The tonic control of cortical responsiveness by inhibitory and facilitatory diffuse influences

ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYS1OLOGY

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THE T O N I C C O N T R O L OF C O R T I C A L RESPONSIVENESS BY I N H I B I T O R Y A N D F A C I L I T A T O R Y DIFFUSE INFLUENCES M. DEMETRESCU, MARIA DEMETRESCU AND G. IOS1F Institute of Endocrinology of the Rumanian People's Republic Academy, Bucharest (Rumania) (Accepted for publication : May 22, 1964)

The highest efficacy of cerebral function is undoubtedly reached during excited wakefulness. To know about the conditions supporting development of this state, attention was, and is still, directed to the arousal phenomenon. This is the first step; the second appears to belong to the tonic maintenance of the aroused state. Although general arousal concerns the whole brain, the function of its philogenetically younger segments, i.e. the neothalamo-cortical complexes, seems to be more enhanced. An excitability increase in them, by arousal, has been inferred (Magoun 1959) on the basis of the dramatic facilitation of thalamo-cortical evoked potentials during reticular stimulation (Bremer and Stoupel 1959; Dumont and Dell 1960). On the other hand, the question was raised whether an uncontrolled increase of excitability, coming to critical self-sustained activity, might be elicited, since the cortex was also able to activate the reticular formation (Bremer 1960). However, it has been established that actual, efficacious arousal is essentially dependent on the reticular formation (RF), as shown by pioneer works of Moruzzi and Magoun (1949), Lindsley et al. 0949, 1950) and French et al. (1952, 1953). The logical necessity of some braking, diffusely acting, inhibitory influences was then raised (see Jung 1961). Their actual existence was inferred on the basis of the inhibition of thalamo-cortical evoked potentials during high rate stimulation of either the caudate nucleus or the pontine ventral RF (Demetrescu and Demetrescu 1962a and b). In this respect the results of Courville et al. (1962), showing alteration of centrally evoked potentials following chemical stimulation or impairment of the lower brain-stem RF, support the same conclusion.

But what is the excitability of a thalamocortical complex deprived of diffuse ascending influences? What is the pattern of diffuse influences able to alter it in order to realize the high efficacy characterizing arousal? And what are the tonic mechanisms patterning these influences, able to maintain wakefulness, but also able to brake critical over-activity? These very current questions have led to the present investigation, which is an attempt to give some answers to them. A comprehensive survey of the alterations occurring within a neothalamocortical complex might, however, not be obtained by the known micro-electrode methods (see Eccles 1961), although they give reliable information on the events occurring at the cortical cellular level. Indeed, both excitation (or activation) and inhibition were elicited by either subcortical (RF, caudate and unspecific thalamic nuclei) or cortical direct stimulation; they were firmly supported by alterations of the rate of firing, as well as by true depolarizing or hyperpolarizing excitatory and inhibitory post-synaptic potentials (Whitlock et al. 1953; Jung et al. 1958; Phillips 1961; Spehlmann et al. 1960; Lehman et al. 1962; Li and Chou 1962). But it has not been possible as yet to ascertain what, as a general picture of relative activation and inhibition, underlies the cortical arousal (or sleep), which however must imply rigid patterning of these processes. Thus, a known macroelectrode method, such as that of the centrally elicited evoked potentials, seemed more suitable, although from this point of view the unitary neothalamo-cortical complex (philogenetically and functionally - see von Bonin 1949) may be envisaged only as a black box. One cannot directly record the intimate phenomena occurring therein, Electroeneeph. olin. Neurophysiol., 1965, 18:1-24

M. DEMETRESCU el al.

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but its o u t p u t is k n o w n as the e v o k e d response r e c o r d e d over the p r i m a r y cortical receiving a r e a ; its i n p u t being also k n o w n as pulses a p p l i e d to the t h a l a m i c relay nucleus, the responsiveness o f the whole c o m p l e x m a y be defined as the i n p u t - o u t p u t relation, a v o i d i n g the t e r m "excitability", whose precise e x p e r i m e n t a l definition m a y present serious difficulties. The responsiveness o f this black b o x a p p e a r s to be c o n d i t i o n e d by influences ascending from the subcortex. To alter t h e m it has thus been preferable to interfere at different levels with the neural circuits in which they arise, rather t h a n to direct attention to certain b r a i n - s t e m areas (as in the old concept o f centres for certain functions). I n this way, b y

excluding b o t h k n o w n i n h i b i t o r y mechanisms, i.e., the c a u d a t e a n d the pontine reticular, and the R F facilitatory influences, we have f o u n d a d r a m a t i c increase in responsiveness. Showing t h a t suppression o f tonic inhibition is m o r e powerful to increase cortical responsiveness than the lack o f only facilitatory influences to decrease it, these findings supply the e x p e r i m e n t a l elements able to s u p p o r t a discussion on the qualitative picture o f ascending influences m a i n t a i n i n g tonically the high functional efficacy o f arousal. TECHNIQUE This w o r k was d o n e on 51 a d u l t cats, p r e p a r ed under ether anaesthesia, a c c o r d i n g to con-

A

Fig. 1 Samples illustrating the types of lesions. Silver impregnation (rapid method) of 60-90 t~ sections, showing the electrolytic iron deposits left by the lesion procedure. A 1 : the commonly used caudate lesion, not involving surrounding structures. A2: a larger caudate lesion, extending into capsula interna; the results were the same as in A 1 (Results lla, Ilc and Ild). B: sagittal section near the midline to show the electrolytic rostro-pontine lesion. C1, C2: medial and more lateral sagittal sections of the lower brain-stem, showing the lesion of the caudal central gray which was effective in suppressing tonic facilitation of evoked potentials. The same results were induced by a central gray midbrain lesion (C3, C4), leaving the RF proper unaffected in its largest part. D: large bilateral lesion of the rostral thalamus, which did not impair the strong increase in responsiveness induced by caudate and RF lesions (Results Ilc and Ild).

