LECTION 4. Clasification and Genesis of biological rhythms
Chronobiology is a branch of science that objectively explores and quantifies mechanisms of biological time structure including important rhythmic manifestations of life right from molecular level of living being, from unicellular organism to complex organism such as human being.
Classification of biological rhythms
Biological rhythms can be classified according to numerous criteria.
This classification is based on the length of the period of oscillation. Table 1 details this repartition.
< 20 h
24 ± 4 h
24 ± 0.2 h
> 28 h
7 ± 3 d
14 ± 3 d
21 ± 3 d
30 ± 5 d
1 y ± 2 m
h = hours;'d = days; m = months; y = year
The rhythms whose period of oscillation is 24 + 4 h are defined as «circadian» (from circa dies, i.e., approximately one day). The cyclic events with a period of less than 20 h and more than 28 h are defined respectively as «ultradian» and «in- fradian».
Besides the physical classification there exists a subdivision based on functional concepts that recognizes four varieties of biological rhythms, i.e., alpha, beta, gamma and delta.
The alpha rhythms coincide with the spontaneous oscillation of biological functions. Alpha rhythms are-subdivided into alpha(s) and alpha(f) according to whether they are produced in conditions of «synchronization» ôr «frèe-running» (see below). The beta rhythms correspond to the periodicity of the response of biological functions toward stimulations or inhibitions applied at different times. The beta rhythms as wéll exist in the varieties beta(s) and beta(f) in relation to the presence of either synchronization or frèé-running conditions. These two varieties are further subdivided into beta(sl) or beta(fl) if thé perturbance is physiological, and alphha(s2) or beta(f2) if the perturbance is not due to a physiological event. Gamma rhythms regard the periodic oscillation of biological functions being modulated, perturbed, or influenced by deterministic factors, either physiological, i.e., gamma(sl) or gamma(fl), or non-physiological, i.e., gamma(s2) or gamma(f2). Here again, the differentiation into gamma(s) and gamma(f) varieties depends on the presence of either synchronization or free-running conditions. Lastly, delta rhythms, which are also subdivided into (s) and (f) varieties, correspond to the modification in the periodic oscillation of a given biological function secondary to manipulation of an alpha, beta, or gamma rhythm.
The examination of rhythmic phenomena in organic matter reveals that there exist events which repeat themselves after a certain lapse of time as isolated occurrences. These are the «qualitative, punctual, discrete, or episodic rhythms» expressed by a binary condition, i.e., present/absent, event/non-event. For example, the menstrual cycle.
Qualitative rhythms are mathematically describable in terms of finite quantities (0 or l) and counted as numerical frequencies. Therefore, qualitative rhythms could also be called «frequential rhythms».
In living organisms it can be noted that several phenomena repeat themselves as entities which vary in a «continuum». In other words, the phenomenon is always present and measurable, even though changing as a function of time. Its magnitude reaches the same level following a given period of time. Therefore, the period of these phenomena is given by the space of time (duration) in which the curve reaches the identical level after a complete oscillation. These periodic events are dhus a quantitative expression of their variability and can be identified as «analogic or continuous or quantitative rhythms». These rhythms are mathematically expressed by numerical values of a potentially infinite order.
From a classification point of view, there exists a third type of biological rhythm consisting in isolated peaks inscribed on the curve of a quantitative oscillation. Whether these spurts show a cadence in time, they can be defined «episodic rhythms».
This classification is used mainly for the description of episodic rhythms or when it is necessary to describe a continuous periodic event in relation to its peak. The rhythms included under this heading are diurnal, nocturnal, serotine, vesperal, morning, daily, weekly, monthly, seasonal, yearly, etc.
Note, however, that these terms define the periodicity only descriptively and do not lend to any inference on the effective duration of the period of the recurring phenomenon. Therefore, a diurnal rhythm is not implicitly circadian; it could be ultradian.
Biological rhythms, like all biological phenomena, undergo an evolutive process that tends to modify the periodic properties in function of chronological age. As shown in (Fig. 1), every periodic in function is defined by its mean level, extent of oscillation, and timing of oscillatory crest, these parameters being called respectively, mesor (M), amplitude (A) and acropfyase (Ø or phi).
Fig. 1. The rhythmometric properties of a biological oscillating function.
Utilizing clinospectror analysis (see below), both positive and negative trends (clinous) have been identified for mesor and amplitude as an effect of age (Fig. 2).
