The influence of hypothalamic thermoceptive structures on the electroencephalogram and gamma motor activity

ELECTROENCEPHALOGRAPHY AND

CLINICAL NEUROPHYSIOLOGY AN INTERNATIONAL JOURNAL

Vol. 9, N u m b e r 3

August 1957

THE I N F L U E N C E OF H Y P O T H A L A M I C T H E R M O C E P T I V E ON THE ELECTROENCEPHALOGRAM

STRUCTURES

AND GAMMA MOTOR ACTIVITY I C U R T VON EULER, M . D .

and

ULr

SODERBERG, I M . K .

Nobel Institute [or Neurophysiology, Karolinska Institutet, Stockholm, Sweden (Received for publication: October 3, 1956) INTRODUCTION

]t is an old well-known observation that moderate heating of the body elicits drowsiness and muscular relaxation. The decreased muscle tone is generally r e g a r d e d as a reaction involved in t e m p e r a t u r e regulation. Changes in the electroencephalogram ( E E G ) have been observed both in hyper- or hypothermie patien{s and in experimental animals. Alterations in E E G obtained by changes in body t e m p e r a t u r e have f r e q u e n t l y been attributed to thermal influence ou cortical cells. ]Iemingway, Rasmussen, W i k o f f and Rasmussen (1940), however, reported that drowsiness and even sleep could be induced by local heating of posterior hypothalamus. Thus the question arose whether the hypothalamie thermoeeptive structures of Magoun, H a r r i son, Brobeek and Ransou (1938) exert a generalized effect on the level of activity of the eentral nervous system and, if that is the ease, whether the effects are mediated by the reticular activating system of Moruzzi and 1 This work has been supported by a g r a n t from the Swedish Medical Research Council. A g r a n t from the Rockefeller Foundation to this I n s t i t u t e for apparatus is greatfully acknowledged.

Magoun (1949) which influences both " w a k e f u l n e s s " and muscle tonus. This system aecording to the work by Bonvallet, Dell and Hiebel (1954) and Dell, Bonvallet and Hugelin (1954) has already been shown to be engaged in the homeostasis of blood pressure both through projection f r o m the baroeeptors of the carotid sinus and through the direct influence of adrenaline on elements within the reticular formation. The results to be described have led us to conclude that the hypothalamic thermosensitive structures like m a n y p e r i p h e r a l receptors can influence cerebral cortex and the a'amma motor system simultaneously and most likely by a common relay system within the reticular formation of the brain stem. I u a subse~tuent publication (Enler and SSderberg 1957) it will be shown that the setting of the " b o d y t h e r m o s t a t " can be adjusted thr{mgh the reticular activating system, which thus seems to be of importance for maintaining homeostasis of body temperature. Dell et al. (1954) used mono- and polysynaptie reflexes as indices of the activity in the reticular formation of the brain stem. Paillard (1955) demonstrated sinmltaneous 391 ]

392

CURT VON EULER and ULF SODERBERG

elhanges in E E G and tendon reflexes. Granit and his collaborators (cf. Granit 1955) have shown the possibility t h a t the activity of the g a m m a motor system m a y be used as an index of the activity in the facilitating and inhibiting systems of the brain stem. This indication was submitted to a test by the present investigation where E E G and g a m m a motor activity were correlated during ehanges in thermal balance and was a m p l y confirmed. METHODS AND PROCEDURES A d u l t male and female cats and rabbits were used. The rabbits were anesthetized with u r e t h a n e (1.5 g. per kg. body weight) or ehloralose-urethane (10 per cent u r e t h a n e in 1 per cent chloralose, 5 ml. per kg. body weight). The eats were anesthetized with Nembutal (Abbott), (40 rag. per kg. body weight). The anesthesia was in some cases complemented with small doses of Peutothal (Abbott), or urethane. Enc@hale isolg p r e p a r a t i o n s of eats were also used. A Horsley-Clarke stereotaxic i n s t r u m e n t was used for the experiments with cat. W h e n rabbits were used the head was attached to another t y p e of head-holder and the plane of tile tangents through the bregma was adjusted at a horizontal level. Stimulating and recording electrodes, the heating electrode unit and the thermocouple could be placed in a n y desired position within the brain. A eraniotomy was p e r f o r m e d to permit the insertion of various electrodes and the placing of silver ball electrodes for cortical stimulation and recording. These usually had an inter-electrode distance of a few millimeters. I n m a n y experiments the cortical and subeortieal electrodes were i m p l a n t e d with the aid of a metaerylate dental cement ( " S w e d o n " ) . The exposed cerebral cortex was covered with w a r m mineral oil. The impulse p a t t e r n generated by single muscle spindles was recorded f r o m fine filaments dissected f r o m the dorsal roots of L7 or S1 according to the description of Granit and K a a d a (1952). Muscle spindles f r o m the gastroenemius or soleus muscle were chosen. The hindleg was completely denervated except for these muscles. The f e m u r was immobilized and the Achilles tendon freed f r o m the calea-

neus and attached to a sensitive strain gauge myograph. Stimulating electrodes were attaehed to the gastroenemius nerve. The spindle a f f e r e n t was identified f r o m the pause obtained by stinmlating the muscle nerve (Matthews 1933) and f r o m the fact that its impulse frequency was influenced b y the p i n n a reflex (Granit, Job and K a a d a 1952). I n the experiments to be described the tension of the muscle was set low and kept constant as seen fronl the undefleeted mechanomyograms. No conclusion could lie d r a w n about the g a m m a motor activity f r o m such cases where the experimental procedure caused a n y contractions of the nmsele being studied. The changes in muscle spindle activity as recorded f r o m nuclear bag afferents was considered as variations in g a m m a motor discharge to the nmsele spindle (Eldred, Granit and Merton 1953). Recordi~g techniq~tc. Two identical channels of AC amplification with differential input were provided for recording eortieal and subcortieal activity as well as muscle spindle activity or the electromyogram. The low cutoff frequencies could be selected with 3 db points at {).2, 0.8, 8 and 80 c/see, and the high frequeneies at 40 ke., 10 kc., 250 e, and 50 e/see. The amplifiers operated two of the four available beams of the cathode r a y oseilloseope. I n the latest experiments a six channel ele~.troeneephalograph (Offner, type A) was used. An audio-unit operating a loudspeaker was coupled in parallel with the cathode r a y tubes. B y means of cut-off diodes impulses smaller than a predetermined amplitude were rejected. ()ne output of the unit was connected to an electronic ordinate writer (interval recorded) designed by Dr. B. Frankenhaeuser. The ins t r u m e n t drove a r a p i d m i r r o r galvanometer (period 2 msec.) the light spot of which wrote on moving photographic paper. The principle of the a p p a r a t u s is briefly as follows. Each impulse resets the light spot of the galvanometer to zero level. H a v i n g reached this level in a negligible time it r e t u r n s along a logarithmic or linear time course, the time constant of which can be selected. The shorter the interval between two impulses the sooner the reset to zero level and the shorter the deflection of the light spot. F i g u r e I gives a

