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J therm B io l VoL 5 pp. 75 to 82 0306-4565/80/0401-0075502.00/0O Pe rga m on Pre ss L t d 1980. Pr i n t e d i n Gre a t Br i t ai n

T H E C O N C E P T O F R E G U L T I O N F O R H U M N B O D YT E M P E R T U R E

J W E R N E RInstitu t for Physiologic, AG Elektrophysiologie, R uhr-Universit~it, MA 4/58,D 4630 Bochum, Fed eral Republic of Germ any

R e c e i v e d 21 M a y 1979; a c c e p t e d i n r e v i s e d f o r m 17 N o v e m b e r 1979)Abstrac t- -1. The regulated var iable of human temperature regulat ion is cer tainly not a local ly def inedsingle temperature, i t is probably not heat f low and not mean bod y temperature, but i t seems to be af lexible and adap table integrative tem perature s ignal according to a dis tr ibuted parame ter controlstrategy.2. Th e regu lator does not need any explicit reference, neither in the form o f a neuronal signal nor inthe form of the indifferent zone.3. Negative feedback is simply achieved by an odd number of negative input/output relations of thesubsystems in the closed loop.

I N T R O D U C T I O NT H E c o n t r o l c o n c e p t o f t h e rm o r e g u l a t i o n h a s b e e nd i s c u s s e d s i n c e t h e e a r l y w o r k o f L i e b e r m e i s t e r ( 18 7 5) .H e i n t e r p r e t e d t h e p h e n o m e n o n o f f e v e r a s a n i m -b a l a n c e b e t w e e n h e a t p r o d u c t i o n a n d h e a t l o s s , c o n -t r o l l e d b y c e n t r e s in t h e b r a i n . T h e i n i t i a l a p p r o a c h e st o t r e a t i n g t h e r m o r e g u l a t i o n a s a s y s te m w e r e m a d eb y B u r t o n ( 1 9 4 1 ) , W y n d h a m e t a t . ( 1952) , H ar dy &H a m m e l ( 19 6 3) , C r o s b i e e t a l . ( 1963) and o the r s . S ince1 9 60 a s e ri e s o f a t t e m p t s h a s b e e n m a d e t o c o n s t r u c ta n a l y t i c a l m o d e l s . T h e s e w e r e r e v i ew e d i n d e t a i l b yH a r d y ( 1 9 7 2 ) . I t s e e m e d t o b e p a r t i c u l a r l y S t o l w i j k ' s& H a r d y ' s t h e o r e t i c a l s t u d y ( 1 9 6 6 ) w h i c h s t i m u l a t e df u r t h e r i n v e s t ig a t i o n s . T h e c o m m o n f e a t u r e o f a l la p p r o a c h e s u n t i l 1 9 7 0 w a s t h e f u n d a m e n t a l c o n t r o lc o n c e p t a d a p t e d f r o m t e c h n i c a l c o n t r o l t h e o r y , d e f i n -i n g t h e s e t - p o i n t a s t h e e q u i v a l e n c e o f r e f e re n c e a n df e e d b a c k s i g n a l. T e r m s li k e s e t - p o i n t a n d r e fe r e n c es i g n a l s t i m u l a t e d d i v e r se d i s c u s s io n s w h i c h w e res u m m a r i z e d i n 1 9 7 2 b y H a m m e l ( T h e s e t - p o i n t i nt e m p e r a t u r e r e g u l a t i o n , a n a l o g y o r r e a l it y ? ) . A l s o i n1 9 72 , C o o p e r d i s c u s s e d t h e p r o b l e m o f s e t - p o i n t w i t hspec ia l r e f e r ence to f ever. Sn e l len d i scussed i t s r e la t ionto exer c i se , and Bl igh i ts r e la t ion to n eur on a ln e t w o r k s .

M e a n w h i l e , a n e w m o d e l h a d b e e n p r o p o s e d b yM i t c h e l l e t a l . ( 1970) in or de r to e l imin a te the need f ora r e f e r en c e si g n a l . A l t h o u g h u s e d b y e v e r y b o d y , t h ist e r m d i d n o t c o n f o r m w i t h r e a l i t y . H e n s e l ( 1 9 7 3 )p o i n t e d o u t t h a t t h e a p p a r e n t d i s c r e p a n c y b e t w e e nv a r i o u s s e t - p o i n t m o d e l s i s o n l y g r a d u a l i n n a t u r e .B u t n e v e r t h e l e s s h e s t i l l r e q u i r e d w i t h i n t h e c o n t r o l -l ing sys tem a t l eas t tw o i npu t s igna ls w i th d i f f e ren ttem per a tur e coef f ic ien ts. Even th i s i s super f luous , a ss h o w n i n t w o v e r y d if f e re n t p r o p o s a l s b y H o u d a s e ta l . ( 1973) and W er ner ( 1977) . The d i scuss ion goes on ,f or examp le , in w or k s by Ca ban ac ( 1975), Bl igh (1978,W h a t i s r e g u l a te d a n d h o w ? ), H o u d a s e t a l . (1978)and W er ner ( 1978) .T h e a i m s o f t h is p a p e r a r e :

( 1 ) t o e v a l u a t e c u r r e n t c o n t r o l c o n c e p t s o f t h e r m o -r e g u l a t i o n a s w e l l a s t o a c c e n t u a t e t h e d i s t r i b u t e d75

p a r a m e t e r c o n t r o l s t r a t e g y o f t h e r m o r e g u l a t i o n , ab a s i c c o n c e p t w h i c h s e e m s t o b e c o m p a t i b l e w i t h e m -p i r i c a l fi n d i n g s a n d( 2 ) t o e v a l u a t e c u r r e n t s e t - p o i n t m o d e l s a n d t oi n t r o d u c e a s i m p l e s t e a d y - s t a t e - c o n c e p t w h i c h d o e sn e i t h e r n e e d a s e t - p o i n t n o r a t w o s i g n a l in p u t f o rt h e c o n t r o l l e r a n d w h i c h s h o u l d i m p l y t h e p o s s i b i l i t yo f r e d u c i n g a l o t o f c o n t r a d i c t o r y d i s c u s s i o n s t o ac o m m o n d e n o m i n a t o r .