Electroenceph. clin. Neurophysiol., 1965, 18:1-24

TONIC CONTROL OF CORTICAL RESPONSIVENESS

ventional methods, either encdphale isold with spinal cord cut at C1 (35 cats), or under Flaxedil (gallamine triiodoethylate) (16 cats). In both cases the tissues to be incised were infiltrated with procaine. As investigation of the problem of natural tonic arousal required disuse of general anaesthesia, recording began at least 1 h after stopping the ether; since no other way was possible only local anaesthesia was kept to protect the animals unable to show distress. That it was an efficacious procedure became evident from the fact that the cats often slept (spindles and slow ECoG waves), as previously observed by Hodes (1962, 1963), and that RF stimulation could still elicit activation ; as known from chronic animals, stimulating the RF does not induce pain or sham-rage. The experiments reported under the first heading of Results were done only in encdphale isold preparations (arterial pressure corrected with intraperitoneal ephedrine). The experiments reported under the other headings (II-IV) were done on both encdphale isol8 and gallamine-immobilized preparations. Since no obvious differences between them were obtained, no special mention will be made of this problem. The brain-stem lesions (or transections) were done either electrolytically (5 mA, 30 sec) at points 1.5 mm from each other, or, sometimes, by a cut with a smooth spatula (only rostropontine and midpontine levels, after cerebellar ablation). All animals which were not in satisfactory condition during the experiments or had poor anatomical locations, were discarded. Evoked potentials were elicited by rectangular pulses (0.1-0.3 msec - high frequency isolation unit) delivered every 1.5-2 sec to the lateral geniculate body (LGB) through a coaxial deep electrode buried stereotaxically according to the conventional technique and coordinates (Jasper and Ajmone Marsan 1954 and 1961 ; also the 30 ° coordinates used p r e v i o u s l y - Demetrescu and Demetrescu 1962b) ; the pulse intensity was taken with 20-50% above the threshold at which a small potential, but having all its known phases, might be initially elicited. If not specified expressly, all the results reported below refer to this stimulating intensity, both for single and paired stimuli. In the same manner some other structures (midbrain RF proper, central gray,

3

posterior hypothalamus, subthalamus, interpeduncular nucleus, caudate nucleus) were stimulated through a coaxial electrode successively buried in them, using high rate (100/sec) rectangular pulses (0.5-1 msec). Recording of evoked responses in the primary receiving area (visual- g. marginalis) was done photographically (single or superimposed sweeps) using the preamplifiers of an Alvar X electroencephalograph, connected through cathode follower stages to a 2-channel oscilloscope. The electrocorticogram (ECoG) was recorded simultaneously. In order not to influence the visual evoked potential, all the experiments were performed with the animal in darkness. The anatomical control following the experiments was made in formalin-fixed brains, by means of both cell stain (Olszewsky) and rapid silver impregnation of thick (60-90 #) sections (see Fig. 1). RESULTS

The visual system has been elected for investigation as being the most systematic sample of a neothalamo-cortical complex. It must be stressed that the most common condition for an intact brain was a large variability of evoked responses; this appears in the main control records.

I. Brain-stem neural circuits involved in the maintenance of tonic arousal. The ventral gray driving mechanism Working hypothesis. It is difficult to survey wakefulness in an acute preparation; however, the arousing effect of a stimulus, protracted after its stopping, may represent the ability of the preparation to maintain its arousal. Previously, it was tentatively advanced that the posterior hypothalamus and the central gray, acting through a descending circuit, constitute a driving mechanism for the RF proper arousing mechanism (Demetrescu and Demetrescu 1962b). Thus, the interruption of only the descending circuit would impair something in the tonic arousal and in the ability of more rostral structures to elicit it. High rate stimulation (100/sec; 0.5-1 msec) of the posterior hypothalamic area (Jasper and Electroencepk. din. Neuropkysiol., 1965, 18:1-24

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M. DEMETRESCUet al.

Ajmone Marsan 1961) induced strong facilitation of the evoked responses (Fig. 2, 3); the stimulus strength was slightly above the threshold for this effect. As in other sites of stimulation, i.e., midbrain and dorsal pontine RF, as

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Fig. 2 Evoked potentials elicited by single LGB pulses (0.2 msec) and recorded over the primary visual area, homolaterally (upper channel) and contralaterally (lower channel), in an encOphale isol# preparation. The successive records in line were made at 5 sec from one another. The control response in the upper line is compared with that after a lesion involving the caudal central gray and partly the dorsal nucleus of Gudden, made at the base of the inferior colliculus. The same electrode has been used to give high rate stimulation (100/sec; 0.5 msec; 10 V) in the posterior hypothalamus, rostral central gray, mesencephalic RF and interpeduncular nucleus (N.I.P.). In this and the following figures the records are monopolar, negativity upwards.