HYPOTHALAMIC THERMODETECTORS AND RETICULAR FORMATION

c a l i b r a t i o n c u r v e for the time c o n s t a n t gene r a l l y used in the e x p e r i m e n t s to be reported. The e l e c t r o m y o g r a m was recorded with a n e n a m e l l e d steel needle electrode a g a i n s t g r o u n d . The m e c h a n o - m y o g r a m was r e c o r d e d by a s t r a i n gauge m y o g r a p h a n d a cathode ray oscillograph, The m a x i m u m s e n s i t i v i t y of this system was 1 g. p e r 1.2 ram, on the r e c o r d i n g paper. Impu(ses ~'sec lOO

8C

393

Changing the brain temperature. Local h e a t i n g of the b r a i n stem was i n d u c e d b y a hig'h f r e q u e n c y a l t e r n a t i n g c u r r e n t (1 megaeyele/sec.) of low voltage p a s s i n g between two pairs of e n a m e l l e d needles i n s u l a t e d to w i t h i n 2 ram. of t h e i r tips (el. M a g o u n (4 , l . 1938; Polkow, S t r 5 m a n d Uwfiis 194!); E u l e r 1950). The i n t e r - n e e d l e d i s t a n c e of each p a i r was 2 ram. a n d the d i s t a n c e between the pairs of eleclrodes was 4 ram. The needles were m o u n t e d t o g e t h e r a n d i n s e r t e d stereotaxieally. A t the bare t i p of one of the needh's a t h i n e n a m e l l e d e o n s t a n t a n wire, 0.1 ram. in diameter, was soldered to form one cud of a t h e r m o c o u p l e b y which the m a x i m a l lmnpcvat u r e i n d u c e d by the h e a t i n g c u r r e n l could be reeorded (see below). The two p a i r s of needles were s h u n t e d by a coil with a low ohmic resistance (55 ohms) m i n i m i z i n g the effect of a n y tissue r e c t i f i c a t i o n . The whole body of the cat or r a b b i t was in m a n y e x p e r i m e n t s w r a p p e d in a large t , u m b e r of t u r n s of r u b b e r t u b i n g , l l o t a n d coht w a t e r couhl be c i r c u l a t e d t h r o u g h the t u b i n g ,.ooling or h e a t i n # 1he skin. Sube<>rtical t e m p e r a t u r e was m e a s u r e d a n d reeorded by m e a n s of t h e r m o c o u p l e s a n d mirror g a l v a n o m e t e r s . The t h e r m o e u r r e n t was compensatessible to read t e m p e r a t u r e changes with an ac(,uracy of -+ 0.005 '~C.

Fig. 1 Calibration of the interval recorder with the time constant generally used in the experiments. The curve gives the full range of performance for this particular time constant. In several of the subsequent figures only a part of this range is used as seen from the ealit>rations in those figures. In the inset an interval reeord is given. The instrument operates in the following way. Eaeh input signal rapidly resets the light spot of the mirror galvanometer to zero level. Having reached this level it returns with logarithmic or linear time course, the time constant of which can be selected. The shorter the interval between two impulses the sooner the resetting of and the shorter the deflection of the light spot. Thus by joining the upper ends of the vertical lines produced on the photographie pnf~er one obtains a eurve inversely proportional to the impulse frequency.

In o r d e r to o b t a i n some q u a n t i t a t i v e e s t i m a t i o n of c u t a n e o u s blood flow the skin t e l n p e r a t u r e of d i f f e r e n t skin areas was recorded t h e r m o e l e e t r i e a l l y with mirr<>r galv a n o m e t e r s i n the w a y described for subcortical t e m p e r a t u r e . S k i n t e m p e r a t u r e a n d rectal t e m p e r a t u r e were s i m u l t a n e o u s l y f<>l: lowed on a t e m p e r a t u r e r e c o r d e r ( E l e k t r o : l a b o r a t o r i e t , C o p e n h a g e n ) . R e s p i r a t i o n was i n some e x p e r i m e n t s recorded with a s t r a i n gauge i n s t r u m e n t a n d a cathode r a y oscilh> g r a p h . In other e x p e r i m e n t s the r e s p i r a t o r y cycles were r e p e a t e d l y t i m e d with a stop watch. Blood p r e s s u r e in the femoral a r t e r y was m e a s u r e d b y m e a n s of a s t r a i n gauge man o m e t e r o p e r a t i n g a r e c o r d i n g m i r r o r galvan o m e t e r . ()xygen c o n s u m p t i o n was r e c o r d e d

;194

CURT VON EULER and ULF SODERBERG

w i t h a K r o g h spirometer w r i t i n g on a smoked

drum.

