the mechanism of circadian rhythm, functioning did not last long, and numerous studies were carried out describing their impact on the etiopathogenesis of diseases as well as the possibility of their application in therapy. Even in the 3–6 weeks after birth, the internal clocks are gradually synchronized with 24-h period. In the greatest extent, the influence of lighting shares on this synchronization, but the role of melatonin, which is found in breast milk only at night, is also discussed. However, circadian rhythms also occur in the blind people, and even 50–75% blind people indicate that they suffer by sleep disorders.

Periodic phenomena are encountered in many studies investigating various diseases. Very often, many symptoms or significant remissions exhibit a cyclic course. The time structure of living organisms is the source of these phenomena: accurate intermodulation over time, changing biological variables, and similar. If the harmony between and among biological rhythms is disrupted or disordered, the subjects themselves detect susceptibility to the disease or the disease itself. It is necessary to capture these different situations by monitoring the biological phenomenon during the day and to estimate the periodicity of the system using precise statistical methods.

The question, then, is when to perform laboratory examinations or diagnostic tests. For example, plasma cortisol exhibits a circadian rhythm. Although secretion increases in response to the stressful stimulus, it is spontaneously released during the day with peak values around 4:00–6:00 in the morning, with a gradual decrease during the day to the lowest values that fall between 23:00 and 2:00 a.m. If the value of "normal" occurs at approximately 08:00 h, approximately 20:00 h would represent Cushing syndrome. If the value of "normal" occurs at approximately 20:00, 08:00 h would represent Addison disease. From a circadian perspective, the conclusion is adrenal cortex hyperactivity would be diagnosed only if a high plasma cortisol concentration was found in the evening and adrenal cortex insufficiency if low levels were found in the morning.

What can be a recommendation? Creation of "individual chronobiological profile" to use of improvement of the diagnostic test accuracy problems at which is not possible to suppose that internal circadian time is equal to the real time:


### **7. Circadian disruption: disruption of biological timing**

The circadian system optimizes daytime behavior and physiology and is organized hierarchically with central clocks in the SCN that are primarily synchronized by light. Currently, we are commonly exposed to less light and more night-light due to artificial lighting, which can negatively impact the organization of the circadian system and disturb sleep, resulting in extensive adverse effects on metabolic health. Interrupted sleep, for example, supports the increase of energy intake and reduction of energy expenditure, which may affect healthy eating. Experiments have also demonstrated that circadian deviations can lead to several metabolic abnormalities [5].

Circadian rhythm disturbance may occur from the level of the molecular clock (which regulates cellular activity) to the mismatch between behavioral and environmental cycles [5]. It is the result of a phase shift in the oscillation of the circadian and activity-controlled physiological processes. A recent study found that chronic disruption of one of the most basic circadian (daily) rhythms—the day-night cycle—leads to weight gain, impulsivity, slower thinking, and other physiological and behavioral changes in mice, similar to those observed in individuals who engage in shift work or experience jet lag.

This circadian pathology can be induced by factors related to **inputs** such as low contrast between day and night synchronizing signals (continuous light, frequent snacking, low levels of physical exercise), by zeitgebers with different periods or unusual phasing (i.e., light at night, nocturnal eating, nocturnal physical activity), or by zeitgeber shifts (i.e., daylight saving time, crossing time zones, shift work).

*Shift work*: because individuals in various occupations often work at night, they are exposed to an extraordinary risk for circadian rhythm and sleep disturbances [6–9].

**9**

*Introductory Chapter: Chronobiology - The Science of Biological Time Structure*

Shift workers are also susceptible to other health disorders such as gastrointestinal problems [10], and exposure to work-related changes can be associated with the risk for certain diseases, including breast cancer and metabolic syndrome [11, 12].