Therefore, there are «dianaclinous» or «dikataclinous» rhythms if both properties have a positive or negative trend during the course of life. Rhythms can also be defined as «mesor-anaclinous» or «mesor-kataclinous», and «amplitude-anaclinous» or «amplitude-kataclinous», if the evolution through chronological time involves only one of the parameters in either a positive or negative sense. There is also the possibility of a trend opposite for the two rhythmic properties defined as an «amphiclinous» rhythm. Finally, there can be an «aclinous» rhythm which is a rhythm that shows itself to be stable even though the age increases.
Observing rhythmic biophenomena it can be ascertained that some of these are «permanent or long-lasting» while others are «transitory or temporary». The ovarian cycle is a typical «transient» rhythm because it disappears with menopause. The rhythm of body temperature is instead a permanent rhythm that is found even in the cadaver in the first 24 h following death.
Fig. 2. - Age-related trends in rhythmometric properties of biological rhythms (clinospectroscopy).
In considering biological rhythms we cannot neglect the important role they play in the economy of vital functions. In this regard it must be kept in mind that there are rhythms which are «essential» or «vital», and rhythms which are «non-essential». The essential rhythms are the pulsatile activity of heart, respiration, and cerebral electrical activity. The suppression of one of the first two coincides with «physical death». The lack of the electroencephalic rhythm, as is seen in the flat electroencephalogram, defines so-called «clinical death».
It can be derived from the aforesaid that the essential rhythms represent biological life. Death coincides with the abrogation of these fundamental rhythms. From this perspective it is seen that life and biological rhythmicity are a counivocous expression.
Non-essential rhythms are those rhythms whose abolition or desynchronization has no repercussion on vital functions. Their lack can, however, contribute to the development of a primary pathology (protochronopathology). The abolition of non-essential rhythms can be secondary to a given disease (deuterochronopathology).
Examined under the profile of their meaning, biological rhythms may be found in two very important aspects of life, (i.e., the conservative and reproductive functions). The rhythms of the conservative sphere are, in turn, mental and physical. These two categories can be further identified as intellective, affective, endocrine, cardiovascular, metabolic, respiratory, digestive, etc. Reproductive rhythms are, on the other hand, related to sexuality and fertility.
In biology, the rhythmic manifestation of life have different values with respect to their robustness. There exist, in fact, «resistant» or «permanent» rhythms as well as bioperiodic events that are «weak» or. «labile». The resistance of a rhythm depends on its role and to which system it belongs. Basically, resistance is inversely proportional to the susceptibility to be desynchronized following acute perturbations.
The lability of a rhythm is mostly dependent on its spontaneous or forced passage to a different order of periodicity (multiplication or démultiplication of frequency). The rhythm of the heart is : said to be labile because it dan easily vary in frequency over the 24 h span. Only rarely the lability of a rhythm is due to its abrogation. The abolition of a biological rhythm is, an : extremely unnatural event which is very improbable to occur. Therefore, the disappearance of a given rhythm must be carefully evaluated and it cannot be established without having verified that the rhythm has just and simply changed its period. :
Biological rhythms are part of the genetic patrimony of living matter. The oscillators are located in each cell, at every level of the biological organization. The rhythms begin to act at the birth of the cell. In metazoes the cellular rhythms take part to a more complex and general rhythmicity whose expression requires coordination and maturation. Some rhythms of very high organized activities, thus, take a certain time for their postnatal ontogeny.
Rhythms in the formative stages are called «immature» rhythms, while those already operant at birth are defined as «mature» rhythms.
Biological rhythms are natural events which recur spontaneously, their periodic component being endogenous. The endogeneous contribution to periodicity can manifest itself freely (free-running rhythms) or it can be conditioned by environmental factors that act cyclically as synchronizers (synchronized or masked rhythms). The free-running rhythms, therefore, may be transformed into synchronized rhythms, and the endpoint of this interplay is a «masking effect» exerted by the exogenous component on the endogenous bioperiodicity. In nature, the overt manifestation for most biological rhythms is the combination of the endogenous component plus the exogenous entrainment. In this case, the masking effect results in a synchronized rhythm, and the external factors of masking can be defined «entraining agents» or «zeitgebers» or «synchronizers».
Importantly, the manipulation of an environmental synchronizer may cause a disturbance of the endogenous periodicity which results in a phenomenon of «external desynchronization». The dyschronic effect must be kept in mind when dealing with a biological rhythm lacking periodicity. This means that the abrogation of a given periodicity may be attributed to an exogenous mechanism being not primarily dependent on an intrinsic defect of internal rhythmicity.