Histological procedure. E l e c t r o d e positions were d e t e r m i n e d a f t e r fixing the brain in l 0 per cent f o r m a l d e h y d e . A p p r o p r i a t e pieces of the brain were embedded in gelatine. ('ut in frozen se('tions at 100 ~ and m o u n t e d in gly(~erol-gelat inc. RESULTS The imlmlse p a t t e r n g e n e r a t e d f r o m a single mus('le sl)ind]e with inta('t e f f e r e n t innervation has been described to be irre~'ular " t h e spike interval w t r y i n g diseontinuously from st)ike to s p i k e " ( E l d r e d , Granit a n d Merton 1953). Besides the conventional w a y of re(,or(ting' the diseharg'e p a t t e r n the time interval p a t t e r n of the action potentials f r o m a single mus(de spindle was reeorde(i, usin?' an or(limit(, w r i t e r interval recorder and a

fashion. The height of the deflections is proportional to the length of the i n t e r v a l between two successive impulses (calibration in fig. 1. see Methods). Itenee, the s t r a t i f i c a t i o n of the interval records means t h a t the impulse pattorn is built up by a few " p r e f e r r e d " lengths of interval. These p r e f e r r e d intervals keep ('onstant for considerable periods of time provided conditions do not change. P r e f e r r e d intervals of the muscle spindle discharge pattern (:ararat be recognized if more t h a n ()lie spike is recorded at the time (('f. fig. 3). The presence of i)referred intervals is, as a m a t t e r of fa(:t, a good indication of the record being' obtained f r o m a single receptor. However, muscle spindles d e p r i v e d of their g a m m a motor i m w r v a t i o n have a lnu(,h lnore reg'ular disehar,/e p a t t e r n as described by Mattlwws (1!)33) (see also E l d r e d , Gral,it amt Mert(m 1.()53, and C r a n i t 1!)55 .

C.

Fig. 2

]~al)bit. Chlornlose-urethane. Record of intervals between eOllseeutive action potentials from "t single lnuscle spindle afferent. Record interrul)ted every 30 see. Thick rertieol lira': Twisting the pilma elicited nlarkedly increased lnuscle spindle activity (shorter deflections hlterv,ds). Note, stratification in the interval record indienting three preferred lengths of intervlll. (The thick horizontal curves are records of tempel':/ture of hypothahlmus (upper) and of enr skill (lower) mid are of no interest for understanding the figure.) condensed time scale. This p r o c e d u r e has revealed some new prop,,wties of the impv, l:e p a t t e r n . In figure 2 two horizontal strata m a y be recognized. The stratification is produced by deflections of d i f f e r e n t heights app e a r i n g again and again in a r a t n ( r i r r e g u l a r 1

•

Hypothalamic temperature and muscle spb~dle activity. A eat u n d e r N e m b u t a l anesthesia with a b o d y t e m p e r a t u r e well below the t h e r m a l thresholds for heat loss mechanisms generally exhibit high muscle spindle activity

HYP()THAI,AM/(~

THERMODETECTORS

as compared with a state of higher body temperature. Thus, an inhibitory effect on the muscle spindle activity was generally obtained by raising the body temperature. This effect, however, was also achieved by h)cal heating of the pre- and supraoptie region of the hypoth-damus l)e means of high fr:'.~tuency

AND

RETiCUI,AR

FORMATION

3!)5

h>w voltage alternating era'rent. This is illustrated in figure 3. In A the inlerval reeor(l shows almost complete inhibition of the muscle spindle discharge during the period ()t' heatlug (tt.T.). B g'ive:~ samples of a simullatwous reeord on sweeps of the c<)rresp<)ndin~z action p:>te:]t:a]s. The ;e came front tw<> muscle

Fig. 3 Cat. N e m b u t a l . S i m u l t a n e o u s records of muscle spindle activity of Lhe g a s t r o e n e m i u s musch,, A a n d B, a n d oeeipital E E G , C. T h e u p p e r p a r t of the figure, A, shows interval record t e n l i b r a t i o n to the r i g h t ) d u r i n g c h a n g e s of the hyl)othalamie t e m p e r a t u r e ( H . T . ) . Ear skin temi)er:lture across lower i)art of tile interv:d record. The action potentials c o r r e s p o n d i n g to the interval record were recorded on sweeps. Samt)les of these records, t a k e n b e f o r e d u r i n g a n d a f t e r the period of h e a t i n g , are s}laWll ill [~, S ' m u l t a n e o u s l y , occipital EE'(~ and lllOeh~/llO-lll)'O~.~lg/llt frclll the gI/S~l'Oetlelllill~ lll/1sele \ v e r e i ' , . e o r ( l e d . (!, the lower p a r t of thl~ f i g u r e , consists of an u n i n t e r r u p t e d p n r t of t h n t record ( m e e h n n o - m y o g r a m u p p e r nnd EGG lower t r n e i n g s ) . The m a r k i n g below the i n t e r v a l reeord in A i n d i c a t e s the period of time d u r i n g which tim records of (I were taken. Note the d i f f e r e n t time scales. Records in A i n t e r r u p t e d every 30 see. The f o u r m a r k i n g s (horizontal lines) in C indicate where the f o u r s a m p l e s of records of B are taken, rl'l|llS, the short s a m p l e s of E E G besides the sweeps ip- B will b:' reeognizsd ns those (;veriaying the m : l r k i n g s in C.

396

CURT VON EULER and ULF SODERBERG

spindles of whieh one, the bigger, is more readily inhibited than the smaller one. The sinmltaneously recorded E E G will be deseribed on page 399. The regions of the brain front which inhibition of the muscle spindle activity could be provoked by local heating corresponds to those from which heat loss mechanisms were activated by the same means (Magoun el al. 1!)38; Folkow et al. 194q) and from which slow " t e m p e r a t u r e p o t e n t i a l s " couht be recorded in response to temperature changes of the brain (Euler 1950). This is

spindle activity increased considerably, a fact which may p a r t l y be ascribed to afferent discharge caused by the stereotaxic instrmncnt and by operatiw, wounds which were usually not treated with local anesthetics. In such a state the inhibitory effect of hcating" the hyl)othalamic thermosensitivc struetm'<'s could be completely hidden in lhc heavy discharge. Sometimes the only inhibitory effect obtained was the ap|lcarallco of another " p r e f e r r e d " interval of greater duration as illustrated in fi,a'ure 4. The administralion of a small addi-

Fig. 4 Rabbit. Chloralose-urethane. Hypothalamie temperature, skin temperature of ear as an index of cutaneous blood flow and interval record from a muscle spindle afferent. Note the appearance of intervals of longer duration trot of two preferred lengths. also the area from which shivering could most efficiently be inhibited by local heating as described by H c m i n g w a y et al. (1940) and confirmed below. The inhibition of muscle spindle activity in response to heating the anterior hypothalamus was partial or complete, but this effect was greatly modified by the prevailing level of activity of the gamma motor neurones whatever its source (cf. below). W h e n the anesthesia became very light the muscle

tional dose of anesthetic, i.e. 5 rag. Ncmbutal or 0.25 g. urcthane per kta'. body weight rcduce(t the spindle activity. I'rovide(l it still was under some gamma influcnce, the inhibitory effect of local hypothalamic heating was readily obtained. F u r t h e r doses of anesthetics tended to abolish the spindle activity also at body temperatures below the point of thermal balance. At such a state of narcosis shivering, if earlier present, disappeared and cutaneous vasodilatation was evoked with