well as periaqueductal central gray or unspecific thalamic system (Bremer and Stoupel 1959; Dumont and Dell 1960; Demetrescu and Demetrescu 1962b), this striking facilitation was followed by a facilitatory after-effect, lasting several seconds and occasionally several tens of seconds. An electrolytic lesion placed in the caudal midbrain central gray, about in the Fr + 2 to + 3 plane (Horsley-Clarke), not or only slightly involving the surrounding RF, abolished both the enduring facilitation and its after-effect on the same stimulation of the posterior hypothalamus, given without removal of the stimulating electrode (Fig. 3). Also, stimulation (at the same strength) of the rostral, unlesioned part of the central gray (Fr --4 to + 6) did not elicit enduring and strong facilitation. In both cases, however, a transitory facilitation sometimes appeared throughout the first 1-2 sec of stimulation; it disappeared systematically even during that stimulation. To check the possibility of general impairment of the animal's condition after the lesion, we gave the same high rate pulses through the same electrode, into the midbrain RF proper. As illustrated in Fig. 2 and 3, strong facilitation of the evoked potentials occurred again, in all points comparable with that initially obtained, except that its after-effect could not be elicited by any stimulation. The same results were obtained when the lesion of the central gray was more caudal (Fig. 2). An electrode inclined at 30 ° was used to impale the central gray just at the base of the posterior colliculus, by a retrotentorial route through the cerebellum ; in this case the lesion was more lateral (up to 3 mm on both sides) and partly involved also the n. laterodorsalis tegmenti (Gudden). Only lesions involving the whole central gray in the given plane gave systematic results. As confirmation, in experiments with inconstant results, we made a deeper midbrain lesion; the anatomical control has shown that only the central gray was mainly damaged, and thus that the ineffective lesion was also incomplete. Because the main tonically acting connection between the central gray and the RF had been supposed to be immediately posterior to the inferior colliculus, under the floor of the fourth Electroenceph. clin. Neurophysiol., 1965, 18:1-24

TONIC CONTROLOF CORTICALRESPONSIVENESS

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Superimposition of 5 evoked potentials (LGB rhythmic stimulation 0.5/sec) recorded over the homolateral (upper channel) and contralateral (lower channel) primary visual areas in an encdphale isold cat with a large lesion of the rostral thalamus in the + 12 frontal plane (Horsley-Clarke). The second record of each series was made during high rate stimulation (100/sec; 1 msec) of: the posterior hypothalamus Stim.H.P.), the rostral central gray (Stim. S.G.C.), the midbrain RF proper (Stim. F.R.), the caudate (Stim. N.C.) and lhe zona incerta (Stim. Z.I.). The third and fourth records are successive controls following the stimulation, containing a contingent after-effect. Between A and B a complete lesion of the central gray in the Fr +2 Horsley-Clarke plane was made, sparing the RF proper.

ventricle (Demetrescu and Demetrescu 1962b), in an area involving the dorsal nucleus of Gudden, we stimulated the interpeduncular nucleus, which is connected with this area (Nauta 1958). As illustrated in Fig. 2, a facilitation comparable with the RF induced one was obtained, also without after-effect. A large lesion of the rostral thalamic pole, made in the Fr + 12 Horsley-Clarke plane, did not alter the results so far reported (Fig. 3). Moreover, caudate high rate stimulation inhibited the evoked responses, in this condition, in the way previously reported in other conditions. As to the ECoG during these experiments, a spindle pattern constantly occurred after the central gray lesion. It in great part resembled the already known picture of the eerveau isold preparation, although less regular. Because the problem of spindle occurrence is raised also by

the midpontine preparation (see point IV) it has been illustrated only in Fig. 11. II. The problem of tonic ascending inhibition Working hypothesis. As previously pointed out (Demetrescu and Demetreszu 1962b), it is conceivable that, at any moment, cortical responsiveness is controlled by a complex of ascending influences, inhibitory and facilitatory. If the inhibitory ones had a tonic, enduring component depending on some subcortical circuits it would disappear after lesions interrupting these circuits. Thus, the attempt was first made to impair those structures which produced, on stimulation, inhibition of cortical responsiveness, i.e. the caudate nucleus and the ascending links of the pontine RF.

a. The effect of caudate lesions on visual thalamo-cortical responsiveness. A large homolateral increase of the thalamo-cortical evoked

Electroenceph. clin. Neurophysiol., 1965, 18:1-24

M. DEMETRESCU et al.

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wit.h Fig. 4 Superimposition of 5 evoked potentials (LGB stimulation every 2 sec) recorded from 2 points of the homolateral visual area. Each column contains responses elicited, in different conditions, by the same stimulus intensity, expressed in multiples of the initial threshold (10 V; 0.1 msec). The control (A) was done in an enc~phale isol~ preparation; the following records were made (B) 1 h after a large homolateral caudate lesion (made electrolytically in the + 16 frontal plane), (C) 1 h 30 min after an additional complete lesion of the midbrain RF (in the + 2 frontal plane) and (D) 1 h after a further homolateral lesion of the thalamic rostral pole (in the + 12 frontal plane).

potentials and abolition of their natural variability occurred 20-30 min after a large lesion in the posterior part of the head of the caudate nucleus (Fig. 4); apparently this delay was necessary for recovery from the general impairment induced by the important lesion current flow (5 mA, 30 sec, given in about 12 points). No obvious differences were found regarding the effects of different lesions made between the frontal planes + 14 to q-16.5. A larger lesion involving also the capsula interna did not alter the results. On the other hand, the anatomical control made in more rostral planes, not directly reached by the lesion, showed numerous haemorrhagic points in the caudate, suggesting that its impairment was more general than only its transection. This very high responsiveness was accompanied by lowering of the LGB threshold, but, to obtain comparable results, the same intensity of stimulation was maintained. However, a comparison between the responses evoked by increasing LGB stimulating intensities (up to 5 times) is illustrated in Fig. 4, to show the different thresholds of two points in the visual area and their equalization after a caudate lesion. It also shows an interesting phenomenon:

high stimulating intensities induced again variability and inhibition in the preparation with a lesion. Therefore, the suprathreshold stimulus might be made responsible for this inhibition, which however disappeared after a further RF lesion. When sufficient time elapsed (2-6 h) after the caudate lesion, variable from one animal to another, some recovery of variability was observed, although the responses had amplitudes towards the upper limit (see the first response of the pair at 50 msec delay in Fig. 5 - about 2 h after caudate lesion). b. The effect o f R F transection on visual thalamocortical responsiveness. RF transection, at levels ranging from the rostro-pontine to the rostral midbrain, has given a strong increase of the evoked responses (see for instance the first evoked potential of the pair in Fig. 7). The transection, giving essentially a cerveau isol~ preparation, was made either in one of the frontal planes + 2 to ÷ 4 (Horsley-Clarke) for the midbrain, or in one of the + 4 to + 6 planes at 30 ° for the rostro-pontine. The increase in amplitude, resembling in all ways that following the caudate lesion, appeared either after a delay Eleetroeneeph. clin. Neurophysiol., 1965, 18:1-24

