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The concept of regulation for human body temperature
J. therm. Biol. VoL 5, pp. 75 to 82
0306-4565/80/0401-0075502.00/0
O Pergamon Press Ltd 1980. Printed in Great Britain
THE CONCEPT OF REGULATION FOR H U M A N BODY TEMPERATURE J. WERNER
Institut for Physiologic, AG Elektrophysiologie, Ruhr-Universit~it, MA 4/58, D 4630 Bochum, Federal Republic of Germany (Received 21 May 1979; accepted in revised form 17 November 1979)
Abstract--1. The regulated variable of human temperature regulation is certainly not a locally defined single temperature, it is probably not heat flow and not mean body temperature, but it seems to be a flexible and adaptable integrative temperature signal according to a distributed parameter control strategy. 2. The regulator does not need any explicit reference, neither in the form of a neuronal signal nor in the form of the indifferent zone. 3. Negative feedback is simply achieved by an odd number of negative input/output relations of the subsystems in the closed loop.
INTRODUCTION
THE control concept of thermoregulation has been
discussed since the early work of Liebermeister (1875). He interpreted the phenomenon of fever as an imbalance between heat production and heat loss, controlled by centres in the brain. The initial approaches to treating thermoregulation as a system were made by Burton (1941), Wyndham et at. (1952), Hardy & Hammel (1963), Crosbie et al. (1963) and others. Since 1960 a series of attempts has been made to construct analytical models. These were reviewed in detail by Hardy (1972). It seemed to be particularly Stolwijk's & Hardy's theoretical study (1966) which stimulated further investigations. The common feature of all approaches until 1970 was the fundamental control concept adapted from technical control theory, defining the "set-point" as the equivalence of reference and feedback signal. Terms like "set-point" and "reference signal" stimulated diverse discussions which were summarized in 1972 by Hammel ("The set-point in temperature regulation, analogy or reality?"). Also in 1972, Cooper discussed the problem of set-point with special reference to fever. Snellen discussed its relation to exercise, and Bligh its relation to neuronal networks. Meanwhile, a new model had been proposed by Mitchell et al. (1970) in order to eliminate the need for a reference signal. Although used by everybody, this term did not conform with reality. Hensel (1973) pointed out that the apparent discrepancy between various set-point models is only gradual in nature. But nevertheless he still required within the controlling system at least two input signals with different temperature coefficients. Even this is superfluous, as shown in two very different proposals by Houdas et al. (1973) and Werner (1977). The discussion goes on, for example, in works by Cabanac (1975), Bligh (1978, "What is regulated and how?"), Houdas et al. (1978) and Werner (1978). The aims of this paper are: (1) to evaluate current control concepts of thermoregulation as well as to accentuate the distributed 75
parameter control strategy of thermoregulation, a basic concept which seems to be compatible with empirical findings and (2) to evaluate current set-point models and to introduce a simple steady-state-concept which does neither need a set-point nor a two signal input for the controller and which should imply the possibility of reducing a lot of contradictory discussions to a common denominator.
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Figure 1 gives a survey on the current view of human temperature regulation, from which some essential control characteristics should already proceed. Temperature-sensitive elements are thought to be heterogenously distributed throughout the body. The existence of warm and cold receptors in the skin is well known. However, there are still some doubts as to the presence of temperature-sensitive elements in skeletal muscles which will be investigated in the near future. Both Rawson & Quick (1970) and Riedel et al. (1973) demonstrated the change of effector activity by thermal stimulation of the visceral muscles. According to the results of Jessen et al. (1978), it is evident that apart from the well-known sensitive areas, skin and CNS, there are most likely other sensitive elements in the body, which taken together should have the same importance as those in the CNS. However, Hellon et al. (1978) have not so far succeeded in finding thermosensitive elements in the main blood vessels. As to the CNS itself, thermosensitivity can be demonstrated almost anywhere, the predominant areas being the spinal cord and the hypothalamus. Mentioning the large variety of important papers dealing with neuronal extrahypothalamic thermosensitivity would exceed the scope of this paper dealing with the control concept of thermoregulation. Fortunately this is done by several reviews (see for example Hensel, 1973; Simon, 1974). The current idea of the thermoafferent system and of the integrating centres is also shown in Fig. 1: spinal cord, medulla oblongata,
76
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Fig. 1. 1 The current view of the thermoregulatory system. midbrain, specific and non-specific thalamus, hypothalamus and cortex. The efferent part of the system includes autonomous and behavioural effector mechanisms. Thermoregulatory behaviour is affected by nutrition, voluntary muscle activities, clothing, change of environment and so on. The autonomous effectors are, above all, heat production via metabolism, skin blood flow via vasomotor activity and evaporation via sweat production and respiration (for details see for example the review by Cabanac, 1975). Regarding the passive system, at least four compartments have to be taken into account: the insulating shell consisting of skin and fat, and the core areas (muscles and viscera). Environmental factors are temperature, humidity, air velocity, and radiation; an important endogenous factor is heat production due to work load. The current concept of the system has thus to take into account locally distributed measurement, processing and actuation. Although there has been con-
siderable experimental evidence for this for a long time, many thermophysiologists do not seem to be aware of this fact, at least not when discussing the control concept of thermoregulation. So, for example, the fact that effector activity may be evoked from different parts of the body, among other reasons, obviously gave rise to the heat flow regulation concept (Houdas et al., 1978), Historically, starting from the hypothalamus, one additional controller had to be added to another, so that finally, Simon (1974) speaks of a multiplicity of controllers. Following control theoretical principles a multiplicity of controllers should be substituted by a distributed parameter control concept which takes into account local distribution in all respects, including the control strategy. Nevertheless, an attempt is now made to develop from Fig. 1 a very simple scheme of thermoregulation. Following the dashed lines in Fig. 1 the system of temperature regulation may be divided into four subsystems cooperating in a closed control loop (Fig. 2): (1) the receptors which measure temperature and
The concept of regulation for human body temperature
77
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Fig. 2. Simplest scheme of thermoregulation. The structure of Fig. I (dashed lines) is retained. transmit this information to the control centres via afferent fibres and neurons, (2) the controlling system which activates the effectors via efferent pathways, (3) the effectors which act upon the passive system and (4) the passive system itself. There is no doubt that the fundamental property of homeothermy is feedback control. In the view of Bligh (for example, Bligh, 1978), the control concept of thermoregulation is, indeed, a regulation concept. Even from this very simple scheme some essential questions emerge which have been discussed again and again, namely: (1) Which is the regulated variable? (2) How does the regulator get its reference? (3) How does the regulator get the error signal? (4) How is negative feedback achieved? (5) What is the nature of temperature change due to fever or circadian rhythm? In attempting to answer the central question "What is regulated?" five different control concepts have been under discussion: (1) control of a locally defined variable, (2) control on the basis of spatial integration of temperatures, (3) control on the basis of spatial integration of temperature + local effector actuation, (4) control of local temperature profiles and (5) heat flow regulation. For many years, concept 1 was the accepted control concept for thermoregulation: hypothalamic temperature was considered to be the controlled variable which determined the amount of effector activity. This concept has been substituted by the somewhat vague concept of control on the basis of spatial integration, which essentially means that temperature measured all over the body contribute, according to a given weighting factor, to the measurement of the overall thermal state, which determines primarily all effector activities. It has turned out that this very reasonable concept has to be complemented by the possibility of evaluating local requirements, i.e. outstanding thermal load of parts of the body yields intensification of the local effector activity involved (concept 3). This concept seems the one that best fulfils experimentally verified requirements. However, a great amount of experimental work has still to be done in order to give a more detailed and a really quantitative description of the control strategy, especially of the coupling matrices between local measurement, its central processing and local effector activity.