H Y P O T H A L A M I C THERMODETECTORS AND RETICUI,AR FORMATION

loss of heat aild as a c o n s e q u e n c e , decreased body temperature. The muscle spindle was, how~.ver, still able to respond to stretch. Noeleel)tire stimuli and twisting the p i n n a elicited a prolonged inerease of muscle spindle activity ((Iranit, ,lob and K a a d a 1952). Raising the hyl>othalamie t e m p e r a t u r e diminished the

397

was also studied in rabbits n n d e r chh)raloseurethane or urethane anesthesia. M(,(h,rate heating gave the same results as th(,se described from the (tats. In the rabbits, howew~r, a f t e r having obtained a re(lu(.tion (d! the frequency of the muscle sl~in(lle (tiseh~lrg'(, in response to moderately (qevate(l h.vlmthalamie

~.4"C

III

I

I

Vig. 5 Rnl)bit. Chloraloseurethane. The afferent activity of a. gastrocnemius muscle spindle during hypothal:mfic heating, qnd the corresponding meehanom y o g r a m . Ilypothalamic temperature given to the left above ench record. Nole the inhibition from moderate heating and the exeitation during lhe period of excessive heating.

duration of the responses to these stimuli. An initially high level of g a m m a activity was, however, usually not influenced by hypolhalamie beating, as stated above. The effect of increased b y p o t h a l a m i e t e m p e r a t n r e on the muscle spindle discharge

t e m p e r a t u r e , f u r t h e r heating generally induced an increased spindle activity, usually even higher t h a n initially. Figure 5 illustrates the inhibition of the muscle spindle activity by moderate hypothalamie heatino' as well as the increase of the spindle discharge in re-

40°C

Fig. 6 Rabbit. Chloralose-urcthane. Hypothalamic temperature and interval record from a gastrocnemius muscle spindle. The heating elicits only increased activity.

3118

(~URT VON EUI~ER :lml UI~F S()I)ERBERtl

sponse to a f u r t h e r rise of the h y p o t h a l a m i e temtmrature. In v'~ry l i g h t l y a n e s t h e t i z e d r a b b i t s with high o'amma m o t o r a c t i v i t y which could not be inhil)ited b y m o d e r a t e h y l ) o t h a l a m i c h(~atiug, excessive h(,atillg' (to 41-43'~(!.) e l i c i t e d f u r t i l e r i n c r e a s e of the Sld]l(tle (lis¢!har~z'e. This is shown in fio'ures 6 m.1 7. In lia'htly a n e s t h e t i z e d r a b b i t s uo~,iccptiv(, s l i m u l i as well as excessive h y p o t h a l a m i c h('atiug often s t a r t e d a p e r i o d of r,stlcssm~ss u s u a l l y r e s t r i c t e d to the cervical s(,ffm(qlls a n d a p p e a r e d a s w a l k i n g m o v e m e n t s in l l w for(dogs. This euablz~d us to c o r r e l a t e the ,,(mt/'m.liv(~ m . t i v i t y in the u p p e r seg'ments

ori~zin since no e o n t r a e t i o n in the muscle could 1,e d e t e c t e d . [ r n d e r the c o n d i t i o n iu w h i c h llltlsc]e s p i n d l e dischar~ze were recorded, i.¢'. w i t h l a m i n e c t o m y a n d e x t e n s i v e den(,rvation, shiveril~g o c c u r r e d o n l y o c c a s i o n a l l y . T h e r e f o r e no d i r e c t c o r r ( ' l a t i o n b(~twecn ('haug('s in nlllscle sl)indle a c t i v i t y a n d lh(~ a p l ) c a r a m ' e a n d d i s a p l ) e a r a u e e of s h i v e r i n g was ma(h'. t [ o w e v e r , 1)rovoeation a n d i n h i b i t i o . ()f shiverill~' was stu(tied in mor( ~ inbtct l ) r e l ) a r a t i o u s of eats a n d r a b b i t s u n d e r light a]wsttwsia. S h i v e r i u g ' eouhl a l w a y s b~, inhibil('d t)y heal-

O-2

2O

40 80 HI ImP/sec 100 50

-420C 40 °

-38 °

-36 o H.T.

mm/Hg Fig. 7 RMdfit. Chloralose-urethane. Intt,rv~d record of the :wtivity of , single muscle spindle. H.T. Hypotholamie temperature. E.T. Ear skin teml,cr, ture as an index of cutaneous blood flow. B.P. Blood pressure in tim femoral artery. Note i'egul'tr bursts each of ab:)tlt 15 so('. dur'~tion. Met'ham)myognml nt;t, shown hi figure was recorded simultaneously with hig|lcr fihn speed. No museul',r contraction was detected. w i t h the g a m m a m o t o r d i s c h a r g e in l u m b a r s e g m e n t s . I t is a well k n o w n f a c t t h a t the lower s e g m e n t s a r e m o r e s e n s i t i v e to a n e s t h e tics t h a n t h e c e r v i c a l ones (c[, P e t e r s ~ n 1952). F i g u r e 7 shows an i n t e r v a l r e c o r d of the disc h a r g e f r o m a single m u s c l e s p i n d l e . I ) u r i n g ' hypothalamie heating bursts of high muscle spindle aetivity appeared rhythmically with a d u r a t i o n of 10 to 20 nee. a n d were syuc h r o n o u s w i t h p e r i o d s of " w a l k i n g movem e r i t s " in t h e f o r e l i m b s . The b u r s t s in the muscle s p i n d l e a f f e r e n t were of g a m m a m o t o r

lug anterior hypothalamie, structures thus c o n f i r m i n g f i u ( l i n g s b y t l e n f i n g w a y ct al. (1940). This is i l l u s t r a t e d iu f i g u r e 8 b~,twe',,n the, a r r o w s " a " a n d " b " w h e r e also the i u f l u e n e e of skin r e c e p t o r s is (h,mons t r a t e d , cf. d i f f e r e n c e b e t w e e n 1 a u d 2. ()eeasionally, it wan o b s e r v e d t h a t the onset of h y p o t h a l a m i c h e a t i n g p r o w ) k e d or f a e i l i t a t ed shivering'. This t r a n s i e n t p a r a d o x i c a l e f f e c t was Ollly o b t a i n e d w h e n the h e a t i n g e l e c t r o d e s were p l a e e d so an to give i n h i b i t i o n of s h i v e r i n g w h e n the heating' was e o n t i m w d .