TONIC CONTROL OF CORTICAL RESPONSIVENESS

of 20-40 min from the electrolytic lesion, or after a shorter one from the spatula brain-stem transection. As after a caudate lesion, strong suprathreshold LGB stimulation induced variability and inhibition of responses; after a highly variable delay (from one animal to another), ranging from 2 to 4 and even 6 h, variability recovered (see Fig. 6). Although not excluding the participation of other inhibitory mechanisms, these facts led us to the idea that recovery of variability was due to some compensatory hyperfunction of the caudate inhibitory mechanism (see Fig. 3 and Demetrescu and Demetrescu 1962a). c. The effeet of combined reticular and caudate lesions. The additional caudate lesion in a eerveau isold preparation, or the additional RF transection with a caudate lesion, was followed, in due course (see above), by a further increase of the evoked potentials. Even the phenomenon of inhibition by large suprathreshold LGB stimulation was abolished (Fig. 4). Besides the correct location of the lesions, the only requirement to obtain maximal responsiveness was a good metabolic condition of the animal. Sometimes an intravenous infusion of 5% glucose (with small amounts of insulin) or correction by ephedrine of a too low arterial pressure was necessary; as is known, these procedures do not induce maximal responsiveness in an intact brain. The order in which the reticular and caudate lesions were made appeared to be unimportant (compare Fig. 4 and 5 with 6 and 7, first response of the pair). Although obvious at a relatively short delay after making both lesions (30 min), the increase of amplitude progressed as time elapsed, so that at 2-4 h the picture of a strong release from inhibition was impressive. In general, for a given animal, the amplitude reached by the evoked response was the largest which could be systematically obtained in any condition, for a given LGB stimulating intensity, initially near the threshold. No recovery of variability or spontaneous inhibition of thalamo-cortical evoked potentials was observed up to the end of these experiments, 4-6 h after the RF and caudate lesions. On the other hand, no difference in evoked potential control was found if the caudate lesion was made bilaterally. However, a new fact

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appeared: many animals, about 2 h after both bilateral caudate and RF lesions, displayed spontaneously (or induced at very low threshold) cortical seizures of long duration or even subintrant (60-90 min, up to the degradation of the preparation). Although the subject of a separate report, we consider that special mention must be made here of this striking fact, it also having the significance of release from inhibition. We shall thus take the liberty of using henceforth the term disinhibitedpreparation for that with RF and caudate lesions. To test if a known system of facilitation, i.e., the diffuse thalamic system (Jasper et al. 1955; Sharpless and Jasper 1956; Bremer and Stoupel 1959; Demetrescu and Demetrescu 1962a) was responsible for this very large responsiveness and even self-sustained ictal activity, we made an additional large lesion in the thalamic rostral pole (frontal plane +11 to +12, HorsleyClarke); as previously claimed, the main diffuse thalamic projections travel upwards through the rostral thalamic pole (Chow et al. 1959; Jasper 1960). However, impairment of the evoked responses did not occur; on the contrary, a slight further enhancement was recorded (Fig. 4, 5). Similar results were obtained for a more caudal lesion of the medial thalamus (Fr ~ 8 to ÷ 10), sparing principally the LGB. Although not taken here as a criterion of cortical responsiveness, the ECoG was also recorded in parallel with the evoked potentials. As already known, the transected RF preparation displayed the typical, regular spindle picture of the cerveau isol& When the caudate lesion was added, only the regularity of the ECoG spindles was impaired. A further rostro-thalamic lesion led to a degraded ECoG picture. d. The exploration o f thalamo-cortical responsiveness with paired evoked potentials. The very high thalamo-cortical responsiveness reached by the preparations with caudate and RF lesions resembled strongly that occurring during arousal induced by RF stimulation in an intact brain. Testing with single evoked responses did not show any significant differences between these two obviously different conditions. It could even be asked if arousal is achieved by disinhibition. Thus, further investigation of thalamo-cortical responsiveness was necessary. After some atElectroenceph. clin. Neurophysiol., 1965, 18:1-24

M. DEMETRESCU e t al.

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tempts by other methods, paired LGB stimuli were used to make another criterion of responsiveness, in which time appeared as a supplemenControl (no Lesion)

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Fig. 5 Superimposed groups (5 sweeps) o f paired evoked potentials (LGB threshold stimuli, every 2 sec) recorded from 2 points o f the homolateral primary visual area. The control in the intact cat, under Flaxedil; the following records were made 2 h after a caudate homolateral lesion (Fr i 15 plane), 1 h after an additional complete lesion o f the midbrain R F (Fr -~ 2 plane) and 1 h after a further lesion o f the thalamic rostral pole (Fr + 12 plane).

tary parameter. We underline again here that only intensities near the threshold (20-50% above it), initially established in the intact brain, were used throughout the whole of the experiments. A highly typical pattern was recorded in the animal after both caudate and RF lesions; a large second response followed the first 1, also large, for intervals between pulses below 20 msec, as illustrated in Fig. 5-8 and graphed in Fig. 9. i We prefer not to use the terms "conditioning" and " t e s t " stimuli, because we consider that both are test stimuli for our purpose. We shall name them only first and second stimuli or responses.