But although human thermoregulation turns out to be essentially a distributed parameter control loop, we must deny the existence of the most sophisticated distributed parameter control concept which enables regulation of whole local profiles (concept 4). Even if the skin areas are not taken into account, an analysis of local temperature distribution under various environmental conditions shows that enormous changes in temperature profiles take place, so that a true regulation of temperature profiles is out of the question. The concept of heat flow regulation (concept 5) of Houdas et al. (1973) is a very natural principle. However, according to this concept, temperatures are not really regulated, they are rather an open-loop result of a balance of heat production and heat loss. STEADY-STATESAND ADJUSTMENT OF "'SET-POINT" The common and necessary element of all control concepts presented is the requirement that steadystates are reached on the basis of a balance of two or more variables. Expressed mathematically: a minus sign or sign inversion in the control loop is required. This may be achieved in the following ways: (a) balance of passive and active (of controlled and controlling) processes in the closed control loop (Werner), (b) balance of reference and actual value of the controlled variable (basic technical control concept), (c) balance of rise and fall feedback elements (Mitchell et al.; Bligh) and (d) balance of heat production and heat loss (no temperature control) (Houdas et al.). Figure 3 translates the verbal formulation into block diagrams. They clearly show how a minus sign is obtained in the control loop: Fig. 3a: no explicit subtraction (only sign inversion at an arbitrary point of the closed control loop, as shall be explained below), Fig. 3b: reference signal minus feedback signal, Fig. 3c: positive minus negative feedback signals, Fig. 3d: heat production minus heat loss. Concept (a) is based on true proportional temperature control with steady-states resulting from a balance of passive and active processes in the control loop. To understand such a closed control loop mechanism, it is convenient to open the control loop in order to get the overall input/output relation of controlling and of controlled subsystems. Figure 4 shows the steady-state relations after coldload. In the upper part (Fig. 4a) the control loop is given with two parallel effectors, metabolism and skin blood flow. We essentially obtain either one (Fig. 4b)
78
J. WERNER
or three (Fig. 4c) steady-state functions with negative slope. This is of course already the necessary realization of sign inversion in the closed control loop (negative feedback)! Just for a simpler explanation (in order to avoid three-dimensional diagrams) in Fig. 4b constant blood flow and in Fig. 4c constant metabolism are assumed. In the closed control loop the four open-loop functions have to interact. The dotted line ( . . . . . ) in Fig. 4b demonstrates that arbitrary values do not yield a closed circuit, i.e. a steady-state. As there is only one quadruple of values (e.g. to, fe, M, T) compatible with all four steady-state functions (solid rectangular line), it is obvious that these values determine the steady-state of the closed control loop. To carry out the control task, neither a reference-signal
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nor a comparison of two or more controller inputs with different temperature coefficients is necessary, as the steady-state reached is the only one which is possible under the assumed conditions. According to this, the steady-state is defined as that state which enables compatibility of the steady-state functions of the components of the control loop. If another variable changes, e.g. air temperature TA. we get another characterizing function for the passive system, e.g. for a higher air temperature TA., > Tal a curve above the one which was regarded up to now. Now the accepted steady-state cannot be maintained. a dynamic process will start and finally a new steadystate is reached which is determined by the new quadruple (dashed line: ) of the curves. The phenomenon of fever can be interpreted in the
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79
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Fig. 4. Steady state concept of thermoregulation after cold load. (a) Closed-control loop with subsystems and their open-loop characteristics. (b) Steady-state after cold load (constant skin blood flow assumed). (c) Steady-state after cold load (constant metabolism assumed). (d) Steady-state after cold load and fever (constant skin blood flow assumed). (e) Steady-state after cold load and fever (constant metabolism assumed). same manner (Fig. 4, d and e). Pyrogens act via several mediators on the thermosensitive characteristics of central neurons so that the overall controller characteristics are changed, resulting again in a new steady-state with increase of heat-production (Fig~ 4d), vasoconstriction (Fig. 4e) and temperature. On the other hand, the opposite process, subsiding fever, is the transition from the higher to the lower temperature, thus requiring decrease of heat production, vasodilatation and sweat production. The demonstrated principle holds for external or internal heat load as well. Of course, now we have primarily afferent spike rates from warm receptors (Fig. 5a). Again there is an odd number of steady-state relations with negative slope (Fig. 5, b and c) in the closed control loop as long as negative feedback control is maintained. The influence of increasing metabolism in warmth (Q,o-aspect) is an additional disturbing factor. It shifts the characteristics of the passive system (like air. temperature, for example) and has no direct influence on the regulation concept. T.I. 5/2--B
Regarding moderate temperature load including the indifferent zone the systems of Figs 4 and 5 have to be superimposed. Control action is now primarily determined by vasomotor action. According to this steady-state concept, with an implicit operating point, resulting only from proportional dosed loop operation with negative feedback, there is no need for an explicit reference for the control operation. Hence, the indifferent status with minimal evaporative and metabolic activity is only one of the manifold steady-states which are possible. Whether it is reached or not depends first on environmental conditions. Environmental conditions outside the indifferent zone bring about, like any proportional controller, permanent deviations in temperature and effector activities, which of course are small compared to the open loop operation. It may be argued that there is almost no deviation of core temperature in the cold. But this is no direct argument against the explained mechanism, because good constancy in the cold primarily is due to the