HYPOTHALAMIC

THERMODETECTORS

Hypolhalamic temperat~tre and electrical activity of the braim In most of the e x p e r i m e n t s a c h a n g e in t h e t e m p e r a t u r e of the a n t e r i o r h y p o t h a l a n m s p r o v o k e d some a l t e r a t i o n of tile electrical m . t i v i t y in both neocovtex a n d h i p p o e a m p u s . M o d e r a t e h e a t i n g t e n d e d to s y n c h r o n i z e the neocortieal a c t i v i t y , t l o w c v e r , it was f o u n d t h a t these effects, lik.:~ the effects of hYl)Ot h a l a m i e temperature on muscle s p i n d l e activ-

AND RETICULAR

3!t9

FORMATION

obtaim,d. The E E ( I p a t t e r n r e c o r d e d in deel)ly a n e s t h e t i z e d a n i m a l s was, however, not influenced from the hypothalamic them|osensitive SlFIl(ttllres. P i K n r e ,'{ is t ' h o s e l l a s ~L t y p i e a l t'xperimcnt in a ('at: u n d e r lig'ht Nemt m t a l a n e s t h e s i a . The sinHtlhmeous r e , o r d i n g of the oc.eipital E E ( I amt of lhe mils(de s p i n d h ' a(,tivity f r o m the h,fl g a s l r o c n e m i u s follow('d th(' usual r o u t i m , (se(' M e t h o d s i . I~]hwation of lhe temt)('ratm'e of the a n l e r i o r

M

EEG 2

7

b,

4

L

200

MY

Fig. 8 Rabbit. Eleetromyogram from left thigh muscles and EEG from left erueiate area. I:retlmne subcutaneously. The appearance of shivering by cooling the skin of the anim:d (2) nml the inhibition of shivering by hypothalamie heating between the arrows ~ nnd b. EE(~ changes gr'Mually from high voltage slow wave to low volt.tge fast activity but is ,minfluem'~,d by the hyl)othalamie he~lting.

it5- , were h i g h l y d e p e n d e n t u p o n t h e a n e s t h e t i c level. A t a v e r y s u p e r f i c i a l level of a n e s t h e s i a w i t h a n " a r o u s a l " p a t t e r n of E E G , w i d e open p u p i l s a n d h i g h muscle s p i n d l e a c t i v i t y , h e a t ing of t h e a n t e r i o r h y p o t h a l a m u s h a d l i t t l e or no e f f e c t on t h e E E G . B u t s m a l l supp l e m e n t a r y doses of N e m b u t a l or u r e t h a n e m a d e the c o r t e x m o r e sensitive to t h e t h e r m a l i n f l u e n c e of t h e a n t e r i o r h y p o t h a l a m u s j u s t as d e s c r i b e d f o r t h e m u s c l e s p i n d l e s , a n d rec o r d s such as t h a t in f i g u r e 3 C c o u l d be

h y p o t h a l a i m l s p r o v o k e d a n i n c r e a s e of the n u m b e r of s p i n d l e c o n f i g u r a t i o n s in t h e E E G . This in shown in C ( l o w e r p a r t of the fi~'ure), which was o b t a i n e d d u r i n g the p e r i o d m a r k e d at the b o t t o m of A. The i n t e r v a l r e c o r d of the nmsele s p i n d l e a c t i v i t y , g i v e n in A, p r o vides a good e x a m p l e of t h e r m a l l y i n ( h w e d inh i b i t i o n of t h e g a m m a m o t o r system. Tire c o r t i c a l a c t i v i t y c o u l d also be inf h t e n c e d b y h y p o t h a l a m i c h e a t i n g in e~c;phale isol( p r e p a r a t i o n s . T h i s is seen in f i g u r e 9,

400

CURT VON EULER and I'LF S()DERBERG

showing E E G tracings from 6 cortical areas. I n this case most skin and muscle afferents of the head were blocked by Xylocaine. During moderate heating there was a change from low voltage fast activity to a synchronized pattern with occasional spindle configurations. The ewmts illustrated in figure 9 were repeated several times with the same result. When the blocking effect of the applied Xylocaine weared off " p a n t i n g " mowmmnts around the upper respiratory tract and saliwttion became more and more evident during the periods of heating. In rabbits at appropriate anesthetic levels similar E E G effects were obtained as in the

in both leads. A f u r t h e r increase of the heating current to 60 mA, i.e. about 43°C, however, elicited a typical " a r o u s a l " reaction. The reverse sequence of eveuts were seen during the fall of the hypothalamic temperature when the heating had been discontinued. hi cases where the E E G initially was dominated by slow wave activity the late " a r o u s a l " reaction was the only effect of hyl)othalamie heating. Su(!h an examl)le is given in figure 11 from an animal in which the initial E E G pattern (top record) appeared to be somewhat abnormal. It resembles very much the " i n h i b i t i o n " seen by eh'etrical stimulation of " i n h i b i t o r y " I)oints iJ~ the

L.F L.P

L.O. R.F, R.P R.O 100uV

base Pine

-

~heatmg on ~03$mA~

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~ott

i

m

10 sec.