Interestingly, the masking effect may be not only exogenous but also endogenous. The endogenous masking effect can be used to explain the complex conditions of rhythm loss not explainable in terms of cause and effect. For example, the loss of the sleep-waking rhythm produces an endogenous masking effect on numerous other rhythms causing their periodicity to be abrogated (see below).
There are rhythms that regard one concrete entity, i.e., «real rhythms». Other rhythms are instead the mere expression of a computational parameter, i.e., «virtual rhythms». The nychtohemeral profile of cortisol rhythm, when studied in blood, coincides with the within-day variations of its concentration in plasma or serum. By contrast, the circadian rhythm of pH is caused by the interplay of numerous factors each one characterized by its own rhythm.
There are biological rhythms which refer to a single variable (something that is definable by its characteristics), i.e., «elementary rhythms», and others which attain to complex functions, i.e., «composite or factorial rhythms». Examples may be the circadian rhythm of prolactin, on one side, and the circadian rhythm of mood, on the other.
If a rhythm is found to be complex, its eventual abolition could be dependent on an internal desynchronization among the constituent cyclic factors or mechanisms. Sometimes, the aperiodicity is merely due to changes in phase resulting in an antiphasic oscillation of the cycles which contribute to the complex rhythm.
In the magnificent organization of bioperiodic phenomena, it has been found that some rhythms play a prominent role in conditioning other biological cycles. These rhythms are called «guide or primary or independent rhythms» while the driven rhythms are called «guided or secondary or dependent rhythms». Guide rhythms have a strategic importance in the sense that their presence is essential for the dependent periodicity. The lack of a guide rhythm usually produces desynchronizing effects mostly due to the abrogation of the rhythmic interplay. The interruption of the relationship between primary and secondary rhythms causes a phenomenon called «internal desynchronization». The guided rhythms will be absent due to an induced effect. Such a dramatic repercussion is called «endogenous masking effect». The endogenous masking may help us in understanding and interpretating the chronopathology of some biological rhythms.
Genesis of biological rhythms
The capacity to undergo rhythmic oscillations is a characteristic intrinsic to living matter. A fundamental statement of chronobiology states «many rhythms persist even in complete isolation from the major known environmental cycles». This affirmation clarifies that the natural rhythms can be considered to lay outside of the period of the geophysical cycles. This means that living matter has its own time, i.e., the «biological time».
Assuming time as a fourth dimension of biology, one can conceptually and syllogistically argue that a chronome exists into the genome. Besides the physical (physemes) and chemical (chememes) signals, one can assume that the genes provide information also in the form of «chronemes», i.e., signals of periodic type. In such a way the process of donation is timed by determined periods, and results in a combination of quantal and temporal messages which cause the biological functions to quantitatively change according to a programmed spectrum of periodicities. Speculatively, one could presume that the temporal signals find their periodic genesis within the helicoidal spirals of DNA where the chronome should reside. The DNA double helix could act as a metronome generating a vibration whose length is the period of donation.
It has been suggested that the gene inherits not only the capacity to clone (ergon) but also the capacity to endure (chronon). The concept of chronon refers to the expression of genes as a function of the chronological time which is linear, irreversible and progressive. The concept of cronome relates to the expression of genes according to the chronobiological time which is cyclical, irreversible but recursive. Accordingly, the chronological time could be seen as the summation of the iterated periods which constitute the time base of biological rhythms.
Biological clocks and control of bioperiodic phenomena
Biological periodicities are driven by a genetic program to run according to a temporal duration (biotemporality) which causes a recursivity in a spectrum of frequencies ranging from milliseconds to years.
The temporal effect of genetic programming, the chronome, is the endogenous component for which the biological rhythms originate as «free-running» bioevents. The free-running rhythms reflect the «time of the body» which is independent from the environmental time measured by the clock, the «physical time». The free-running rhythms reflect the endogenous mechanisms of cyclic temporization whose expression is morphologically seen as an internal clock, a «biological or body clock».
Observing the animals integrated into their environment, it can be noted that the endogenous rhythms are usually not «free-running». The «time of the body» is masked, and the spontaneous biological rhythms are obliged by the exogenous cycles to adjust their period in accordance.
This means that the biological time has innately the capacity to uniform itself with the physical time. Therefore, events that perturbate the environment can modulate the periodic cadence of the genetically determined endogenous rhythms. The strongest interferences are those provided by systematic events having a cyclical character in their manifestation. The light-dark alternation, meal timing schedule, social routines, including work shifts, etc. (see below) are deterministic as entraining agents.