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distributed parameter concept, as constancy of central areas is reached by considerable temperature decreases of other areas. I now should like to consider the implications and assumptions of the other proposals (b-d) and to show the relations of all four concepts. Concept (b), the basis of most technical control loops, has definitely to be rejected in this form. There is no evidence at all for a reference signal in thermoregulation. There must be some doubt regarding concept (c) as it requires further assumptions, namely the balance of the whole population of neuronal rise and fall feedback signals and the implication that negative feedback is only achieved by cooperation of two inverse sets of receptors. Nevertheless, following the concept of two populations of receptors ("warm" and "cold") the model could be of some help in temperature regulation, but it would not hold for those vegetative control loops, which have not been provided with two inverse receptor populations. When considering the systems of blood pressure regulation or respiratory control for example, there is no evidence for two inverse receptor populations. The heat flow regulation concept (d) implies temperatures as an open loop consequence of heat flow regulation. This conclusion is based above all on the lack of overshoot in the effector dynamics. I do not consider this a necessary conclusion, as the absence of differential or oscillatory behaviour does not contradict the closed control loop concept. The heat flow regulation concept confirms that negative feedback does not necessarily have to be visualized as the comparison of two neuronal inputs. But the meritorious effort to get rid of the direct subtraction of actual and reference temperatures implies further assumptions which can hardly be verified experimentally, namely, heat-flow measurement ("transducers") and central temperatures as an "open-loop consequence", in contrast to skin temperatures which in this concept are
necessarily fed back via the heat-loss mechanism on the body-surface. CONCLUSIONS
It has been the term "'set-point", which, in particular, stimulated many discussions and proposals, some of which could have been avoided if terminology had always been applied more strictly. In the past the term "set-point" has been used for: (1) steady-state (which, indeed, can be very different in the thermoregulatory system depending on environmental and internal conditions) (2) indifferent state (which results from minimal evaporative and metabolic activity; it is one of the possible steady-states and must not play the role of a reference) and (3) reference value or signal (which according to this paper is totally superfluous for thermoregulation). From the control theoretical point of view, the differences of the four presented concepts (a-d) are rather trivial. Nevertheless, in thermal physiology we have been confronted with extensive discussions concerning this topic for about 20 years. Therefore, let me try to show the common denominator of the concepts, thereby hoping that future discussions may concentrate on the essential point. The concept of balance of controlling and controlled processes seems to me the simplest process allowing feedback control. There is only one indispensable requirement for it, namely the existence of a closed loop with sign inversion at an arbitrary point. It seems that there has never been any doubt that this requirement is fulfilled. But obviously it has not been recognized that this is indeed already sufficient for proportional regulation, because additional and special assumptions have been made in other concepts, which can hardly be verified experimentally,
The concept of regulation for human body temperature namely temperature-independent reference signals (concept b), balance of positive and negative neuronal inputs (concept c) and heat flow measurements (concept d). So concepts (b) and (c) are not real contradictions to concept (a) presented here, rather, they may be characterized as unproven special forms of the more general concept (a). On the whole, concepts (b) and (c) are convertible into one another, as stated by Hensel (1973), by "geometrical rotation of the activity/temperature characteristics". Omitting the second controller inputs they are transformed into concept (a), recognizing, according to the considerations above, that negative feedback is already achieved separately for each loop of the Mitchell model and not only when both loops cooperate, as implied by the authors. The heat flow regulation concept may also be converted into concept (a), as heatflow measurement can easily be realized by processing differences of temperatures. It we substitute the "transducers" by the familiar thermosensitive elements, temperatures are again within the closed control loop and may again be considered the controlled variable. So the only important difference of the concepts presented seems to be the way of explaining how negative feedback is achieved. In this way, however, all former proposals involve, compared to concept (a), additional assumptions. To sum up, an attempt has been made to give short answers to the five questions which were asked in the section "Distributed parameter control":
81
SUMMARY One of the basic aspects of human body temperature control is the dependence of system variables and parameters. Furthermore, there is great evidence for a heterogenous distribution of thermosensitive elements throughout the body. The integrative control centres appear to extend quasicontinuously from the spinal cord up to the hypothalamus and finally, control actions obviously affect the passive system with distinct local dependence. A control theoretical device which takes into account these aspects is the distributed parameter control loop. However, the crucial question which remains still unanswered is the quantitative description of the coupling matrices between local measurement, its central processing and local effector activity. At present, a general control concept based on adaptive spatial integration of temperatures plus local effector actuation seems to be the one which is most adequately supported by system theoretical as well as by experimental results. The discussion about "reference" and "set-point" of temperature regulation is still going on, concentrating on four concepts. The concept of balance of passive and active processes, i.e. of controlling and of controlled subsystems, defines the steady-state as the only compatible operating point of the open loop functions of the subsystems in the closed control loop. It does not need an explicit reference input or difference of controller inputs and solves simultaneously the socalled problem of changing set-point due to fever or to circadian rhythm. This is explained as an adjustment of control parameters requiring another balance of controller and passive system. It is tried to show that the suggested concept is a very fundamental and simple functional mechanism. It may be regarded as a generalization of other special proposals, which require additional assumptions not yet proven.