At a delay of about 10 (7-12) msec the second response was systematically higher ("supramaximal") than the first; the comparison is of their positive phases, which can both be fully developed after such a short delay. Going towards 20 msec, the second response became less large but was obviously present. At a threshold delay of about 20 msec the second response was variable from one preparation to another, but always present (compare Fig. 5 with 6, 7 and 8). Any response elicited outside the early 20 msec period was very small or even incomplete (regarding its phases) compared with that elicited inside this period. This pattern of responsiveness was not significantly altered by a further rostro-thalamic lesion (Fig. 5), like that found for single evoked potentials. It was highly stable and reproducible from one experiment to another, in the conditions reported above (IIc). The upper limit of the period of inhibition of the second response reached values over 150-200 msec, but has not been systematically explored. As will be shown and discussed, we think that the most characteristic delay for this period is about 50 msec; therefore, no illustration is given for greater delays. Control (lOhours after midbroin R,E lesion)

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The response pattern of the disinhibited preparation being of a reliable constancy, we shall compare it at once with that, also constant, of arousal in the intact brain, to solve the principal problem raised in this chapter of experiElectroenceph. olin. Neurophysiol., 1965, 1 8 : 1 - 2 4

TONIC CONTROL OF CORTICAL RESPONSIVENESS

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Superimposed evoked potentials (5 sweeps - LGB threshold paired stimuli) recorded over the primary visual area. The control recorded in a Flaxedil-maintained cat, without (Control) and with (R.F. Stim.) simultaneous stimulation (100/sec; 0.5 msec) of the midbrain RF. 2 h after a rostropontine transection (post-collicular) and 1 h after an additional caudate lesion (Fr -- 15 plane), the same stimuli have been given, without removing the LGB and RF stimulating electrodes. The striking release of the 10 mec delayed second response, even during RF stimulation after both lesions, is to be remarked. ments. It must first be said that although spontaneous arousal might occur in these unanaesthetized preparations (encdphale isold or only under Flaxedil), it was somewhat difficult to ascertain whether the responsiveness was tested on a true b a c k g r o u n d o f strong arousal. We considered it preferable to record the paired responses during efficacious midbrain R F stimulation (100/sec; 0.5 msec), which simultaneously induced facilitation o f the fi_rst evoked potential, mydriasis and E C o G flattening. Thus, the certitude of strong

arousal was reached on the basis of the whole previous evidence (French 1960). Besides the facilitation of the first evoked potential, the second, elicited outside the early 20 msec period, was also obviously facilitated, more strongly if elicited after a longer delay and reaching towards 50 msec the amplitude o f the first (Fig. 7, 8, 1 0 intact brain). Inside the f~rst 20 msec the facilitation o f the second response was abolished, as c o m p a r e d with the first (Fig. 7, 10). Moreover, if before R F stimulation the second response was Eleetroeneeph. olin. Neurophysiol., 1965, 18:1-24

M. DEMETRESCU et al.

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Fig. 8 Single sweeps of paired evoked potentials elicited by suprathreshold ( × 2) LGB paired stimuli in an intact, but old (6 h), preparation (the 3 columns at left). Compare with the effect of the same LGB and midbrain R F stimulations, given after rostro-pontine (post-collicular) and caudate (Fr + 15 plane) lesions (5 sweeps superimposed) recorded from the same point of the visual area (the 2 columns at

right); for further comment see text. sporadically present, it was greatly reduced (10 msec in Fig. 8). Therefore, in all instances the same pattern of arousal consistently appeared, characterized by a large first response, an early period (about 20 msec)of inhibition of the second response ("refractoriness"), followed by a period of facilitation, progressive with increasing delay (maximal from about 50 msec). The contrast between the pattern with a first period (about 20 msec) of large responsiveness and a second of inhibition, found in the disinhibited preparation, and that of arousal, with a first period of strong inhibition and a second of great facilitation, found in the intact brain, is so striking that any further comment is superfluous. A more difficult problem is the systematization of the responsiveness to paired LGB stimuli in moderately aroused, intact brains; the natural variability, as well as uncontrolled drowsiness or sleep, may give an inconstant picture. This may explain the diversity of previously reported pictures (Clare and Bishop 1952; Malis and Kruger 1956; Schoolman and Evarts 1959) in preparations with or without anaesthesia. Throughout the experiments reported here we recorded several interchanging patterns in the same animal (the pairs of threshold LGB pulses were rhyth-

mically repeated at 1.5-2 sec intervals), but as only the constant responsiveness pattern of arousal (RF stimulation) is essential for the present investigation, only 2 cases of the spontaneous background have been illustrated, for comparison: (1) The most common case was that in which the first evoked potential was variable, rather large, followed by an inhibited second response up to 50 msec, in the frame of the well known refractoriness (Fig. 5; the same picture appears also in Fig. 7 and 10, although sporadically a small evoked potential broke into the inhibition period at 10 msec). (2) Two large responses occurring almost systematically at delays below 20 msec, in an intact brain (Fig. 8), were found only in 3 old preparations, with the cortex having been exposed for a long time and with suprathreshold LGB stimulation 1. This borderline case has been selected here in order to give a more striking illustration of the effect of arousal by R F stimulation. Although the individual pairs of responses displayed variability, the averaging of 10-15 successive pairs gave more constant results; ] In a report in preparation, by Steriade and Demetrescu, the influence of diffuse retinal illumination in eliciting this type of pattern is stressed.