D I S T R IB U T E D P A R A M E T E R C O N T R O LF i g u r e 1 g i v es a s u r v e y o n t h e c u r r e n t v i e w o fh u m a n t e m p e r a t u r e r e g u l a t i o n , f r o m w h i c h s o m ee s s e n t i a l c o n t r o l c h a r a c t e r i s t i c s s h o u l d a l r e a d y p r o -c e e d . T e m p e r a t u r e - s e n s i t i v e e l e m e n t s a r e t h o u g h t t ob e h e t e r o g e n o u s l y d i s t r i b u t e d t h r o u g h o u t t h e b o d y .T h e e x i s t e n c e o f w a r m a n d c o l d r e c e p t o r s i n t h e s k i ni s w e l l k n o w n . H o w e v e r , t h e r e a r e s ti l l s o m e d o u b t s a st o t h e p r e s e n c e o f t e m p e r a t u r e - s e n s i t i v e e l e m e n t s i ns k e l e t a l m u s c l e s w h i c h w i l l b e i n v e s t i g a t e d i n t h e n e a rf u tu r e . B o t h R a w s o n & Q u i c k ( 1 97 0 ) a n d R i e d e l e t a l .( 19 7 3) d e m o n s t r a t e d t h e c h a n g e o f e f fe c t o r a c t i v i t y b yt h e r m a l s t i m u l a t i o n o f t h e v i s c e ra l m u s c l e s . A c c o r d i n g

t o t h e r e s u l t s o f J e s s en e t a l . (1978) , i t is evident thata p a r t f r o m t h e w e l l - k n o w n s e n s i ti v e a r e a s , s k i n a n dC N S , t h e r e a r e m o s t l i k e l y o t h e r s e n s i ti v e e l e m e n t s i nt h e b o d y , w h i ch t a k e n t o g e t h e r sh o u l d h a v e t h e s a m ei m p o r t a n c e a s t h o s e i n t h e C N S . H o w e v e r , H e l l o n e ta l . ( 19 7 8) h a v e n o t s o f a r s u c c e e d e d i n f i n d i n g t h e r m o -s e n s i ti v e e l e m e n t s i n t h e m a i n b l o o d v e s se l s. A s t o t h eC N S i t s el f, t h e r m o s e n s i t i v i t y c a n b e d e m o n s t r a t e da l m o s t a n y w h e r e , t h e p r e d o m i n a n t a r e a s b e i n g t h es p i n a l c o r d a n d t h e h y p o t h a l a m u s . M e n t i o n i n g t h el a r g e v a r i e t y o f i m p o r t a n t p a p e r s d e a l i n g w i t hn e u r o n a l e x t r a h y p o t h a l a m i c t h e r m o s e n s it i v it y w o u l de x c e e d t h e s c o p e o f t h i s p a p e r d e a l i n g w i t h t h e c o n -t r o l c o n c e p t o f t h e r m o r e g u l a t i o n . F o r t u n a t e l y t h i s i sd o n e b y s e v e r a l r e v i e w s ( s e e f o r e x a m p l e H e n s e l ,1 9 73 ; S i m o n , 1 9 74 ). T h e c u r r e n t i d e a o f t h e t h e r m o -a f f e r e n t s y s t e m a n d o f t h e i n t e g r a t i n g c e n t r e s i s a l s os h o w n i n F i g . 1 : s p i n a l c o r d , m e d u l l a o b l o n g a t a ,

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76 J. WEANERRECEPTORS CONTROLLER EFFECTORS

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m i d b r a i n , s p e c if i c a n d n o n - s p e c i f i c t h a l a m u s , h y p o -t h a l a m u s a n d c o r te x .T h e e f f e r e n t p a r t o f t h e s y s t e m i n c l u d e s a u t o n o -m o u s a n d b e h a v i o u r a l e f f ec t or m e c h a n i sm s . T h e r m o -r e g u l a t o r y b e h a v i o u r i s a f f e c t e d b y n u t r i t i o n , v o l u n -t a r y m u s c l e a c t i v i t ie s , c l o t h i n g , c h a n g e o f e n v i r o n -m e n t a n d s o o n . T h e a u t o n o m o u s e ff ec to r s a r e, a b o v ea l l, h e a t p r o d u c t i o n v i a m e t a b o l i s m , s k in b l o o d f lo wv i a v a s o m o t o r a c t i v i t y a n d e v a p o r a t i o n v i a sw e a t p r o -d u c t i o n a n d r e s p i r a t i o n f o r d e t a i l s s e e f o r e x a m p l et h e r e v i e w b y C a b a n a c , 1 9 75 ).R e g a r d i n g t h e p a s s i v e s y s t e m , a t l e a s t fo u r c o m -p a r t m e n t s h a v e t o b e t a k e n i n t o a c c o u n t : t h e i n s u l at -i n g s h el l c o n s i s t i n g o f s k i n a n d f a t, a n d t h e c o r e a r e a sm u s c l e s a n d v i s c e r a ) . E n v i r o n m e n t a l f a c t o r s a r et e m p e r a t u r e , h u m i d i t y , a i r v e l o c i t y , a n d r a d i a t i o n ; a ni m p o r t a n t e n d o g e n o u s f a c t o r i s h e a t p r o d u c t i o n d u et o w o r k l o a d .T h e c u r r e n t c o n c e p t o f t h e s y s te m h a s t h u s t o t a k ei n t o a c c o u n t l o c a l ly d i s tr i b u t e d m e a s u r e m e n t , p r o -c e s s i n g a n d a c t u a t i o n . A l t h o u g h t h e r e h a s b e e n c o n -