(1) The regulated variable is certainly not a locally defined single temperature, it is probably not heatflow and not mean body temperature, but is seems to be a flexible and adaptable integrative temperature signal according to the so far unknown distributed parameter control strategy. (2) The regulator does not need any explicit referAcknowledgements--The results presented in this paper ence, neither in the form of a neuronal signal nor in are part of a research project within the Sonderforschungsthe form of the indifferent zone. (3) There is no need for an explicit error signal bereich No. 114 "BIONACH'" of the Deutsche Forschungsgemeinschaft. (subtraction of signals) as input to the controller. (4) Negative feedback is simply achieved by an odd number of negative input/output relations of the subREFERENCES systems in the closed loop. (5) Fever and circadian rhythm change central BLIGHJ. (1972) Neuronal models of mammalian temperaneuronal activity and by this affect the controller ture regulation. In Essays on Temperature Regulation. characteristics. This may be achieved by change of (Edited by BLIGHJ. & MOORER. E.) pp. 105-120, Northgain and/or change of threshold. Holland, Amsterdam. BLIGHJ. 0978) Thermoregulation: what is regulated and how? In New Trends in Thermal Physiology (Edited by Finally, some suggestions on the additional quesHOUDASY. & Gumu J. D.) pp. 1-10, Masson, Paris. tion as to the impact of these and similar theoretical BURTONA. C. (1941) The operating characteristics of the considerations on experimental research: human thermoregulatory system. In Temperature, its Measurement and Control in Science and Industry, pp. 522-527, Reinhold, New York. (i) Further development of experimental devices to M. (1975) Temperature regulation. A. Rev. Phyelucidate the distributed parameter control strategy, CABANAC siol. 37, 415--439. e.g. serial and simultaneous application of different COOPERK. E. (1972) The body temperature "set-point" in temperature loads to different parts of the body and fever. In Essays on Temperature Regulation (Edited by measurement of local distribution and change of disBLIGHJ. & MOORER. E.), pp. 149-162, North-Holland, Amsterdam. tribution of the effector mechanisms. (ii) Immediate cessation of looking for neuronal CROSmER. J., HARDYJ. D. & FESSENDENE. (1963) Electrical analog simulation of temperature regulation in man. reference signals. In Temperature, its Measurement and Control in Science (iii) Further investigation of the nature of adaptive and Industry, Part Ill, pp. 627-635, Reinhold, New changes of controller action. York.
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HAMMEL H. T. (1972) The set-point in temperature regulation: analogy or reality. In Essays on Temperature Reyulation (Edited by BLIGH J. & MOORE E.). pp. 121-137, North-Holland, Amsterdam. HARDY J. D. & HAMMEL H. T. 0963) Control system in physiological temperature regulation. In Temperature, its Measurement and Control in Science and Industry, Part Ill, pp. 613-625, Reinhold, New York. HAROY J. D. (1972) Models of temperature regulation--a review. In Essays on Temperature Regul,ztion (Edited by BLIGH J. & MOORE R. E.), pp. 163-186, North-Holland, Amsterdam. HELLON R. F., TOWNSEND Y. & CRANSTON W. I. (1978) A search for thermal receptors in central vasculature. In New Trends in Thermal Physiology (Edited by HOUDAS Y. & GUIEU J. D.) p. 101, Masson, Paris. HENSEL H. (1973) Neuronal processes in thermoregulation. PI,ysiol. Rev. 53, 948-1017. HOUDAS Y., SAUVAGEA., BONAVENTURE M., LEDRU C. & GUIEU J. D. (1973) Thermal control in man: regulation of central temperature or adjustments of heat exchanges by servo-mechanism? J. Dyn. Syst. Measur. Control 95 G, 331-335. HOUDAS Y., LECROART J. L., LEDRU C., CARETTE G. & GUIEU J. D. (1978) The thermoregulatory mechanisms considered as a follow-up system. In New Trends in Thermal Physiology (Edited by HOUDAS Y. & GUIEU J. D.), pp. 11-18, Masson, Paris. JESSEN C., MERCER J. B. ~ SCHMIEG G. (1978) Extra-spinal and extra-hypothalamic thermosensitivity of the body core in conscious goats. In New Trends in Thermal Physiology (Edited by HOUDAS Y. & GUIEU J. D.), pp. 88-90, Masson, Paris. LIEBERMEISTER D. (1875) Handbuch der Pathologie und Therapie des Fiebers. Vogel, Leipzig.
MITCHELL D.. SNELLEN J. W. & ATKINS A. R. {1970) Thermoregulation during fever: change of set-point or change of gain. Pfliiyers Arch. 9es. Physiol. 321,293-302. RAWSON R. O. & QUICK K. P. (1970) Evidence of deepbody thermoreceptor response to intra-abdominal heating of the ewe. J. Appl. Physiol. 28, 813-820. RIEDEL W., SIAPLAURAS G. • SIMON E. (1973) Intraabdominal thermosensitivity in the rabbit as compared with spinal thermosensitivity. Pfliigers Arch. 9es. Physiol. 340, 59-70. SIMON E. (1974) Temperature regulation: The spinal cord as a site of extrahypothalamic thermoregulatory functions. Rer. Physiol. Biochem. Pharmac. 71, 1-76. SNELLEN W. (1972) Set point and exercise. In Essays on Temperature Regulation (Edited by BLIGH J. & MOORE R. E.), pp. 139-148, North-Holland, Amsterdam. STOEWIJK J. A. J. & HARDY J. D. (1966) Temperature regulation in man--A theoretical study, Pfliigers Arch. ges Physiol. 291, 129-162. WERNER J. (1977) Mathematical treatment of structure and function of the human thermoregulatory system. Biol. Cybernet. 25, 93-101. WERNER J. (1978) A contribution to the problem of setpoint of human temperature-regulation. In New Trends in Thernud Physiology (Edited by HOUDAS Y. & GUIEU J. D.), pp. 26-28, Masson, Paris. WYNDHAM G. H., BOUWER W. V. D. M., DEVINE M. G., PATERSON H. E. & MACDONALD D. K. C. (1952) Examination of the use of heat-exchange equations for determining changes in body temperature. J. appl. Physiol. 5, 299-301.