Electroenceph. clin. Neurophysiol., 1965, 18:1-24

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TONIC CONTROL OF CORTICAL RESPONSIVENESS

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Fig. 9 Percentage differences (A %) between the second and first paired evoked potentials, function of the interval (T)plotted as abscissa, as altered by RF and caudate lesions. Each point represents the average of 10 responses in the same animal and condition. 10 experiments have been graphed, each ordinal number corresponding to the same animal taken in different experimental conditions, to show the resemblance of different animals' curves and the similar influence of the subcortical lesions. The figure in the right upper corner of each graph is an attempt to represent the typical configuration of the mean curve in the given condition. The reversed slope of the 2 curves pertaining to the same animal, with and without RF stimulation, and their intersection near 20 msec is to be noted in the intact brain. As the disappearance of the inhibitory effect in the RF (rostro-pontine) and caudate lesion preparations (3, 10)has lifted the initial portion of any curve (with or without remaining RF stimulation), no obvious intersection has resulted. Fig. 9 shows the percentage decrement of the second response referred to the first, as a function of the interval; the data are based on the average amplitudes o f ten successive groups of responses and ten different experiments have been graphed. These animals had similar curves, occupying the same areas in similar conditions (except for the control in animal 10, with a raised curve due to p o o r inhibition). As in testing responsiveness with single evoked potentials, the caudate lesion alone or R F transection (rostro-pontine to rostral midbrain) gave similar results (see points I I a and lib and compare Fig. 5 with Fig. 7). In the first period o f increase o f the first response (30-120 min), following recovery from the shock induced by making the lesion, the second response delayed by a b o u t 10 msec was released from the inhibition seen before the lesion; this picture however did not resemble that obtained with both caudate and R F lesions, because of the remaining inhibition exerted on the second potential delayed by 15-20 msec (Fig. 5-7). Neither was release from inhibition o f the second response complete at 10 msec, as m a y be seen by

comparison of the results of both caudate and R F lesions. On the other hand, as time elapsed and the constant large first response again recovered variability, inhibition of the second, 10 msec delayed, response was not seen (Fig. 6). The c o m m o n feature in all animals submitted to a lesion o f only one of the two subcortical inhibitory mechanisms was just this partial release from inhibition, obvious on the 10 msec delayed second response (Fig. 5-7), irrespective o f whether the variability of the first response had recovered. III. An attempt to separate the purely facilitatory

ascending influences Working hypothesis. Having established that the inhibitory influences act (on the second response of a pair) during arousal, we have supposed that some distinct, facilitatory influence must account for the facilitation in this condition. Thus, brain-stem ascending influences able only to increase the cortical response have been sought. As in the intact brain, facilitation o f both responses, evoked at delays longer than 20 msec,

Electroenceph. clin. Neurophysiol., 1965, 18:1-24

12

M. DEMETRESCUet al.

._...I

___1,

nnnnn

-r" t_l..J Z

1Urns

1~rns

m Fig. lO Superimposed (5) groups of paired evoked potentials (LGB stimulation every 1.5 sec) as influenced by direct RF stimulation, midpontine transection and central gray lesion. The lowest 3 lines illustrate another experiment of the same type. Compare with midbrain RF stimulation in rostropontine transected preparations (Fig. 7). were induced by high rate stimulation of the remaining midbrain R F of a preparation with either a brain-stem transection or only an RF (electrolytic) lesion at the rostro-pontine level. The new element which appeared in this special condition was the dramatic facilitation of both potentials separated by 15-20 msec (Fig. 7); however, partial inhibition of the second potential (which had spontaneously been large) elicited at 10 msec occurred. Therefore, although obviously impaired, the phenomenon of inhibition was still present.

A caudate lesion was then added to the RF one. The large responsiveness described above (point IIe) occurred but, in addition, stimulation of the remaining RF, which had inhibited the shortly delayed second response, no longer did so; on the contrary, it facilitated both responses, at any delay (Fig. 7). This exclusively facilitatory action was especially striking at 30-50 msec, showing that RF stimulation was still fully effective. As said above, a special case is illustrated in Fig. 8; the spontaneous responsiveness of the intact brain there occasionally resembled Electroenceph. olin. Neurophysiol., 1965, 18 : 1-24

TONIC CONTROL OF CORTICAL RESPONSIVENESS

that occurring after caudate and RF rostropontine lesions. However, the strong inhibitory action of midbrain R F stimulation on the shortly delayed second evoked potentials was entirely abolished by the lesions, while its facilitatory effect was kept intact, as in all other animals. We consider then just this effect, which undoubtedly existed before the lesions, as representing the action of the distinct facilitatory influences, elicited by RF stimulation. IV. A complex preparation: the midpontine pretrigeminal cat Working hypothesis. This preparation (Batini et al. 1959: Cordeau and Mancia 1959) having

13

cation", which appears after brain-stem transection at a midpontine level, we have found a particular response pattern. A large facilitation of the first response has been accompanied by facilitation also of the second, throughout delays ranging from 10 to 50 msec. Two experiments are shown in Fig. 10 to illustrate this; at 30-50 msec delays the facilitation of the second response resembled that obtained during RF stimulation, before brain-stem transection. At shorter delays the large second response was different from the initial (intact) picture, even during arousal by RF stimulation. This spontaneous pattern suggested the one found in the rostropontine transected and midbrain RF stimulated

t-2

A -4

B1

B

Fig. 11 The ECoG picture of a midpontine pretrigeminal preparation (A); after a central gray lesion in the caudal midbrain (Fr + 2 plane), a spindle ECoG picture results, as shown 2 h later (B), resembling the known eerveau isold picture, recorded after a further midbrain RF transection (C). The ECoG picture of an ene~phale isol~ preparation (A1), altered in the same manner by a similar central gray lesion (Ba), is given for comparison.

given rise to much discussion on the tonic maintenance of arousal, represents a challenge to anybody working in this field. The idea that long-lasting activation following midpontine brain-stem transection is due to the central gray driving circuit, besides suppression of some inhibitory influences, was previously advanced (Demetrescu and Demetrescu 1962b). Further investigation of this special condition, by the method of paired evoked responses, is supported by the results so far reported. On the known background of ECoG "acti-

preparation (compare Fig. 10 with Fig. 7). Moreover, stimulation of the remaining RF did not change essentially the response pattern (as it did in the intact brain), but only induced a slight further facilitation of all responses. A central gray lesion in the caudal mesencephalon (as reported a b o v e - point I) abolished the large facilitation of both responses; again, strong inhibition of the second response at 30-50 msec delays appeared, but the second response was comparable with the first at 10-15 msec. This last pattern (although somewhat less striking in Eleetroenceph. olin. Neurophysiol., 1965, 18:1 24