s i d e r a b l e e x p e r i m e n t a l e v i d e n c e f o r t h is f o r a l o n gt im e , m a n y t h e r m o p h y s i o l o g i s t s d o n o t s e e m t o b ea w a r e o f th i s f a c t, a t l e a s t n o t w h e n d i s c u s s in g t h ec o n t r o l c o n c e p t o f t h e r m o r e g u l a t i o n . S o , f o r e x a m p l e ,t h e f a c t t h a t e f f e c t o r a c t i v i t y m a y b e e v o k e d f r o md i f fe r e n t p a r t s o f t h e b o d y , a m o n g o t h e r r e a s o n s ,o b v i o u s l y g a v e r i se t o t h e h e a t f l o w re g u l a t i o n c o n -c e p t H o u d a s e t a l . 1978) , H is to r ica l ly , s ta r t ing f r omt h e h y p o t h a l a m u s , o n e a d d i t i o n a l c o n t r o l le r h a d t o b ea d d e d t o a n o t h e r , s o t h a t f i n a l l y , S i m o n 1 9 74 ) s p e a k so f a m u l t i p l i c i t y o f c o n t r o l l e r s . F o l l o w i n g c o n t r o lt h e o r e t i c a l p r i n c i p l e s a m u l t i p l i c i t y o f c o n t r o l l e r ss h o u l d b e s u b s t i tu t e d b y a d i s t r i b u t e d p a r a m e t e r c o n -t r o l c o n c e p t w h i c h t a k e s i n t o a c c o u n t l o c a l d i s t r i b u -t i o n i n a l l r e s p e c t s , i n c l u d i n g t h e c o n t r o l s t r a t e g y .N e v e r t h e l e s s , a n a t t e m p t i s n o w m a d e t o d e v e l o pf r o m F i g . 1 a v e r y s i m p l e s c h e m e o f t h e r m o r e g u l a t i o n .F o l l o w i n g t h e d a s h e d l i n e s in F i g . 1 t h e s y s t e m o ft e m p e r a t u r e r e g u l a t i o n m a y b e d i v i d e d i n t o f o u r s u b -s y s t e m s c o o p e r a t i n g i n a c l o s e d c o n t r o l l o o p F i g . 2 ):1 ) t h e r e c e p t o r s w h i c h m e a s u r e t e m p e r a t u r e a n d

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The concept o f regulation for human bod y temperature

RECEPTORSr

EFFECTORS

Fig. 2. Simplest scheme of thermoregulation. The structure of Fig. I (dashed lines) is retained.

77

t ransmi t t h i s i n fo rma t ion t o t he con t ro l c en t re s v i aafferent f ibres and neurons,(2) the cont rol l ing system which ac t iva tes the effec-tors via e fferent pa thways,(3) the effec tors w hich ac t u po n the passive systema n d(4) the passive system itself.T h e r e is n o d o u b t t h a t t h e f u n d a m e n t a l p r o p e r t y o fhomeothe rmy i s f e edback con t ro l . In t he v i ew o f

Bl igh ( for example, Bl igh, 1978) , the c ont r ol co ncep tof therm oreg ula t ion i s , indeed, a regula t io n concep t .Even from this very simple scheme some essent ia lques t i ons emerge which have been d i scussed aga inand aga in , name ly :(1) Which i s the regula ted var iable?(2) How does the regula tor ge t i t s re ference?(3) How does t he r egu l a to r ge t t he e r ro r s ignal ?(4) Ho w i s nega t ive f eedback ach i eved?(5) W ha t i s the na tu re o f t empe ra tu re c hange du e t ofeve r o r c i r cad i an rhy thm ?In a t t empt ing t o answer the cen t ra l ques t i on W ha tis regula ted? f ive di fferent co nt ro l concep ts havebeen unde r d i scuss ion :(1) con t rol of a loca l ly def ined var iable,(2) con t ro l o n t he ba s i s o f spa t i a l i n t eg ra t i on o ftempera tures,(3) con t ro l o n t he ba s i s o f spa t i a l i n t eg ra t i on o ftemp era ture + loca l e ffec tor ac tua t ion,(4) con t rol of loca l temp era tur e prof iles an d(5) hea t f low regula t ion.Fo r m any yea r s , concep t 1 was t he accep t ed con t ro lc o n c e p t f o r th e r m o r e g u l a t i o n : h y p o t h a l a m i c t e m p e r a -tu re was cons ide red t o be t he con t ro l l ed va r i ab l ewhich de t e rmined t he am oun t o f e f f ecto r a c t iv i t y . Th i s