Key Word Index--Temperature regulation; control concept; distributed parameter control; set point; reference; fever.
0306-4565/80/0401-0075502.00/0
O Pergamon Press Ltd 1980. Printed in Great Britain
THE CONCEPT OF REGULATION FOR H U M A N BODY TEMPERATURE J. WERNER
Institut for Physiologic, AG Elektrophysiologie, Ruhr-Universit~it, MA 4/58, D 4630 Bochum, Federal Republic of Germany (Received 21 May 1979; accepted in revised form 17 November 1979)
Abstract--1. The regulated variable of human temperature regulation is certainly not a locally defined single temperature, it is probably not heat flow and not mean body temperature, but it seems to be a flexible and adaptable integrative temperature signal according to a distributed parameter control strategy. 2. The regulator does not need any explicit reference, neither in the form of a neuronal signal nor in the form of the indifferent zone. 3. Negative feedback is simply achieved by an odd number of negative input/output relations of the subsystems in the closed loop.
INTRODUCTION
THE control concept of thermoregulation has been
discussed since the early work of Liebermeister (1875). He interpreted the phenomenon of fever as an imbalance between heat production and heat loss, controlled by centres in the brain. The initial approaches to treating thermoregulation as a system were made by Burton (1941), Wyndham et at. (1952), Hardy & Hammel (1963), Crosbie et al. (1963) and others. Since 1960 a series of attempts has been made to construct analytical models. These were reviewed in detail by Hardy (1972). It seemed to be particularly Stolwijk's & Hardy's theoretical study (1966) which stimulated further investigations. The common feature of all approaches until 1970 was the fundamental control concept adapted from technical control theory, defining the "set-point" as the equivalence of reference and feedback signal. Terms like "set-point" and "reference signal" stimulated diverse discussions which were summarized in 1972 by Hammel ("The set-point in temperature regulation, analogy or reality?"). Also in 1972, Cooper discussed the problem of set-point with special reference to fever. Snellen discussed its relation to exercise, and Bligh its relation to neuronal networks. Meanwhile, a new model had been proposed by Mitchell et al. (1970) in order to eliminate the need for a reference signal. Although used by everybody, this term did not conform with reality. Hensel (1973) pointed out that the apparent discrepancy between various set-point models is only gradual in nature. But nevertheless he still required within the controlling system at least two input signals with different temperature coefficients. Even this is superfluous, as shown in two very different proposals by Houdas et al. (1973) and Werner (1977). The discussion goes on, for example, in works by Cabanac (1975), Bligh (1978, "What is regulated and how?"), Houdas et al. (1978) and Werner (1978). The aims of this paper are: (1) to evaluate current control concepts of thermoregulation as well as to accentuate the distributed 75
parameter control strategy of thermoregulation, a basic concept which seems to be compatible with empirical findings and (2) to evaluate current set-point models and to introduce a simple steady-state-concept which does neither need a set-point nor a two signal input for the controller and which should imply the possibility of reducing a lot of contradictory discussions to a common denominator.
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Figure 1 gives a survey on the current view of human temperature regulation, from which some essential control characteristics should already proceed. Temperature-sensitive elements are thought to be heterogenously distributed throughout the body. The existence of warm and cold receptors in the skin is well known. However, there are still some doubts as to the presence of temperature-sensitive elements in skeletal muscles which will be investigated in the near future. Both Rawson & Quick (1970) and Riedel et al. (1973) demonstrated the change of effector activity by thermal stimulation of the visceral muscles. According to the results of Jessen et al. (1978), it is evident that apart from the well-known sensitive areas, skin and CNS, there are most likely other sensitive elements in the body, which taken together should have the same importance as those in the CNS. However, Hellon et al. (1978) have not so far succeeded in finding thermosensitive elements in the main blood vessels. As to the CNS itself, thermosensitivity can be demonstrated almost anywhere, the predominant areas being the spinal cord and the hypothalamus. Mentioning the large variety of important papers dealing with neuronal extrahypothalamic thermosensitivity would exceed the scope of this paper dealing with the control concept of thermoregulation. Fortunately this is done by several reviews (see for example Hensel, 1973; Simon, 1974). The current idea of the thermoafferent system and of the integrating centres is also shown in Fig. 1: spinal cord, medulla oblongata,
76
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Fig. 1. 1 The current view of the thermoregulatory system. midbrain, specific and non-specific thalamus, hypothalamus and cortex. The efferent part of the system includes autonomous and behavioural effector mechanisms. Thermoregulatory behaviour is affected by nutrition, voluntary muscle activities, clothing, change of environment and so on. The autonomous effectors are, above all, heat production via metabolism, skin blood flow via vasomotor activity and evaporation via sweat production and respiration (for details see for example the review by Cabanac, 1975). Regarding the passive system, at least four compartments have to be taken into account: the insulating shell consisting of skin and fat, and the core areas (muscles and viscera). Environmental factors are temperature, humidity, air velocity, and radiation; an important endogenous factor is heat production due to work load. The current concept of the system has thus to take into account locally distributed measurement, processing and actuation. Although there has been con-
siderable experimental evidence for this for a long time, many thermophysiologists do not seem to be aware of this fact, at least not when discussing the control concept of thermoregulation. So, for example, the fact that effector activity may be evoked from different parts of the body, among other reasons, obviously gave rise to the heat flow regulation concept (Houdas et al., 1978), Historically, starting from the hypothalamus, one additional controller had to be added to another, so that finally, Simon (1974) speaks of a multiplicity of controllers. Following control theoretical principles a multiplicity of controllers should be substituted by a distributed parameter control concept which takes into account local distribution in all respects, including the control strategy. Nevertheless, an attempt is now made to develop from Fig. 1 a very simple scheme of thermoregulation. Following the dashed lines in Fig. 1 the system of temperature regulation may be divided into four subsystems cooperating in a closed control loop (Fig. 2): (1) the receptors which measure temperature and
The concept of regulation for human body temperature
77
