Consistency classification

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.

Constitutive classification

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.

Hierarchical classification

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

Suprachiasmatic nuclei

Olfactory bulbs

Fornix

Septum

Limbic structure

Hippocampus

Preoptic area

Retino-hypothaiamic connection

Midbrain raphe nuclei

Ventromedial hypothalamus

Dorsomedial hypothalamus

Locus coeruleus

Brain stem

Autonomic nervous system

Superior cervical ganglic

Pineal giand

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».

C

Suprachiasmatic nuclei Olfactory bulbs Fornix Septum

Limbic structure Hippocampus Preoptic area

Retino-hypothaiamic connection Midbrain raphe nuclei Ventromedial hypothalamus Dorsomedial hypothalamus Locus coeruleus Brain stem

Autonomic nervous system Superior cervical ganglic Pineal giand

hronoanatomic 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

Pacemakers
Paceresetters
Modifiers
Transducers
Logic-controllers
Synchronizers

Desynchronization, resynchronization, chronization

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).

Acceleration	Retardation
Extroversion	Introversion
Serality	Manility
Phase advance	Phase delay
Delay shift	Advance shift
Labile rhythms	Stabile rhythms
Strong temporal pressures	Weak temporal pressures
Higher performance task	Lower temporal task
Yought	Ageing
Low neuroticism	High neuroticism
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».

Ontorhythmogenesis and gerorhythmoclinia

As an innate expression of vital dynamism, bio­logical rhythms originate at the time of fecondation, the so called «ontogénie zero point». In order to show overt expression and integration, some rhythms require a central coordination which is controlled by biological clocks whose development is related to the maturation of the central nervous system.

The need of maturation indicates that the on­togenesis of biological rhythms results from the recruitment, organization and phase synchronization of the myriad of cycles generated by cells at the peripheral level.

It is important, however, to remark that some rhythms which require a high degree of integration can be already found in fetuses. The fetal synchron­ization reinforces the idea that maternal influences of cyclical nature are active on the temporal organ­ization of bioperiodic functions in utero.

After the period of maturation, what is the destiny of biological rhythms as a function of chronological age? In other words, what is the effect of aging on biological rhythms?

In traditional biology, the aging process is thought to consist in a phenomenon of linear loss for biological functions (Fig. 3).

Fig. 3. - Diagrammatic representation of the traditional concept of aging as a process of linear decay.

Chronobiology considers aging in the context of cyclicity which characterizes biological functions. Studies done in this regard have demonstrated that senescence is associated with a decline which affects the mean level (gérontologie decline of tonic activ­ity), and the extent (gérontologie decline of phasic activity) of oscillation;, as well as a shift in the phase (gérontologie rephasement) and/or a change in the period (gérontologie démultiplication/multi­plication) of biological rhythms. Accordingly, it can be said that aging is a process associated with a trend (clinous) which is negative for height and oscillatory extent of bioperiodic functions. This implies that the effects of senescence consist in a model of periodic-linear regression, in which one can see the combined decline of the oscillation in its mean level and amplitude, i.e., a phenomenon of gerorhythmoclinia (Fig. 4).

Fig. 4. - Diagrammatic representation of the chronobiological concept of .aging as a process of rhythmometric decay (gerorhythmoclinia or clinospectroscopy).

Presently, the periodic-linear regression analysis of gerontological trends of biological rhythms is feasible by means of the clinospectror method. This procedure, developed by this author, combines the estimation of the oscillatory changes, period by period, as a function of linear advancing age. The model of the gerontological destiny of biological rhythms is represented by a curve, i.e., the gerorhythmoclinogram (Fig. 2).

Interestingly, the clinorhythmometric study of senescence has documented that some biological rhythms may show a decline (kataclinous rhythms or katarhythms), some others may exhibit an am­plification (anaclinous rhythms or anarhythms), in either the mean or amplitude of oscillation, and, finally, some others may appear not to change at all (aclinous rhythms or isorhythms), with advancing age. The gerorhythmoclinograms of these trends have been already illustrated in Fig. 2.

The kataclinous trend is a typical expression of rhythms «causative» of senescence. The anaclinous trend, by contrast, represents the periodic-linear model of rhythms «adaptive» to aging.

Because of the gerorhythmoclinia the concept of «homeorhythomostasis or rhythmostasis» has to be seriously criticized unless limited to a very short period of life cycle.