concep t ha s been subs t i t u ted by t he somew ha t vagueconcep t o f con t ro l o n t he ba s i s o f spa t ia l i n t eg ra ti on ,which e ssen t i a l l y means t ha t t empe ra tu re measureda l l ove r t he body con t r i bu t e , a ccord ing t o a g ivenwe igh t ing f ac to r , t o t he measuremen t o f t he ove ra l lthermal s ta te , which de termines pr imari ly a l l e f fec torac t ivi t ies . I t has turned out tha t th is very reasonableconcep t ha s t o be complemen ted by t he poss ib i l i t y o feva lua t i ng l oca l r equ iremen t s , i . e . ou t s t and ing t he r -ma l l oad o f pa r t s o f t he bod y y i e lds in t ens i fi c a t ion o fthe loca l e ffec tor ac t ivi ty involved (concept 3) . Thisconcept seems the one tha t best ful f i l s exper imenta l lyve ri fi ed r equ i remen t s . H oweve r , a g rea t am oun t o f ex -pe r imen ta l w ork ha s s t il l t o be done i n o rde r t o g ive amore de t a i l ed and a r ea l l y quan t i t a t i ve de sc r ip t i on o fthe con t ro l s t r a t egy , e spec i a l l y o f t he coup l ingma t r i c e s be tween l oca l measuremen t , i t s c en t ra l p ro -cessing and loca l e ffec tor ac t ivi ty .

B u t a l t h o u g h h u m a n t h e r m o r e g u l a t i o n t u r n s o u t t obe e ssen t i a l l y a d i s t r i bu t ed pa rame te r con t ro l l oop ,we mus t den y t he ex is tence o f t he m os t sop h i s t i c a tedd i s t r i bu t ed pa rame te r con t ro l concep t wh ich enab l e sregula t ion o f wh ole loca l prof iles (co ncep t 4) . Even i ft he sk in a rea s a re no t t aken i n to accoun t , an ana lys i so f l oca l t empe ra tu re d i s t r i bu t i on unde r va r ious en -v i r o n m e n t a l c o n d it i o n s s h o w s t h a t e n o r m o u s c h a n g e sin tempera ture prof i les take place , so tha t a t rue regu-l a t i on o f t empe ra tu re p rof il es i s ou t o f t he ques t i on .The concep t o f hea t f l ow regu l a t i on ( concep t 5 ) o fH o u d a s e t a l . (1973) i s a very na tura l pr inc iple . Ho w -eve r , a ccord ing t o t h i s concep t , t empe ra tu re s a re no trea ll y r egu l a t ed , t hey a re r a the r an o pen - loop re su l t o fa ba l ance o f hea t p ro duc t ion an d hea t l o ss.

STEADY-STATES AND ADJUSTM ENT OF'SET-POINTT h e c o m m o n a n d n e c e s s a r y e l e m e n t o f a l l c o n t r o lconcep t s p re sen t ed i s t he r equ i remen t t ha t s t e ady-s t a t e s a re r eached on t he ba s i s o f a ba l ance o f two o rmo re var iab le s . Expre ssed ma the ma t i ca l l y : a m inuss ign o r s i gn i nve r s ion i n t he con t ro l l oop i s r equ i red .Th i s m ay be ach i eved i n t he fo ll owing way s :( a) ba l ance o f pa ss ive and ac t i ve (o f con t ro l l ed andcon t ro l l i ng ) p rocesse s i n t he c losed con t ro l l oop(Werner),(b ) ba l ance o f r e ference and ac tua l va lue o f t he co n-t rol led var iable (basic technica l cont rol concept ) ,(c ) ba lanc e of ri se and fa ll feedb ack e lem ents(Mitchel l e t a l . ; Bligh) and(d ) ba l ance o f hea t p ro duc t io n and hea t l o ss (not e m p e r a t u re c o n t r o l ) ( H o u d a s e t a l . .Figure 3 t r ans l a t e s t he ve rba l fo rmula t i on i n to

b lock d i ag rams . They c l ea r ly show how a minus s i gni s ob t a ined i n t he con t ro l l oop : F ig . 3a : no exp l i c i tsub t rac t i on (on ly s i gn i nve rs ion a t an a rb i t r a ry po in to f t he c losed con t ro l l oop , a s sha l l be exp l a inedbelow), Fig . 3b: re ference signal minus feedback sig-nal , Fig . 3c : posi t ive minus negat ive feedback signals ,F ig . 3d : hea t p roduc t ion minus hea t l o ss .Concep t ( a ) i s ba sed on t rue p ropor t i ona l t empe ra -tu re con t ro l wi th s t e ady-s t a t e s r e su l t i ng f rom aba l ance o f pa ss ive and ac t i ve p rocesse s i n t he con t ro ll o o p . T o u n d e r s t a n d s u c h a c lo s e d c o n t ro l l o o p m e c h -an i sm, i t i s conven ien t t o open t he con t ro l l oop i no rde r t o ge t t he ove ra l l i npu t /ou tp u t r e l a t i on o f con-t ro l li ng an d o f con t ro l l ed subsys t ems .F igure 4 shows the s t e ady-s t a t e r e l a t i ons a f t e r co ld -load . In t he uppe r pa r t (F ig . 4a ) t he con t ro l l oop i sgiven wi th two para l le l e ffec tors , metabol ism and skinblood f low. We essent ia l ly obta in e i ther one (Fig. 4b)