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Fig. 2. Simplest scheme of thermoregulation. The structure of Fig. I (dashed lines) is retained. transmit this information to the control centres via afferent fibres and neurons, (2) the controlling system which activates the effectors via efferent pathways, (3) the effectors which act upon the passive system and (4) the passive system itself. There is no doubt that the fundamental property of homeothermy is feedback control. In the view of Bligh (for example, Bligh, 1978), the control concept of thermoregulation is, indeed, a regulation concept. Even from this very simple scheme some essential questions emerge which have been discussed again and again, namely: (1) Which is the regulated variable? (2) How does the regulator get its reference? (3) How does the regulator get the error signal? (4) How is negative feedback achieved? (5) What is the nature of temperature change due to fever or circadian rhythm? In attempting to answer the central question "What is regulated?" five different control concepts have been under discussion: (1) control of a locally defined variable, (2) control on the basis of spatial integration of temperatures, (3) control on the basis of spatial integration of temperature + local effector actuation, (4) control of local temperature profiles and (5) heat flow regulation. For many years, concept 1 was the accepted control concept for thermoregulation: hypothalamic temperature was considered to be the controlled variable which determined the amount of effector activity. This concept has been substituted by the somewhat vague concept of control on the basis of spatial integration, which essentially means that temperature measured all over the body contribute, according to a given weighting factor, to the measurement of the overall thermal state, which determines primarily all effector activities. It has turned out that this very reasonable concept has to be complemented by the possibility of evaluating local requirements, i.e. outstanding thermal load of parts of the body yields intensification of the local effector activity involved (concept 3). This concept seems the one that best fulfils experimentally verified requirements. However, a great amount of experimental work has still to be done in order to give a more detailed and a really quantitative description of the control strategy, especially of the coupling matrices between local measurement, its central processing and local effector activity.
But although human thermoregulation turns out to be essentially a distributed parameter control loop, we must deny the existence of the most sophisticated distributed parameter control concept which enables regulation of whole local profiles (concept 4). Even if the skin areas are not taken into account, an analysis of local temperature distribution under various environmental conditions shows that enormous changes in temperature profiles take place, so that a true regulation of temperature profiles is out of the question. The concept of heat flow regulation (concept 5) of Houdas et al. (1973) is a very natural principle. However, according to this concept, temperatures are not really regulated, they are rather an open-loop result of a balance of heat production and heat loss. STEADY-STATESAND ADJUSTMENT OF "'SET-POINT" The common and necessary element of all control concepts presented is the requirement that steadystates are reached on the basis of a balance of two or more variables. Expressed mathematically: a minus sign or sign inversion in the control loop is required. This may be achieved in the following ways: (a) balance of passive and active (of controlled and controlling) processes in the closed control loop (Werner), (b) balance of reference and actual value of the controlled variable (basic technical control concept), (c) balance of rise and fall feedback elements (Mitchell et al.; Bligh) and (d) balance of heat production and heat loss (no temperature control) (Houdas et al.). Figure 3 translates the verbal formulation into block diagrams. They clearly show how a minus sign is obtained in the control loop: Fig. 3a: no explicit subtraction (only sign inversion at an arbitrary point of the closed control loop, as shall be explained below), Fig. 3b: reference signal minus feedback signal, Fig. 3c: positive minus negative feedback signals, Fig. 3d: heat production minus heat loss. Concept (a) is based on true proportional temperature control with steady-states resulting from a balance of passive and active processes in the control loop. To understand such a closed control loop mechanism, it is convenient to open the control loop in order to get the overall input/output relation of controlling and of controlled subsystems. Figure 4 shows the steady-state relations after coldload. In the upper part (Fig. 4a) the control loop is given with two parallel effectors, metabolism and skin blood flow. We essentially obtain either one (Fig. 4b)
78
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or three (Fig. 4c) steady-state functions with negative slope. This is of course already the necessary realization of sign inversion in the closed control loop (negative feedback)! Just for a simpler explanation (in order to avoid three-dimensional diagrams) in Fig. 4b constant blood flow and in Fig. 4c constant metabolism are assumed. In the closed control loop the four open-loop functions have to interact. The dotted line ( . . . . . ) in Fig. 4b demonstrates that arbitrary values do not yield a closed circuit, i.e. a steady-state. As there is only one quadruple of values (e.g. to, fe, M, T) compatible with all four steady-state functions (solid rectangular line), it is obvious that these values determine the steady-state of the closed control loop. To carry out the control task, neither a reference-signal
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79
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Fig. 4. Steady state concept of thermoregulation after cold load. (a) Closed-control loop with subsystems and their open-loop characteristics. (b) Steady-state after cold load (constant skin blood flow assumed). (c) Steady-state after cold load (constant metabolism assumed). (d) Steady-state after cold load and fever (constant skin blood flow assumed). (e) Steady-state after cold load and fever (constant metabolism assumed). same manner (Fig. 4, d and e). Pyrogens act via several mediators on the thermosensitive characteristics of central neurons so that the overall controller characteristics are changed, resulting again in a new steady-state with increase of heat-production (Fig~ 4d), vasoconstriction (Fig. 4e) and temperature. On the other hand, the opposite process, subsiding fever, is the transition from the higher to the lower temperature, thus requiring decrease of heat production, vasodilatation and sweat production. The demonstrated principle holds for external or internal heat load as well. Of course, now we have primarily afferent spike rates from warm receptors (Fig. 5a). Again there is an odd number of steady-state relations with negative slope (Fig. 5, b and c) in the closed control loop as long as negative feedback control is maintained. The influence of increasing metabolism in warmth (Q,o-aspect) is an additional disturbing factor. It shifts the characteristics of the passive system (like air. temperature, for example) and has no direct influence on the regulation concept. T.I. 5/2--B
Regarding moderate temperature load including the indifferent zone the systems of Figs 4 and 5 have to be superimposed. Control action is now primarily determined by vasomotor action. According to this steady-state concept, with an implicit operating point, resulting only from proportional dosed loop operation with negative feedback, there is no need for an explicit reference for the control operation. Hence, the indifferent status with minimal evaporative and metabolic activity is only one of the manifold steady-states which are possible. Whether it is reached or not depends first on environmental conditions. Environmental conditions outside the indifferent zone bring about, like any proportional controller, permanent deviations in temperature and effector activities, which of course are small compared to the open loop operation. It may be argued that there is almost no deviation of core temperature in the cold. But this is no direct argument against the explained mechanism, because good constancy in the cold primarily is due to the