Other sources of circadian disruption can be unusual photoperiod (polar regions), circadian rhythm sleep (wake disorders [non-24-h sleep-wake disorders], senescence, disease states [Alzheimer's disease, Smith-Magenis syndrome, Parkinson disease]), and pregnancy, menopause, mental health problems, or

Circadian pathology can be induced by factors related to oscillators such as the uncoupling between the different oscillators inside the SCN caused by aging and the uncoupling between the central and peripheral oscillators or clock gene functional alterations result in circadian disruption or can be induced by factors related to outputs such as nocturnal melatonin suppression and loss of cortisol rhythmicity, which are also chronodisrupters. Many pathological states can be induced or

*Jetlag or rapid time zone change syndrome*: individuals with this syndrome exhibit symptoms that include excessive sleepiness and a lack of daytime alertness in those

*Shift work sleep disorder*: this sleep disorder affects individuals who frequently

*Advanced sleep phase disorder (ASPD)*: this is a disorder in which an individual goes to sleep earlier and wakes earlier than desired. ASPD results in symptoms of evening sleepiness, going to bed earlier (e.g., between 6:00 and 9:00 p.m.) and

*Non-24-h sleep-wake disorder*: this disorder frequently affects those that are totally blind because the circadian clock is set by the light-dark cycle over a 24-h period. In non-24-h sleep-wake disorder, the cycle is disturbed. The disorder results in drastically reduced sleep time and quality at night and problems with sleepiness

Some behavioral and pharmaceutical interventions balance the adverse effects of circadian rhythm and sleep disorders; however, some of the beneficial effects of these interventions may be independent of the circadian system and sleep. Because understanding of the relationships between the healthy phases of the SCN and peripheral clock systems is poorly characterized, clarifying these relationships may help to personalize chronobiotic prescriptions, some of which still require safety and efficacy studies. It is then necessary to compare these interventions and to

*Delayed sleep phase syndrome (DSPS)*: this is a disorder of sleep timing. Individuals with DSPS tend to fall asleep very late at night and have difficulty wak-

*Jetlag*: in addition to shift work, jetlag also induces circadian rhythm and sleep disturbances. Although the health consequences of frequent jetlag are ambiguous [13], any harmful effects of jetlag-induced circadian rhythm and sleep disturbances are becoming more widespread as an increasing number of passengers are projected to cross multiple time zones. While shift work and jetlag bring a clear disruption of the circadian system and sleep, even "normal" work hours can result in a smoother imbalance of circadian rhythm and sleep deprivation, especially among evening chronotypes. This is because many individuals use alarms to produce wakefulness

*DOI: http://dx.doi.org/10.5772/intechopen.88583*

when sleep would otherwise occur [5].

impaired as consequence of circadian disruption [3]. Common circadian rhythm disorders include:

ing up in time for work, school, or social engagements.

waking up earlier than desired (e.g., between 1:00 and 5:00 a.m.).

assess which are most effective and under what circumstances [5].

who travel across time zones.

rotate shifts or work at night.

during daylight hours.

medications.

#### *Introductory Chapter: Chronobiology - The Science of Biological Time Structure DOI: http://dx.doi.org/10.5772/intechopen.88583*

Shift workers are also susceptible to other health disorders such as gastrointestinal problems [10], and exposure to work-related changes can be associated with the risk for certain diseases, including breast cancer and metabolic syndrome [11, 12].

*Jetlag*: in addition to shift work, jetlag also induces circadian rhythm and sleep disturbances. Although the health consequences of frequent jetlag are ambiguous [13], any harmful effects of jetlag-induced circadian rhythm and sleep disturbances are becoming more widespread as an increasing number of passengers are projected to cross multiple time zones. While shift work and jetlag bring a clear disruption of the circadian system and sleep, even "normal" work hours can result in a smoother imbalance of circadian rhythm and sleep deprivation, especially among evening chronotypes. This is because many individuals use alarms to produce wakefulness when sleep would otherwise occur [5].

Other sources of circadian disruption can be unusual photoperiod (polar regions), circadian rhythm sleep (wake disorders [non-24-h sleep-wake disorders], senescence, disease states [Alzheimer's disease, Smith-Magenis syndrome, Parkinson disease]), and pregnancy, menopause, mental health problems, or medications.

Circadian pathology can be induced by factors related to oscillators such as the uncoupling between the different oscillators inside the SCN caused by aging and the uncoupling between the central and peripheral oscillators or clock gene functional alterations result in circadian disruption or can be induced by factors related to outputs such as nocturnal melatonin suppression and loss of cortisol rhythmicity, which are also chronodisrupters. Many pathological states can be induced or impaired as consequence of circadian disruption [3].

Common circadian rhythm disorders include:

*Jetlag or rapid time zone change syndrome*: individuals with this syndrome exhibit symptoms that include excessive sleepiness and a lack of daytime alertness in those who travel across time zones.

*Shift work sleep disorder*: this sleep disorder affects individuals who frequently rotate shifts or work at night.