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78 J. WERNERo r t h r e e ( F i g . 4 c ) s t e a d y - s t a t e f u n c t i o n s w i t h n e g a t i v es l o p e . T h i s i s o f c o u r s e a l r e a d y t h e n e c e s s a r y r e a l i z a -t i o n o f si g n i n v e r s i o n i n t h e c lo s e d c o n t r o l l o o p ( n e g a -t i v e f e e d b a c k ) J u s t f o r a s i m p l e r e x p l a n a t i o n ( in o r d e rt o a v o i d th r e e - d i m e n s i o n a l d i a g r a m s ) i n F i g . 4 b c o n -s t a n t b l o o d f l o w a n d i n F i g . 4 c c o n s t a n t m e t a b o l i s ma r e a s s u m e d .I n t h e c l o s e d c o n t r o l l o o p t h e f o u r o p e n - l o o p f u n c -t i o n s h a v e t o i n t e r a c t. T h e d o t t e d l i n e ( . . . . . ) i nF i g . 4 b d e m o n s t r a t e s t h a t a r b i t r a r y v a l u e s d o n o ty i e l d a c l o s e d c i r c u i t , i .e . a s t e a d y - s t a t e . A s t h e r e i so n l y o n e q u a d r u p l e o f v a l u e s (e .g . t o , f e , M , T ) c o m -p a t i b l e w i t h a l l f o u r s t e a d y - s t a t e f u n c t i o n s ( s o l i d r e c -t a n g u l a r l i n e) , i t is o b v i o u s t h a t t h e s e v a l u e s d e t e r -m i n e t h e s t e a d y - s t a t e o f t h e c l o s e d c o n t r o l l o o p . T oc a r r y o u t t h e c o n t r o l t a s k , n e i t h e r a r e f e r e n c e - s ig n a l

n o r a c o m p a r i s o n o f t w o o r m o r e c o n t r o l l e r in p u t sw i t h d i f f e r e n t t e m p e r a t u r e c o e f f i c i e n t s i s n e c e s s a r y , a st h e s t e a d y - s t a t e r e a c h e d i s t h e o n l y o n e w h i c h i s p o s s -i b l e u n d e r t h e a s s u m e d c o n d i t i o n s .

A c c o r d i n g t o t h i s , t h e s t e a d y - s t a t e i s d e f i n e d a s t h a ts t a t e w h i c h e n a b l e s c o m p a t i b i l i t y o f th e s t e a d y - s t a t ef u n c t i o n s o f t h e c o m p o n e n t s o f t h e c o n t r o l l o o p .I f a n o t h e r v a r i a b l e c h a n g e s , e . g . a i r t e m p e r a t u r e T A.w e g e t a n o t h e r c h a r a c t e r i z i n g f u n c t i o n f o r t h e p a s s i v es y s t e m , e . g. f o r a h i g h e r a i r t e m p e r a t u r e T A ., > T a l ac u r v e a b o v e t h e o n e w h i c h w a s r e g a r d e d u p t o n o w .N o w t h e a c c e p te d s t e a d y - s ta t e c a n n o t b e m a i n t a i n e d .a d y n a m i c p r o c e s s w i l l s t a r t a n d f i n a ll y a n e w s t e a d y -s t a t e is r e a c h e d w h i c h i s d e t e r m i n e d b y t h e n e w q u a d -r u p l e ( d a s h e d l i n e : ) o f t h e c u r v e s .T h e p h e n o m e n o n o f f e v er c a n b e i n t e r p r e t e d i n t he

t o ) ~ ~ r _ _ _ _ ~ l m e t a b o l~ . m 1 4 . , I , i. . . . , , , , ~ f f r ~ l , , , , ~ , . , le t t t r e q u l d o f f , , ,n , , l - b ~ P Oss ve temper tureI - 1 . . . . . . . . . i - t Z . . . . . . . I - i . . . . . . . . . s s e mi i i . . . . I I i - I

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( c ) , .m e t o b o lis m 1 4~ _ . . ~ I b l o o c l f l o w ( 2e f t f Tec lue ~ e f fe c t o r s I e v o D o r o tio n [- ~ p a s s i v e te m p e r a tu r e s// I b e h a v i o u r H . ._ I y s t e m IJf"~quencies ' ' ]

, y s t ~ e m ~ e m p e ra ~ r~ s

j l e f e c ]F i g . 3. B l o c k d i a g r a m s o f c o n t r o l c o n c e p t s o f th e r m o r e g u l a t i o n . ( a ) C o n t r o l w i t h o u t r e f e re n c e a n de x p l i c i t s i g n a l s u b t r a c t i o n ; s i g n - i n v e r s i o n a t a n a r b i t r a r y p o i n t o f t h e c l o s e d - c o n t r o l l o o p ( W e r n e r ). ( b)C o n t r o l w i t h r e f e r e n ce s i g n a l ( t e c h n i c a l c o n t r o l c o n c e p t ) . ( c) C o n t r o l w i t h p o s i t i v e a n d n e g a t i v e f e e d b a c k( M i t c h e l l et a l . ; B l ig h ). ( d) H e a t f l o w r e g u l a t i o n ( H o u d a s et al. .