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distributed parameter concept, as constancy of central areas is reached by considerable temperature decreases of other areas. I now should like to consider the implications and assumptions of the other proposals (b-d) and to show the relations of all four concepts. Concept (b), the basis of most technical control loops, has definitely to be rejected in this form. There is no evidence at all for a reference signal in thermoregulation. There must be some doubt regarding concept (c) as it requires further assumptions, namely the balance of the whole population of neuronal rise and fall feedback signals and the implication that negative feedback is only achieved by cooperation of two inverse sets of receptors. Nevertheless, following the concept of two populations of receptors ("warm" and "cold") the model could be of some help in temperature regulation, but it would not hold for those vegetative control loops, which have not been provided with two inverse receptor populations. When considering the systems of blood pressure regulation or respiratory control for example, there is no evidence for two inverse receptor populations. The heat flow regulation concept (d) implies temperatures as an open loop consequence of heat flow regulation. This conclusion is based above all on the lack of overshoot in the effector dynamics. I do not consider this a necessary conclusion, as the absence of differential or oscillatory behaviour does not contradict the closed control loop concept. The heat flow regulation concept confirms that negative feedback does not necessarily have to be visualized as the comparison of two neuronal inputs. But the meritorious effort to get rid of the direct subtraction of actual and reference temperatures implies further assumptions which can hardly be verified experimentally, namely, heat-flow measurement ("transducers") and central temperatures as an "open-loop consequence", in contrast to skin temperatures which in this concept are
necessarily fed back via the heat-loss mechanism on the body-surface. CONCLUSIONS
It has been the term "'set-point", which, in particular, stimulated many discussions and proposals, some of which could have been avoided if terminology had always been applied more strictly. In the past the term "set-point" has been used for: (1) steady-state (which, indeed, can be very different in the thermoregulatory system depending on environmental and internal conditions) (2) indifferent state (which results from minimal evaporative and metabolic activity; it is one of the possible steady-states and must not play the role of a reference) and (3) reference value or signal (which according to this paper is totally superfluous for thermoregulation). From the control theoretical point of view, the differences of the four presented concepts (a-d) are rather trivial. Nevertheless, in thermal physiology we have been confronted with extensive discussions concerning this topic for about 20 years. Therefore, let me try to show the common denominator of the concepts, thereby hoping that future discussions may concentrate on the essential point. The concept of balance of controlling and controlled processes seems to me the simplest process allowing feedback control. There is only one indispensable requirement for it, namely the existence of a closed loop with sign inversion at an arbitrary point. It seems that there has never been any doubt that this requirement is fulfilled. But obviously it has not been recognized that this is indeed already sufficient for proportional regulation, because additional and special assumptions have been made in other concepts, which can hardly be verified experimentally,
The concept of regulation for human body temperature namely temperature-independent reference signals (concept b), balance of positive and negative neuronal inputs (concept c) and heat flow measurements (concept d). So concepts (b) and (c) are not real contradictions to concept (a) presented here, rather, they may be characterized as unproven special forms of the more general concept (a). On the whole, concepts (b) and (c) are convertible into one another, as stated by Hensel (1973), by "geometrical rotation of the activity/temperature characteristics". Omitting the second controller inputs they are transformed into concept (a), recognizing, according to the considerations above, that negative feedback is already achieved separately for each loop of the Mitchell model and not only when both loops cooperate, as implied by the authors. The heat flow regulation concept may also be converted into concept (a), as heatflow measurement can easily be realized by processing differences of temperatures. It we substitute the "transducers" by the familiar thermosensitive elements, temperatures are again within the closed control loop and may again be considered the controlled variable. So the only important difference of the concepts presented seems to be the way of explaining how negative feedback is achieved. In this way, however, all former proposals involve, compared to concept (a), additional assumptions. To sum up, an attempt has been made to give short answers to the five questions which were asked in the section "Distributed parameter control":
81
SUMMARY One of the basic aspects of human body temperature control is the dependence of system variables and parameters. Furthermore, there is great evidence for a heterogenous distribution of thermosensitive elements throughout the body. The integrative control centres appear to extend quasicontinuously from the spinal cord up to the hypothalamus and finally, control actions obviously affect the passive system with distinct local dependence. A control theoretical device which takes into account these aspects is the distributed parameter control loop. However, the crucial question which remains still unanswered is the quantitative description of the coupling matrices between local measurement, its central processing and local effector activity. At present, a general control concept based on adaptive spatial integration of temperatures plus local effector actuation seems to be the one which is most adequately supported by system theoretical as well as by experimental results. The discussion about "reference" and "set-point" of temperature regulation is still going on, concentrating on four concepts. The concept of balance of passive and active processes, i.e. of controlling and of controlled subsystems, defines the steady-state as the only compatible operating point of the open loop functions of the subsystems in the closed control loop. It does not need an explicit reference input or difference of controller inputs and solves simultaneously the socalled problem of changing set-point due to fever or to circadian rhythm. This is explained as an adjustment of control parameters requiring another balance of controller and passive system. It is tried to show that the suggested concept is a very fundamental and simple functional mechanism. It may be regarded as a generalization of other special proposals, which require additional assumptions not yet proven.