Fig. 9

Cat. Ence~,phale isold prepared under ether. Large amounts of Xyloc.line were injected into the skin and the muscles of the head and also into the trigeminal ganglia. EEG from frontal (F), pariet.d (P), occipital (O) areas from left (L) and right (R) hemispheres. He'tting current but not hypothalamic temperature recorded. Approximnte calibration: 0.35 mA _-- 39°(!, 0.40 mA _-- 42°C. Spindles appeared soon after the onset of 0.35 mA heating. (lra(hml in figure, indicated no muscle contractions.

cats. I n figure 10 the activity of the hippocampus and of the temporal cortex were recorded simultaneously. The hypothalamic temperature was not recorded but the heating c u r r e n t is graphically represented. Initially there was a regular sinusoidal hippocampal activity and desynehronized activity of the temporal cortex. A moderate increase of the hypothalamie stimulus provoked slow waves

brain stem (Moruzzi and Magoun 1.949, and [ngvar and SSderberg 1957). After the heating it gradually returned to the abnormal pattern (bottom record). In the rabbit the arousal pattern in the E E G produced by strong hypothalamic heating or by twisting the pinna was generally acemnpanied by polypnoea, dilation of the pupil, I>rotrusion of the eyeballs and restless-

HYPOTHALAMIC THERMODETECTORS AND RETICULAR FORMATION

Rect.temp.

Heatingcurrent

Ear temp.

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401

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.

.

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Fig. 10 Rabbit. Urethane. Xyloeaine locally. Samples of EEG from hippoeampus, H (the upper traeing in each pair) and left erueiate cortex, C. Rectal temperature, heating current and ear skin temperature. The effect of hypothalamie heating is an initial cutaneous vasodilatation simultaneously with the appearance of high voltage slow wave activity. During the period of heating with 55 mA current there is an arousal reaction and a small decrease in ear skin temperature. A f t e r discontinuing the heating the slow wave activity appears a g a i n but is replaced by desynehronization in neo-eortex and theta r h y t h m in tfippoeampus when the ear vessels reach their initial state of constriction.

4(12

CURT VON EULER and ULF SODERBERG

ness. Decreasing the h y p o t h a l a m i e temperature again evoked synchronization of the neoeortieal E E G , constriction of the pupil and cessation of the restlessness. At a f u r t h e r drop of t e m p e r a t u r e the animal entered into a labile state: " a c t i v e " E E G , dilated pupils and increased r e s p i r a t o r y rate alternating with a state of reduced " w a k e f u l n e s s " . Rapid alternation between wakefulness and drowsin('ss is i~ fact characteristic of the normal rabbit.

The r(lation between m,usde spbtdle actirity a , d lhc clcch'ical activity of the brain. The separate studies of the influence ()f hypothalamie heating on muscle spindle discharge aud on (.ortieal synchronization leads one to suppose that there would be some

eonsequenee the body t e m p e r a t u r e rose. I n the case of excessive heating, however, there seems to be a r i v a l r y between cutaneous vasodilation and vasoconstriction (cf. fig. 11). Chant~'es in thresholds of themnoregulator:- events will be dealt with elsewhere ( E u l e r and SSderberg 1!)57). (JorresI)ondingly, decreased muscle spindle discharge and eortieal synehronizario, g'enerally occurred simult~meously in response to raising the body temperature, local heating of the hyl)othalamn s or some skin reflexes from the u p p e r thoracic and neek region au(l were aeeompauied by dilatation of skin vessels of the ear and inhibition of sbiverinR'. ('onse(luently there was a drop in body temperature. Figure 12 is an other example of the close parallelislu between mus(qe spin(the' and eorResin

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Fig. 11

Ral)bit. Uretlmne. Saml)les of EE(; from the left temporal cortex. Col resl)onding temperatures (hyi)othalamie, H.T. ear skin, E.T.) and respiratory frequeneies are given. Note, gradual desynehronization during the heqting periad concomitantly with polypnoea. After cessation of heating gra,hml rehlrn to a pattern similar to the initial one. No cutaneous vasodilatation (el. p. 402). The pattern of the bottom reeord resembles those see]l from stimulation of 'qnhibitory '~ areas in the brMn. parallelism between these activities. Simultaneous r e c o r d i , g s of E E G and muscle spindle activity such as in figure 2 has demonstrated a ('orrelation of an even higher degree than was initially expected. Generally, an " a r o u s i n g " stinmlus such as twisting the pinna, lowering the, body t e m p e r a t u r e or electrical stimulation of midbrain teo'mentum desynehronized the cortical aetivity and increased the nmsele spindle aetivity simultaneously, These events were usually followed by eutaneous vasoeonstrietion in ears and pads and by provocation or faeilitation of shivering. I n

tieal activities. I n this figure, which was obtained f r o m a lightly a,esthetized rabbit, there were " s p o n t a n e o u s " fluctuations in muscle spindle discharge and cortical activity. This is a good illustration of the r a p i d ehantzes in the state of wakefulness charaeteristie for rabbits. The fita'ure also gives an interval reeord with eharaeteristie stratifieation due to the presence of p r e f e r r e d lengths of intervals, often found in diseharges f r o m muscle spindles u n d e r g a m m a eontrol (eft p. 394). Results such as that illustrated in figure 12 were, however, dependent upon a

HYPOTtlALAMIC THERMODETE(JTORS AND RETICULAR FORMATION s n e e e s s f u l b a l a n c i n g of th e a n e s t h e t i c level a n d p r o b a b l y also u p o n th e c o r t i c a l a r e a b e i n g s t u d i e d . To j u d g e by the E E G , c o r t i c a l act i v i t y was m o r e s e n s i t i v e to a n e s t h e t i c s t h a n was the g a m m a m o t o r s y s t e m a n d h i g h m u s , l e

403

was o c c a s i o n a l l y r e c o r d e d s i m u l t a n e o u s l y in r e s p o n s e to e l e c t r i c a l s t i m u l a t i o n of the midb r a i n t e g m e n t m n . Th e a p p e a r a n e ~ a n d disapp e a r a n c e of s h i v e r i n g nlay o ev u r w i t h o u t notieeable ehan,_,'es in the E L G . as sh o w n in

II

|

3

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line

'

Fig. 12 Rabbit. Chloralose-urethane. Activity from n single muscle spindle in left gastroenemius nmscle and EE(; from the left sensory motor cortex. Top record gives time intervals between consecutiw, action potentials; calibration to the right. The action potentials together with EEG recorded on a cathode ray tube. 1 to 4 samples of records as indicated In'low interval record. Different time scale in top and bottom records. Mechano-myogram~ not reproduce,1 in figure, indicated no muscle contractions. Note, high frequency muscle spindle discharge simultnneously with periods of desynehronized EEG. Muscle spindle silent when slow waves appear in EEG. Interval record shows charm'toristic stratification due to preferred lengths of interv:d. s p i n d l e a c t i v i t y was s o m e t i m e s p r e s e n t sinmltaneously with synchronized cortical activity. H o w e v e r , n e g a t i v e c o r r e l a t i o n s h a v e also been f o u n d , since c o r t i c a l d e s y n e h r o n i z a t i o n a n d d e c r e a s e in m u s c l e s p i n d l e d i s c h a r g e f r e q u e n c y

f i g u r e 8. Tiffs f i g u r e d e s c r i b e d on p. 3!)8 shows s i m u l t a n e o u s r e c o r d s of t h e E E G a n d t h e eleetromyogram, t I y p o t h a l a m i e heating which i n h i b i t e d s h i v e r i n g in a cold a n i m a l (lid n o t i n f l u e n c e the desyl~ehronized c o r t i c a l a c t i v i t y .