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The concept of regulat ion for human b ody tem perature( a ) r cont ro ller e f fec tors pass ive sys tem. . . . . . . . . . . -~ F . . . . . . . . . . - ' r . . . . . i - . . . . 1;

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( e )a f f f m q u f o / ( no r m a l )/ . c on t r o l l e r( f e v e r ). . . . / ~ _ . . / r e c ~ ~ - -e f f f r equ fe t e m P T . . . . . . .

ef fectorsm e t a b o l i s m M( l~ l ood f l ow c on s t )

a f f f r e q u f / n o r m a l/ c o n t r o l l e t

/ e f f e C t sblood f low(rnetobolm n c o n s t )

Fig. 4. Steady state concept of thermoregulation after cold load . (a) Closed-control loo p with subsystemsand their op en-lo op characteristics. (b) Steady-state after cold loa d (constant skin b loo d flow assumed).(c) Stea dy-sta te after cold loa d (constant metabolism assumed). (d) Steady-sta te after cold lo ad a nd fever(constant sk in bloo d flow assumed). (e) Steady-state after co ld loa d an d fever (constant metabolismassumed).s a m e m a n n e r ( F i g . 4 , d a n d e ) . P y r o g e n s a c t v i as e v e r a l m e d i a t o r s o n t h e t h e r m o s e n s i t i v e c h a r a c t e r -i s t ic s o f c e n t r a l n e u r o n s s o t h a t t h e o v e r a l l c o n t r o l l e rc h a r a c t e r i s t ic s a r e c h a n g e d , r e s u l t i n g a g a i n i na n e w s t e a d y - s t a t e w i t h i n c r e a s e o f h e a t - p r o d u c t i o n( Fig~ 4d) , vaso con s t r ic t ion ( F ig . 4e ) and temp er a tur e .O n t h e o t h e r h a n d , t h e o p p o s i t e p r o c e s s , s u b s i d i n gf e v e r , i s t h e t r a n s i t i o n f r o m t h e h i g h e r t o t h e l o w e rt e m p e r a t u r e , t h u s r e q u i r i n g d e c r e a s e o f h e a t p r o d u c -t i o n , v a s o d i l a t a t i o n a n d s w e a t p r o d u c t i o n .T h e d e m o n s t r a t e d p r i n c i p l e h o l d s f o r e x t e r n a l o ri n t e r n a l h e a t l o a d a s w e l l . O f c o u r s e , n o w w e h a v ep r i m a r i l y af f er e n t s p i k e r a t e s f r o m w a r m r e c e p t o r s( F i g . 5 a) . A g a i n t h e r e i s a n o d d n u m b e r o f s t e a d y - s t a t er e l a t i o n s w i t h n e g a t i v e s l o p e ( F i g . 5 , b a n d c ) i n t h ec l o s e d c o n t r o l l o o p a s l o n g a s n e g a t i v e f e e d b a c k c o n -t r o l i s m a i n t a i n e d . T h e i n f lu e n c e o f in c r e a s i n g m e t a b -o l i s m in w a r m t h ( Q , o - a s p e c t ) i s a n a d d i t i o n a l d i s t u r b -i n g f a c t o r . I t s h i f ts t h e c h a r a c t e r i s t i c s o f t h e p a s s i v es y s t e m ( l ik e a ir . t e m p e r a t u r e , f o r e x a m p l e ) a n d h a s n od i r e c t i n f lu e n c e o n t h e r e g u l a t i o n c o n c e p t .

R e g a r d i n g m o d e r a t e t e m p e r a t u r e l o a d i n c l u d i n gt h e i n d i ff e r en t z o n e t h e s y s t e m s o f F i g s 4 a n d 5 h a v et o b e s u p e r i m p o s e d . C o n t r o l a c t i o n i s n o w p r i m a r i l yd e t e r m i n e d b y v a s o m o t o r a c t io n .A c c o r d i n g t o t h i s s t e a d y - s t a t e c o n c e p t, w i t h a n i m -p l i c i t o p e r a t i n g p o i n t , r e s u lt i n g o n l y f r o m p r o p o r -t i o n a l d o s e d l o o p o p e r a t i o n w i t h n e g a t iv e f e ed b a c k ,t h e r e i s n o n e e d f o r a n e x p l i c i t r e f er e n c e f o r t h ec o n t r o l o p e r a t i o n . H e n c e , t h e i n d i f f e r e n t s t a t u s w i t hm i n i m a l e v a p o r a t i v e a n d m e t a b o l i c a c t i v i t y i s o n l yo n e o f t h e m a n i f o l d s t e a d y - s t a t e s w h i c h a r e p o s s i b le .W h e t h e r i t is re a c h e d o r n o t d e p e n d s f i rs t o n e n v i r o n -m e n t a l c o n d i t i o n s . E n v i r o n m e n t a l c o n d i t i o n s o u t s i d et h e i n d i ff e r en t z o n e b r i n g a b o u t , l i k e a n y p r o p o r t i o n a lc o n t r o ll e r , p e r m a n e n t d e v i a t io n s i n t e m p e r a t u r e a n de f fe c t o r a c t i v it i e s , w h i c h o f c o u r s e a r e s m a l l c o m p a r e dt o t h e o p e n l o o p o p e r a t i o n .I t m a y b e a r g u e d t h a t t h e r e i s a l m o s t n o d e v i a t i o no f c o r e t e m p e r a t u r e i n t h e c o l d . B u t t h i s i s n o d i r e c ta r g u m e n t a g a i n s t t h e e x p l a i n e d m e c h a n i s m , b e c a u s eg o o d c o n s t a n c y i n t h e c o l d p r i m a r i l y is d u e t o t h e