(1) The regulated variable is certainly not a locally defined single temperature, it is probably not heatflow and not mean body temperature, but is seems to be a flexible and adaptable integrative temperature signal according to the so far unknown distributed parameter control strategy. (2) The regulator does not need any explicit referAcknowledgements--The results presented in this paper ence, neither in the form of a neuronal signal nor in are part of a research project within the Sonderforschungsthe form of the indifferent zone. (3) There is no need for an explicit error signal bereich No. 114 "BIONACH'" of the Deutsche Forschungsgemeinschaft. (subtraction of signals) as input to the controller. (4) Negative feedback is simply achieved by an odd number of negative input/output relations of the subREFERENCES systems in the closed loop. (5) Fever and circadian rhythm change central BLIGHJ. (1972) Neuronal models of mammalian temperaneuronal activity and by this affect the controller ture regulation. In Essays on Temperature Regulation. characteristics. This may be achieved by change of (Edited by BLIGHJ. & MOORER. E.) pp. 105-120, Northgain and/or change of threshold. Holland, Amsterdam. BLIGHJ. 0978) Thermoregulation: what is regulated and how? In New Trends in Thermal Physiology (Edited by Finally, some suggestions on the additional quesHOUDASY. & Gumu J. D.) pp. 1-10, Masson, Paris. tion as to the impact of these and similar theoretical BURTONA. C. (1941) The operating characteristics of the considerations on experimental research: human thermoregulatory system. In Temperature, its Measurement and Control in Science and Industry, pp. 522-527, Reinhold, New York. (i) Further development of experimental devices to M. (1975) Temperature regulation. A. Rev. Phyelucidate the distributed parameter control strategy, CABANAC siol. 37, 415--439. e.g. serial and simultaneous application of different COOPERK. E. (1972) The body temperature "set-point" in temperature loads to different parts of the body and fever. In Essays on Temperature Regulation (Edited by measurement of local distribution and change of disBLIGHJ. & MOORER. E.), pp. 149-162, North-Holland, Amsterdam. tribution of the effector mechanisms. (ii) Immediate cessation of looking for neuronal CROSmER. J., HARDYJ. D. & FESSENDENE. (1963) Electrical analog simulation of temperature regulation in man. reference signals. In Temperature, its Measurement and Control in Science (iii) Further investigation of the nature of adaptive and Industry, Part Ill, pp. 627-635, Reinhold, New changes of controller action. York.
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HAMMEL H. T. (1972) The set-point in temperature regulation: analogy or reality. In Essays on Temperature Reyulation (Edited by BLIGH J. & MOORE E.). pp. 121-137, North-Holland, Amsterdam. HARDY J. D. & HAMMEL H. T. 0963) Control system in physiological temperature regulation. In Temperature, its Measurement and Control in Science and Industry, Part Ill, pp. 613-625, Reinhold, New York. HAROY J. D. (1972) Models of temperature regulation--a review. In Essays on Temperature Regul,ztion (Edited by BLIGH J. & MOORE R. E.), pp. 163-186, North-Holland, Amsterdam. HELLON R. F., TOWNSEND Y. & CRANSTON W. I. (1978) A search for thermal receptors in central vasculature. In New Trends in Thermal Physiology (Edited by HOUDAS Y. & GUIEU J. D.) p. 101, Masson, Paris. HENSEL H. (1973) Neuronal processes in thermoregulation. PI,ysiol. Rev. 53, 948-1017. HOUDAS Y., SAUVAGEA., BONAVENTURE M., LEDRU C. & GUIEU J. D. (1973) Thermal control in man: regulation of central temperature or adjustments of heat exchanges by servo-mechanism? J. Dyn. Syst. Measur. Control 95 G, 331-335. HOUDAS Y., LECROART J. L., LEDRU C., CARETTE G. & GUIEU J. D. (1978) The thermoregulatory mechanisms considered as a follow-up system. In New Trends in Thermal Physiology (Edited by HOUDAS Y. & GUIEU J. D.), pp. 11-18, Masson, Paris. JESSEN C., MERCER J. B. ~ SCHMIEG G. (1978) Extra-spinal and extra-hypothalamic thermosensitivity of the body core in conscious goats. In New Trends in Thermal Physiology (Edited by HOUDAS Y. & GUIEU J. D.), pp. 88-90, Masson, Paris. LIEBERMEISTER D. (1875) Handbuch der Pathologie und Therapie des Fiebers. Vogel, Leipzig.
MITCHELL D.. SNELLEN J. W. & ATKINS A. R. {1970) Thermoregulation during fever: change of set-point or change of gain. Pfliiyers Arch. 9es. Physiol. 321,293-302. RAWSON R. O. & QUICK K. P. (1970) Evidence of deepbody thermoreceptor response to intra-abdominal heating of the ewe. J. Appl. Physiol. 28, 813-820. RIEDEL W., SIAPLAURAS G. • SIMON E. (1973) Intraabdominal thermosensitivity in the rabbit as compared with spinal thermosensitivity. Pfliigers Arch. 9es. Physiol. 340, 59-70. SIMON E. (1974) Temperature regulation: The spinal cord as a site of extrahypothalamic thermoregulatory functions. Rer. Physiol. Biochem. Pharmac. 71, 1-76. SNELLEN W. (1972) Set point and exercise. In Essays on Temperature Regulation (Edited by BLIGH J. & MOORE R. E.), pp. 139-148, North-Holland, Amsterdam. STOEWIJK J. A. J. & HARDY J. D. (1966) Temperature regulation in man--A theoretical study, Pfliigers Arch. ges Physiol. 291, 129-162. WERNER J. (1977) Mathematical treatment of structure and function of the human thermoregulatory system. Biol. Cybernet. 25, 93-101. WERNER J. (1978) A contribution to the problem of setpoint of human temperature-regulation. In New Trends in Thernud Physiology (Edited by HOUDAS Y. & GUIEU J. D.), pp. 26-28, Masson, Paris. WYNDHAM G. H., BOUWER W. V. D. M., DEVINE M. G., PATERSON H. E. & MACDONALD D. K. C. (1952) Examination of the use of heat-exchange equations for determining changes in body temperature. J. appl. Physiol. 5, 299-301.
Key Word Index--Temperature regulation; control concept; distributed parameter control; set point; reference; fever.