*Delayed sleep phase syndrome (DSPS)*: this is a disorder of sleep timing. Individuals with DSPS tend to fall asleep very late at night and have difficulty waking up in time for work, school, or social engagements.

*Advanced sleep phase disorder (ASPD)*: this is a disorder in which an individual goes to sleep earlier and wakes earlier than desired. ASPD results in symptoms of evening sleepiness, going to bed earlier (e.g., between 6:00 and 9:00 p.m.) and waking up earlier than desired (e.g., between 1:00 and 5:00 a.m.).

*Non-24-h sleep-wake disorder*: this disorder frequently affects those that are totally blind because the circadian clock is set by the light-dark cycle over a 24-h period. In non-24-h sleep-wake disorder, the cycle is disturbed. The disorder results in drastically reduced sleep time and quality at night and problems with sleepiness during daylight hours.

Some behavioral and pharmaceutical interventions balance the adverse effects of circadian rhythm and sleep disorders; however, some of the beneficial effects of these interventions may be independent of the circadian system and sleep. Because understanding of the relationships between the healthy phases of the SCN and peripheral clock systems is poorly characterized, clarifying these relationships may help to personalize chronobiotic prescriptions, some of which still require safety and efficacy studies. It is then necessary to compare these interventions and to assess which are most effective and under what circumstances [5].

*Chronobiology - The Science of Biological Time Structure*

• In students during examination periods

the continual work of nurse

phase orientation is at the start

in shift work or experience jet lag.

• In shift workers

The question, then, is when to perform laboratory examinations or diagnostic tests. For example, plasma cortisol exhibits a circadian rhythm. Although secretion increases in response to the stressful stimulus, it is spontaneously released during the day with peak values around 4:00–6:00 in the morning, with a gradual decrease during the day to the lowest values that fall between 23:00 and 2:00 a.m. If the value of "normal" occurs at approximately 08:00 h, approximately 20:00 h would represent Cushing syndrome. If the value of "normal" occurs at approximately 20:00, 08:00 h would represent Addison disease. From a circadian perspective, the conclusion is adrenal cortex hyperactivity would be diagnosed only if a high plasma cortisol concentration was found in the evening and adrenal cortex insufficiency if low levels were found in the morning. What can be a recommendation? Creation of "individual chronobiological profile" to use of improvement of the diagnostic test accuracy problems at which is

not possible to suppose that internal circadian time is equal to the real time:

• During hospitalization—at the relative constant levels of murmurs, light, and at

• Resulting in the disorders of the circadian orientation, although the normal

The circadian system optimizes daytime behavior and physiology and is organized hierarchically with central clocks in the SCN that are primarily synchronized by light. Currently, we are commonly exposed to less light and more night-light due to artificial lighting, which can negatively impact the organization of the circadian system and disturb sleep, resulting in extensive adverse effects on metabolic health. Interrupted sleep, for example, supports the increase of energy intake and reduction of energy expenditure, which may affect healthy eating. Experiments have also demonstrated

Circadian rhythm disturbance may occur from the level of the molecular clock (which regulates cellular activity) to the mismatch between behavioral and environmental cycles [5]. It is the result of a phase shift in the oscillation of the circadian and activity-controlled physiological processes. A recent study found that chronic disruption of one of the most basic circadian (daily) rhythms—the day-night cycle—leads to weight gain, impulsivity, slower thinking, and other physiological and behavioral changes in mice, similar to those observed in individuals who engage

This circadian pathology can be induced by factors related to **inputs** such as low contrast between day and night synchronizing signals (continuous light, frequent snacking, low levels of physical exercise), by zeitgebers with different periods or unusual phasing (i.e., light at night, nocturnal eating, nocturnal physical activity), or by zeitgeber shifts (i.e., daylight saving time, crossing time zones, shift work).

*Shift work*: because individuals in various occupations often work at night, they are exposed to an extraordinary risk for circadian rhythm and sleep disturbances [6–9].

• At the transitions through more time zones (jetlag syndrome)

**7. Circadian disruption: disruption of biological timing**

that circadian deviations can lead to several metabolic abnormalities [5].

**8**

Currently, it is no longer sufficient to classify health as the potential ability of an organism to cope with the varying effects of the environment without disturbing biologically important functions. We have the resources and a relatively accurate statistical methodology that enables us to assess the maximum and minimum functional capacities of each functional system at any time.