T.I. 5 / 2 - - B

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80 J. WERNER, c o n ~ o i e r e f fe c ' c ~ s p c s ~ v e s ~ s t e mO ) . . . .. . .. . .. . ~ r . . .. . .. . .. . . ~ , - . . .. . T . . . . . . . . J~ p t o r s ,, I , ~ , t o r - t e r q 0 T~

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Fig. 5. Steady-state concept of thermoregulation after heat-load. (a) Closed-control loop with subsystemsand their open-loop characteristics. (b) Steady-state after heat-load (constant skin blood flow assumed).(c) Steady-state after heat-load (constant evaporation assumed).

distributed parameter concept, as constancy of centralareas is reached by considerable temperature de-creases of other areas.I now should like to consider the implications andassumptions of the other proposals (b-d) and to showthe relations of all four concepts. Concept (b), thebasis of most technical control loops, has definitely tobe rejected in this form. There is no evidence at all fora reference signal in thermoregulation . There must besome doubt regarding concept (c) as it requiresfurther assumptions, namely the balance of the wholepopula tion of neu ronal rise and fall feedback signalsand the implication that negative feedback is onlyachieved by cooperation of two inverse sets of recep-tors. Nevertheless, following the concept of two popu-lations of receptors ( warm and cold ) the modelcould be of some help in temperature regulation, butit would not hold for those vegetative control loops,which have not been provided with two inverse recep-tor populations. When considering the systems ofblood pressure regulation or respiratory control forexample, there is no evidence for two inverse receptorpopulations.The heat flow regulation concept (d) implies tem-peratures as an open loop consequence of heat flowregulation. This conclusion is based above all on thelack of overshoot in the effector dynamics. I do notconsider this a necessary conclusion, as the absence ofdifferential or oscillatory behaviour does not contra-dict the closed control loop concept. The heat flowregulation concept confirms that negative feedbackdoes not necessarily have to be visualized as the com-parison of two neuronal inputs. But the meritoriouseffort to get rid of the direct subtrac tion of actual andreference temperatures implies further assumptionswhich can hardly be verified experimentally, namely,heat-flow measurement ( transducers ) and centraltemperatures as an open-loop consequence , in con-trast to skin temperatures which in this concept are

necessarily fed back via the heat -loss mechanism onthe body-surface.C O N C L U S I O N S

It has been the term 'set-point , which, in particu-lar, stimulated many discussions and proposals, someof which could have been avoided if terminology hadalways been applied more strictly. In the past theterm set-point has been used for:

(1) steady-state (which, indeed, can be very differentin the thermoregulatory system depending on en-vironmental and internal conditions)(2) indifferent state (which results from minimalevaporative and metabolic activity; it is one of thepossible steady-states and must not play the role of areference) and(3) reference value or signal (which according tothis paper is totally superfluous for thermoregulation).From the control theoretical point of view, the dif-

ferences of the four presented concepts (a-d) arerather trivial. Nevertheless, in thermal physiology wehave been conf ronted with extensive discussions con-cerning this topic for abou t 20 years. Therefore, let metry to show the common denominator of the con-cepts, thereby hoping that future discussions mayconcentrate on the essential point.The concept of balance of controlling and con-trol led processes seems to me the simplest processallowing feedback control. There is only one indis-pensable requirement for it, namely the existence of aclosed loop with sign inversion at an arbitrary point.It seems that there has never been any doubt that thisrequirement is fulfilled. But obviously it has not beenrecognized that this is indeed already sufficient forproportional regulation, because additional andspecial assumptions have been made in other con-cepts, which can hardly be verified experimentally,

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The concept of regulationnam ely tem pera tu re- ind epen den t reference signals(concep t b ), ba l ance o f pos i t ive an d nega t i ve neurona linpu t s ( concep t c ) and hea t f l ow m easurem en t s ( con-cep t d ). So concep t s (b ) and ( c ) a re no t r e a l con t rad i c -t i ons t o concep t ( a) p re sen t ed he re , r a the r , t hey m aybe cha rac t e r i z ed a s unproven spec i a l fo rm s o f t hem o re gene ra l concep t ( a ) . O n the w ho le , concep t s (b )and ( c ) a re conve r t i b le i n to one ano the r , a s s t a t ed b yHense l (1973) , by geom e t r i c a l ro t a t i on o f theac t i v i t y / tem p e ra tu re cha rac te r i s ti c s . Om i t t i ng t hesecond con t ro l l e r i npu t s t hey a re t r ans fo rm ed in toconce p t ( a ) , r e cogn iz ing , a ccord ing t o t he cons ide r -a t i ons above , t ha t nega t i ve f eedback i s a l r eadyach i eved sepa ra t e ly fo r e ach l oop o f t he Mi t che l lm o d e l a n d n o t o n l y w h e n b o t h l o o p s c o o p e r a te , a sim pl i ed by t he au thor s . T he hea t f l ow regu l a t i on con-cep t m ay a l so be con ve r t ed i n to concep t ( a ) , a s hea t -f l ow m easurem en t c an ea si ly be r ea li z ed by p rocess ingdifferences of tempe ra tures. I t we subst i tu te thet r ansduce r s by t he fam i l i ar t he rm osens i t ive e le -m en t s , t em pe ra tu re s a re aga in wi th in t he c losed con-t ro l l oop and m ay aga in be cons ide red t he con t ro l l edvariable.