14

M. DEMETRESCUet al.

Fig. 10) was in all points comparable with that of a rostro-pontine preparation. This is further supported by the fact that, in all midpontine preparations with a central gray lesion added, an enduring (over 6 h) ECoG spindle pattern was seen, similar to that obtained with central gray lesions in encdphale isold preparations (Fig. 11). This pattern resembled that of a cerveau isold preparation, but was not identical with it. On the basis of these facts, we may legitimately conclude that the midpontine pretrigeminal preparation, although spontaneously displaying strong facilitatory influences and some remaining inhibitory ones, was not in a condition identical with true arousal, just because of the impairment of the active process of inhibition. It was, however, the nearest condition to arousal, among those obtained by brain-stem transection. This would also explain the findings ofArmengol et al. (1961) that photic evoked potentials were facilitated by midpontine as well as by rostro-pontine transection. DISCUSSION

I. Brain-stem active inhibitory distinct f r o m facilitatory ones

influences as

To use inhibition as a general concept may give rise to confusion, this term not meaning the same to all those employing it. Therefore, for the purpose of the present discussion, we will consider that active inhibition is an exclusively neural active process that prevents the discharge of crude energy from the system upon which it is exerted, without impairment of either the structure or energetic supply of the nervous tissue, protecting it and permitting energy discharge only by the action of inputs carrying large amounts of information. In this way the sphere of the concept of inhibition, as used here, is restricted; a more precise meaning results for this very real process, which is not the reverse of excitation, achieving a potential state that becomes obvious only by excitation. The experiments reported above lead to the conclusion that active inhibition at the neothalamo-cortical level is due mostly to influences ascending from the brain-stem. Neither the diffuse thalamic nor other known systems of facilitation can be incriminated in the maintemance of maximal responsiveness of a prepara-

tion with rostral RF, caudate and rostral thalamus largely destroyed. Logically, the suppression of ascending influences, which before the caudate and RF lesions had braked the cortical responses, may account for the process of true disinhibition, which may affect the first response, but which becomes much more obvious if referred also to the second, elicited within the first 20 msec. Moreover, this large and even "supramaximal" second response, systematically occurring only in the preparation having both RF and caudate lesions, is a pattern essentially opposed to the "activation" realized by arousal (see R e s u l t s point IId). Consequently, the refractoriness found in the aroused (intact) brain in this early 20 msec period cannot be considered as being due to exhaustion of responsive capacity, but only as a result of active inhibition elicited by influences ascending from lower levels. If an exhausting process of any kind were present in the normal brain, it would necessarily be all the more present after caudate and RF lesions, or the experimental evidence disproves this. Thus, it is legitimate to conclude that active inhibition, elicited by caudate and RF influences, is always present in the normal brain, probably just to prevent exhaustion by over-response. As regards the relative contributions of the caudate and RF mechanisms to the tonic braking of cortical responsiveness, it appears certain that both must be excluded to obtain the disinhibited preparation, since a lesion of only one gave only intermediate situations. A pontine location of the RF area giving ascending inhibitory influences seems obvious, because, as demonstrated, rostropontine transection sufficed to suppress the reticular inhibitory influences and more rostral transections did not essentially change this result; it was previously shown that electrical as well as chemical stimulation of the ventral pontine RF induced inhibition of cortical responsiveness (Demetrescu and Demetrescu 1962b). In the same way, the results of Courville et al. (1962- see also Cordeau 1962) also demonstrated inhibition of thalamo-cortical evoked potentials by chemical stimulation of the lower brain-stem RF and facilitation by chemical inactivation of the same area. In addition, impairment of the RF inhibitory mechanism appeared after midElectroeneeph. olin. Neurophysiol., 1965, 18:1-24

TONIC CONTROLOF CORTICALRESPONSIVENESS pontine transection (Fig. 10), although intermingled with a facilitatory effect. The caudate lesion induced essentially the same pattern as the RF transections, characterized principally by the same release from inhibition of the second response at about 10 msec. As previously reported, inhibition of a single thalamo-cortical evoked potential has been obtained also by caudate high rate stimulation (Demetrescu and Demetrescu 1962a, see also Fig. 3). It is therefore justifiable to assume approximately equal contributions by the caudate and pontine RF inhibitory mechanisms, both succeeding in braking cortical responsiveness, or perhaps better expressed, cortical over-responsiveness. The suppression of only one of these two principal inhibitory mechanisms appears to elicit a slight compensatory hyperfunction of the remaining one, an interpretation which would explain the recovery of variability (and thus of braking) some time after a lesion in either the caudate nucleus or the RF, as well as the inhibition of responses elicited by largely superthreshold LGB stimuli in this experimental condition. As to the slight further disinhibition following additional impairment of the diffuse thalamic system (by a rostral thalamic lesion), it is uncertain whether it was due to suppression of thalamic influences (Tissot and Monnier 1959; Buser 1964) or only to the greater delay after the caudate and RF lesions since, as reported, the pattern of disinhibition progressively grew stronger as time elapsed; this problem requires further investigation. On the other hand, some distinct facilitatory influences must account for the active facilitation of the first response by arousal, or of the second if delayed more than 30 msec (intact brain). Going further in this line of thought, we demonstrated the possibility of separating these influences; the rostro-pontine transected and caudate lesion preparation, when stimulated in the remaining midbrain RF, displayed only facilitation of both paired responses at any delay, including those shortly delayed second responses which had been inhibited by arousal in the intact brain. We are then on safe ground to assert that the .facilitator), iniquences actually mean those ascending influences arising in the brain-stem