404

CURT VON EULER and ULF S()DERBERG

I n a f e w e x p e r i m e n t s th e d i s c h a r g e f r o m t wo a c t i v e nmscle s p i n d l e s was r e c o r d e d at t he same t i m e in the same f i l a m e n t . I t was obs e r v e d t h a t one s p i n d l e was easily i n f l u e n c e d b y h y p o t h a l a m i e h e a t i n g a n d t w i s t i n g the p i n n a b u t u l l i n f l u e n e e d by s p i n a l reflexes such as pinching' the skin of the e o n t r a l a t e r a l

ev(~r, be i n f l u e n c e d s u p r a s p i n a l levels.

both

from

spinal

and

DISCUSSION Th e e f f e c t s d e s c r i b e d as resl)(mses t() local h e a t i u g of the a n t e r i o r hyl)othalanluS have also been o b t a i n e d following' an im:rease in

A

B .

.

.

.

.

.

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.

.a

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C

Fig. 13 (~at. Nembutal. Sinus nerve and cervical sympathetic tmmc bilaterally cut. A :rod P,. Ele('tromyogrmn, hypothalamic temperature m~d rectal teml)eraturc. C. (?utaneous blood flow from the right forepaw. The time interval between blood drops from the c:lmml:lted right ~.ul)it:d vein are registered by an ordinate recorder writing on a smoked drmn. Arteri:ll t)lood l)r~,ssur(~ from the femoral artery recorded by a mercury manometer. C is recorded on :~ shm't(,r time so:de tlmn A nnd B. Time nmrks imme(li,qte@ below fI(>w record every :~1) st,(,. Iloriz(ml,I lines i~l C synchronize the two sets of curves. The figure shows that the threshold temperature for inhibition of shivering t>)" h.vt)oth:~l:mlic heating with high frequency alternating current (in A) is roughly the san,' as wlmn the' carotid blood is he-~ted with thermo
body teml)erature, l t o w e v e r , lhe t h e r m a l t h r e s h o l d f o r t h e t e m p t ' r a t u r e r(,~'ulatory reactions were usually low(,r wh(,n the t e m p e r a t u r e of the w h o l e 1)o(ly was c h a n g e d t h a n w h e n a n t e r i o r h y p o t h a l a m u s was heated locally. These t h r e s h o h t d i f f ( ' r e n e e s were

HYPOTIIALAMIC THERMODETECTORS AND RETICULAR FORMATION bigger for the rabbit than for the eat. Their most likely explanation is that the tissue between the four heating electrodes is not m[iformly heated as it is when the t e m p e r a t u r e of the whole hody is increased or when the ~'arotid blood is heated by thermodes. In figure 13 the two methods of raising the hypothalanfic t e m l w r a t u r e by high fre:luency (period A) and by thermodes (period B) are ~.ompared. Roughly the same threshold was obtaim,d with both methods with respect to inhibition of shivering (A and B) and cutaneous vasodilat:ation ((I). Since one of the four heating electrodes also constitutes the recording thermoeouple only the m a x i m u m t e m p e r a t u r e is recor(led. There is a considerable spatial t e m p e r a t u r e gradient out f r o m each electrode. The engaR'cment of cutaneous thermoeeptors is also v e r y different in the three situations, when the whole body is heated, when the caryatid bh)od is w a r m e d by thermodes or when the anterior hyl)othalanms is heated locally. This will he discussed in another publiealion ( E u l e r and SSderberg" 1957). ()utside the anterior bypothalamus, the region situated between the optic ehiasma and the anterior commissure, local heating" had none of the described effects. Mechanical slimulation of anterior h y p o t h a l a m n s by alterin R' the position of the heating electrode set. sometimes produced effects similar to those in(lueed by the heating. Effects f r o m mechanical stimulation have, however, also been obtained in other p a r t s of the brain stem. The rcR'ion of the brain f r o m which the described effect on muscle spindle and electrical activity of the brain has been induced in response to local heating has not been found to exceed the well-known area of thermoceptive stmwtures described by Magoun et al. (1938). I I e m i n g w a y et al. (1940), F o l k o w et al. (1949), E u l e r (1!)50) and StrSm (1950). The last mentioned author has also described ehanR'cs in cutaneous blood flow induced by mechanical stimulation of hypothalamic struttriPeS.

The influence of body t e m p e r a t u r e on the electrical activity of the brain has f r e q u e n t l y been dealt with, since H o a g l a n d (1936a, b) and Bennet, Cash and Hoekstra (1941) studied the , f l e e t of artificial fever on E E G in man.