So t he on ly im p or t an t d i f fe rence o f t he concep t sp re sen t ed seem s to be t he way o f exp l a in ing hownegat ive feedback i s achieved. In th is way, however ,a ll fo rm er p roposa l s i nvo lve , com pared t o concep t (a ),add i t i ona l a ssum pt ions .T o s u m u p , a n a t te m p t h a s b e e n m a d e t o g i ve s h o r tanswers t o t he f ive ques t ions w hich we re a sked i n t hesec ti on Di s t r i bu t ed pa ram e te r con t ro l :(1) Th e regula ted v ar iable i s cer ta inly not a lo ca l lydef ined single tempera ture , i t i s probably not hea t f lowand no t m ean body t em pe ra tu re , bu t i s seem s to be af lexible and adaptable in tegra t ive tempera ture signalaccord in g t o t he so f ar unkno wn d i s t r ibu t ed p a r -am e te r con t ro l s t r a t egy .(2 ) T he r egu l a to r does no t need any exp l i c i t r e fe r -ence , ne i t he r i n the fo rm o f a neu rona l s i gna l no r i nthe fo rm of the indifferent zone .(3) Th ere i s no need fo r an expl ic i t e r ror s ignal(subt ra c t ion of signals) as input to the cont rol le r .(4) Nega t ive f eedback i s s im ply ach i eved by an oddnum ber o f nega t i ve inpu t /ou tpu t r e l a t i ons o f t he sub-sys t em s in t he c losed l oop .(5 ) Feve r and c i r cad i an rhy thm change cen t ra lneuronal ac t ivi ty and by this a ffec t the cont rol le r

cha rac t e r i s t i c s . T h i s m ay be ach i eved by change o fga in and /o r change o f t h re sho ld .F ina l l y , som e sugges t i ons on t he add i t i ona l ques-t i on a s t o t he im pac t o f t he se and s im i l a r t heore t i c a lcons ide ra t i ons on expe r im en ta l r e sea rch :

( i) Fur the r deve lopm ent o f expe r im en ta l dev i ce s t oe luc ida t e t he d i s t r i bu t ed pa ram e te r con t ro l s t r a t egy ,e .g. ser ia l an d sim ul tane ous appl ica t ion of di fferentt em pe ra tu re l oads t o d if fe ren t p a r t s o f t he bod y andm easu rem en t o f l oca l d is t r i bu t i on an d c hange o f d is -t r i bu t i on o f t he e f f ec to r m echan i sm s .( i i ) Im m edia t e c e ssa t i on o f l ook ing fo r neurona lreference signals.( ii i) Fu r th e r i nves t iga t i on o f t he na tu re o f adap t ivechanges o f con t ro l l e r a c t i on .

for human body temperature 8SUMMARY

O n e o f t h e b a s ic a s p ec t s o f h u m a n b o d y t e m p e r a -tu re con t ro l i s t he dependence o f sys t em va r i ab l e s andpa ram e te r s . F ur the rm ore , t he re i s g rea t ev idence fo r ahe t e rogenous d i s t r i bu t i on o f t he rm osens i t i ve e l em en t sth roughou t t he body . T he i n t eg ra t i ve con t ro l c en t re sappea r t o ex t end quas i con t inuous ly f rom the sp ina lco rd up t o t he hypo tha l am us and f i na l l y , con t ro lac t ions obviously affec t the passive system wi th dis-t i nc t l oca l dependence . A con t ro l t heore t i c a l dev i cewhich t akes i n to accoun t t he se a spec t s i s t he d i s t r i -bu t ed pa ram e te r con t ro l l oop . Howeve r , t he c ruc i a lques t i on which r em a ins s t i l l unanswered i s t he quan-t i ta t i ve de sc r ip t ion o f t he coup l ing m a t r i c e s be tweenloca l m easurem en t , i t s c en t ra l p rocess ing and l oca leffec tor ac t ivi ty . At present , a genera l cont rol conceptbased on adap t ive spa t i a l i n t eg ra t i on o f t em pe ra tu re sp lus l oca l e f f ec to r a c tua t i on seem s to be t he onewhich i s m os t adequa t e ly suppor t ed by sys t em theor -etical as well as by experimental results.T he d i scuss ion abou t r e fe rence and se t -po in t o ft em pe ra tu re r egu l a t i on is s ti ll go ing on , concen t ra t i ngon four concep t s . T he concep t o f ba l ance o f pa ss iveand ac t i ve p rocesses , i . e . o f con t ro l l i ng an d o f con-t rol led subsystems, def ines the steady-sta te as the onlyc o m p a t i b l e o p e r a t i n g p o i n t o f th e o p e n l o o p f u n c ti o n sof the subsys t em s in the c losed con t ro l l oop . I t d oesnot need an expl ic i t re ference input or di f ference ofcon t ro l l e r i npu t s and so lve s s im ul t aneous ly t he so -ca l led p rob l em of chang ing se t -po in t due t o f eve r o rto c i r cad i an rhy thm . T h i s i s exp l a ined a s an ad jus t -m e n t o f c o n t ro l p a r a m e t e rs r e q ui r in g a n o t h e r b a l a n c eo f c o n t r o l l e r and passive system. I t i s t r ied to showtha t t he sugges t ed concep t i s a ve ry fundam enta l and

s im ple func t i ona l m echan i sm . I t m ay be r eg a rded a s agene ra l i z a t ion o f o the r spec ia l p roposa l s , wh ichrequ i re add i t i ona l a ssum pt ions no t ye t p roven .Acknowledgements --The results presented in this paperare part o f a research project within the S onderforschungs-bereich No. 114 BION ACH ' of the Deutsche Forschungs-gemeinschaft.

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