In the entrainment of endogenous rhythms many structural entities intervene with a role of mediation (Table 2).
Table 2. - Central nervous structures involved in the chronoregulation of biological functions
Midbrain raphe nuclei
Autonomic nervous system
Superior cervical ganglic
The most important determinants of biological timing are the endogenous oscillators, structures of the organism that function as rhythmic «pacemakers». Other machineries of synchronization are the «pace-resetters», elements of the organism that regulate the temporal structure of one or more rhythms in response to one or more environmental synchronizers. The informative relationships between pacemakers and paceresetters are determined by special connecting structures called «transducers» that translate the exogenous stimuli to the internal clocks. Transducers may have either negative or positive effects on the oscillators.. The series can be integrated by the «modifiers» and the «logic controllers» which act, respectively, in modifying arid controlling the exogenous and endogenous stimuli. /
With regard to biological clocks there exists an eternal diatribe between positivists arid negativists. The prevalent opinion is positivistic in the sense that the biological clocks are accepted as identifiable entities which reside inside tissues and organs. Those who believe in the' existence of biological clocks assert that these structures of self-sustaining timing play a primary role in coordinating the miriad of peripheral biological rhythms. Such a coordinative capacity presupposes a leadership with which the biological clocks drive the phase of the rhythms provided by each cell of the organism. This implies that the biological clocks are formally equipped to ubiquitarily interact with all the cells by means of neural, physical arid chemical messages. For this reason they are prominently located inside the non-mitotic-structures of the nervous system, both encephalic and spinal.
The structural organization of biological clocks is difficult to be deciphered. An attempt will be made here by presenting the principal models. The model I, the simplest, is made by an oscillator that times a second oscillator, and so forth. This primordial model proposes a linear cybernetic control. The model II describes a primary oscillator followed by a series of oscillators in succession. The model III proposes an interaction between various oscillators of equal hierarchical importance arranged in a cybernetic network. The control by nodal clocks explains the occurrence of collateral interactions conditioning the mechanisms of positive or negative feedback. This interactive mechanism of chronoregulation has been called « feed-sideward».
Chronoanatomic research has brought to light a series of structures responsible for rhythmic programming and chronobiological integration of the organism with the environment. Information on the neuroanatomical structures involved in the central regulation of biological rhythms derive essentially from animal studies. Table 3 lists the structures which are presently recognized to play a rhythmogenic role as oscillators.
Table 3. - Central structures involved in the coordination of oscillating biological functions
Chronobiological studies provided evidence that various environmental factors act hierarchically as synchronizers of biological rhythms. The most powerful synchronizer is the light-dark alternation. Isolated from geophysical temporality, human beings progressively tend to delay the resting time. This phenomenon occurs even in conditions of perennial light or darkness. A rapid change in time zones (passing through three or more time zones), as occurs in transmeridian flights, gives rise to a psychophysical disturbance commonly known as «jet lag syndrome» prominently due to the dyschronism between biological time and physical time. The resynchronization following geographical dyschronism occurs with a phase shift of about 90 min every 24 h. It is, however, necessary to keep in mind that the direction of time zone transiction is crucial. In east-west bound flights, travellers must recuperate a time span equal to the temporal difference between the time zones. In west-east bound flights, subjects must recuperate 24 h minus the difference in time zones, i.e., the physical time already passed in that zone , which was not biologically «lived» by the travellers. This implies that the resynchronization takes much more time. The resynchronization can be, however, accelerated or delayed by numerous factors (Table 4).
Strong temporal pressures
Weak temporal pressures
Higher performance task
Lower temporal task
Low pulse/respiration ratio
High pulse/respiration ratio
The meal schedule is also a robust synchronizer. Subjects eating a complete meal only once a day will show a phase shift for many biological rhythms toward the hour that the meal is given. Social routines (sociotemporality) are also important, especially shift work. A random shift can produce desynchronizing effects for many periodic functions, especially those related to physical and mental performance. Other environmental agents causing dyschronism are stress, fasting, fatigue, etc., if abnormally prolonged in time and/or cyclically repeated.
Several drugs can induce desynchronization as well. The lists of these drugs should compose a new chapter of pharmacology to be used in pharmacological surveillance.
Interestingly, some drugs may be used for resynchronizing the biological rhythms disturbed by exogenous interferences. These drugs are called «chronizing agents or chronizers».