405

Similar results were obtained by ten Cate, i t o r s t c n and K o o p m a n (1949) in rats, Gaenshirt, Krcnkcl and Zylka (1954) using perfused cat's heads under urethane, and by Koclla a~(1 Ballin (1.q54) on ~,ats umlcr Dial anesthesia. The results obtaim,d by these workers seem to cstahlish that raisillg tlw body teml),~rature to above 40°C imq'eases the amplitudes and decreases the t'rcqucn,dcs of the electrical activity of the cortex. A related ohserw~tion was also nlade by l)r. ()h. l'hillips (personal eomnmni{~ation) who observed in exper'imcnts on the ntotor cortex of lightly anesthetized cats that when additi(mal heating was applied to the animals to ehet,k a fallinta' rectal tcmperat tire, the cle(,t rival motto" I h rcshoht was ther'eby raised. Tlw eFt'eel was as striking' as that following em.h t'm,sh injection of am,sth.,ti~.. Although (.crcbra] ('re'rex. tik~' all m,rwms tissues, is sensitive l~ teml)m'aturc changes, mu' results clearly demonstralc that thermal stimulatiou applied lo,ally ~o llw anterior hylmthalamus may lWOVOke l)rofouml alterations in lhc clectri(.al a,,livily ,d' lhc cerebral ~,ortex. Wcrtheimer (lSg:/) ,am(', in fact, to a similar t,om.lusio., wlwn he t'ouml signs of incm,ascd brain ~.ir~mlaliou in (.ooh,1 animals. Excessive heating of the anlcrim' hylmthalanms provoked general arousal r ' a ' t i ns ineluding blocking reaction i,, EE(I. Th,sc effects have been seen in wt~'ious ,orli(.al ar,,as and may therefore be described as ,,,'~mc~-alizcd cortical events, most likely mediated through the reticular actiwtting system of 5h)ruzzi aml M a g m m (1949) upon which hypothalami~. thermocet>tiw+ structures may proje~:l like other receptors. Itowcvcr, attempts to exclu
406

CURT VON EULER and ULF SOI)ERBERG

seen a little earlier in the hippocampus than in the cortex. This is in good agreement with the work of Green and Arduini. Dr. J. D. Green (personal communication), studying rabbits with chronically implanted electrodes in the hippoeampus, found that theta r h y t h m was provoked by overheating the whole animal. In cohl enviromnent when the ear vess(,ls were constricted, theta rhythms were also obtained. The p a t h w a y by which these E E G chang'cs are transmitted have not been studied in the present papcr. The work of C,ranit and K a a d a (1952), fset correlation between muscle spindle activity and those nmscular events involved in thermoregulation is, however, not available. in this connection it m a y also be of interest to mention that, aeeording to Birzis and Hemingway (1956), the spinal pathways mediating shivering r u n in the lateral white colunms in the vicinity of the rubro- and retieuh)spinal tracts, where a direct p a t h w a y front the brain slem to the gamma motoneurones also has

been found (Granit and Hohngren 1955). The fibres concerned in shivering were, however, both crossed and uncrossed whereas the direct gamma p a t h w a y seemed to consist of crossed fibres only. It has also been found recently, that nmsele circulation can be influenced by hypothalamie heating (Siiderber~' 1956). I n this ease also the " e x t e r n a l l o o p " seems to be of importance sinee the effects were only fmmd when the muscle was umh,r some st retc h. The inerease in muscle spindle activity in response to excessive heating" of the structures of the anterior hypothalamus in the rabbit, ean h a r d l y be considered a sig'u of physical thermoreg:ulation. This stimulus provoked a general " a r o u s a l " of the animal w i t h " a c t i v a t i o n " of the E E G pattern, polypnoea and restlessness, which all nlay be regar(led as equivahmts to tim signs o1! diseomfort seen in overheated animals, Oranit and K a a d a (1952) and ( I r a . i t and Hohngren (1955) have demonstrated the close ert the view that hypothalamic therm<>deteet<>rs project to the reticular activatintz system. This conelnsion is streng'thened eonsin which has been found between the E E ( ] and muscle sI>inse parallelism between gamma motor and cortical events under the i)revailing conditions with the i11fluene,e of spinal reflexes minimized and constant. This invites two possible explanations :

HYPOTHALAMIC

(i)

THERMODETECTORS

both activities are coordinated by the same structures;

AND

RETICULAR

FORMATION

407

SUMMARY

The influence of hypothalanfic and body t e m p e r a t u r e on the E E G and the -'aroma (ii) o~e o]' the two systems drives the other motor system was studied in cats and rabbits. O~tC. 3_'he index of g a m m a motor activity was obE EG changes have been induced by hypo- tained by recording nmsele spindle
408

CURT VON E U L E R and U L F SODERBERG

ELDRED, E., GRANI% R. and MERTON, P. A. Supraspinal control of the muscle spindles and its significance. J. Physiol., 1953, 122: 498-523. YON EULER, C. Slow " t e m p e r a t u r e p o t e n t i a l s " in the hypothalamus. J. cell. comp. Physiol., 1950, 36: 333-350. ,,'ON EULER, C. and SODERBERG, V. To be published, 1957. ]~OLKOW, B., STRiJ]~, G. and UvNXs, B. Cutaneous vasodilatation elicited by local heating of the anterior hypothalamus in cats and dogs. Acta physiol, seand., 1949, 17: 317-326. (~AENSHIRT, U.~ KRENKEL, W. and ZYLKA, W. The electrocorticogr~tm of the c a t ' s brain at temperatures between 4O°C and 20°C. EEG Clin. Neurophysiol., 1954, 6: 409-413. GRANIT, ]~. Receptors and Sensory Perception. Yale Univ. Press, New Haven, 1955. (~RANIT, R. and HOLMGREN, B. Two pathways from brain stem to gamma ventral horn cells. Acta physiol, seand., 1955, 35: 93-108. {~RANIT, R., Jol~, C. and KAADA, B. R. Activation of muscle spindles in pinna reflex. Acta physiol. seand., 1952, 27: 161-168. t~RANIT, R. and KAADA, B. R. Influence of stimulation of central nervous structures on muscle spindles in cat. Acta physiol, scand., 1952, 27: 130-160. I]REEN, J. D. and ARDUINI, A. A. Hippocampal electrical ,~ctivity in arousal. J. Ncnrophysiol., 1954, 17: 533-557. HEMING~,VAY, A., I~ASMUSSEN, T., WIKOFF, ~ . and RASMUSSEN, A. T. E f f e c t of heating hypothalamus of dogs by diathermy. J. Neurophysiol., 1940, 3 : 329-338. HOAGLAND, H. Temperature characteristics of " B e r ger r h y t h m " in man. Science, 1936, 83: 84-85. HOAGLAND, B. Pace makers of hunmn brain waves in normals and in general paretics. Amer. J. Physiol., 1936, 116: 604-615. INGVAR, D. H. and SODERBERG, U. Two principally different effects of brain stenl stimulation upon the EEG and cerebral blood flow. To be publishcd, 1957. ,lUNG, R., DOUPE, J. and CARMICIIAEL, E. A. Shivering: A clinical study of the influence of sensation. Brain, 1937, 60: 28-38.

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