15

RF, able only to increase thalamo-cortical responses in any condition, although in the intact brain they may be counteracted by the strong inhibitory process exerted on a shortly delayed second response, especially during arousal. The term facilitatory influences must be understood as distinct from that of "activating" ones, which means a blending of influences achieving arousal, by means of both facilitatory and inhibitory processes. II. The mechanism of active inhibition with& the

neothalamo-cortical complex (the inhibitory network) It is obvious that the size and even the appearance of a second response elicited from LGB depends on its position throughout a temporal cycle, started by the first evoked potential. Two kinds of inhibition, as exerted on the second response of a pair, are suggested by the reported evidence: (1) A short latency, strong inhibition, acting within an early period beginning a few milliseconds (below 5) after the first stimulus and ending at about 20 msec. It cannot be counteracted by any true facilitatory process, as seen during RF-induced arousal, but may be greatly impaired by suppressing either the caudate or reticular mechanism, when the inhibition increases its latency over 10 msec; it is entirely suppressed if both inhibitory mechanisms are inactive, resulting in a facilitatory-like picture owing to a passive process of disinhibition. (2) A long latency, less strong inhibition, exerted throughout a delayed period, beginning slightly after 20 msec, typical towards 50 msec and protracted to a few hundreds of milliseconds. This type of inhibitory action is obviously counteracted by the facilitatory active process, in any condition (see Fig. 7-10), but is not altered by impairment of the caudate or reticular inhibitory mechanism. Although two different inhibitory mechanisms could possibly underlie these two apparently different kinds of inhibition, it is much more probable that a single intermediary apparatus of inhibition exists, located just within the neothalamo-cortical complex. Only this view would explain the short latency of the inhibitory action in the intact brain and its similar alteration by either a caudate or reticular lesion, as well as the Electroenceph. clin. Neurophysiol., 1965, 18:1-24

16

M. DEMETRESCUet al.

intrinsic remaining inhibition (towards 50 msec) even after suppressing the main ascending influences. The same hypothesis may account for the fact that an essentially intracortical event, the first evoked potential, systematically sets in motion the mechanism underlying inhibition, exciting it in order to start the inhibitory cycle which, in its turn, affects all phases of a subsequent evoked potential except only the first spike, an extracortical event (radiation spike Bremer and Stoupel 1956). On the other hand, the strong influence exerted by the brain-stem mechanisms on the first part of this cycle of inhibition suggests that the "inhibitory" ascending influences act by activating this intermediate inhibitory apparatus. Its latency of action appears impaired as a consequence of its disactivation by partial or more advanced suppression of the ascending inhibitory influences, but its presence can always be shown by the remaining inhibition, found at 20-50 msec delays, in all the conditions in which no facilitatory influences are present. Thus we advance the hypothesis of an intracortical network of inhibitory neurones, excited by any sufficiently strong event arising in the cortical primary receiving complex, and activated by the diffuse ascending influences arising in the caudate and RF inhibitory mechanisms (and perhaps in other structures). The activation of the inhibitory network during strong arousal explains the strong inhibition of the second response within the early 20 msec period, in which the active facilitatory process is entirely counteracted ; the protracted inhibition displayed by the intracortical network is weaker outside this period and the facilitatory influences progressively counteract it as the delay increases. A direct effect on the inhibitory network by the facilitatory influences is not conceivable, since the latter were not able to impair in any way the evoked responses after suppression of the subcortical inhibitory mechanisms (see again Fig. 7-9). In our opinion, the hypothesis of the intracortical inhibitory network is highly convincing and in great part demonstrated; apart from the evidence presented here, powerful arguments arise from micro-electrode investigations. It is obviously supported by the fact that, as arousal occurs, some neurones are activated, while the

firing of others is reduced or arrested (Whitlock et al. 1953; Jung et al. 1958; Purpura 1958). Working with intracellular micro-electrodes, Phillips (1961 and previous works) found firing and excitatory postsynaptic potentials in the cells of the motor cortex, as a result of weak cortical stimulation, while stronger stimulation inhibited the discharge and gave true inhibitory postsynaptic potentials. Also by strong cortical stimulation, Li and Chou (1962) found prolonged hyperpolarisation with a latency shorter than 10 msec, which is consistent with the inhibitory latency inferred here, by another way. They accept the higher threshoid of an inhibitory mechanism, "but once set in motion it was more powerful than the excitatory mechanism". Unfortunately, these results were not correlated with the diffuse influences ascending from the brain-stem. As regards the visual cortex, the extensive review of Jung et al. (1958) on their micro-physiological studies points out that low rate cortical stimulation elicited inhibitory pauses in cell firing (extracellular recording), lasting about 100 msec. This would be consistent with protracted inhibition of evoked potentials. On the other hand, the same authors report that by increasing the frequency of cortical stimulation "this inhibitory process appears to become fatigued" and, as known, critical self-sustained activity ensues. But impairment of the inhibitory process may be obtained by disactivation of the intracortical inhibitory network as well, as shown by the great susceptibility to afterdischarges of the chronically isolated cortex (Sharpless 1963; see also Ajmone Marsan 1961) and by the fact that the preparation with bilateral caudate and RF lesions often displayed subintrant seizures; although devoted to another report, it must be stressed that this fact gives rise to the idea that the critical activity is permanently prevented by the braking exerted by the inhibitory network upon any powerful intracortical event following, at too short a delay, another powerful one. It would act as a negative feed-back mechanism, suppressing in this way the potentially selfsustained activity. One fact must still beenvisaged : the occurrence of "supramaximal", 10 msec-delayed, second responses in the preparation with RF and caudate lesions. An explanation would reside in the Electroenceph. din. Neurophysiol., 1965, 18:1-24

TONIC CONTROL OF CORTICAL RESPONSIVENESS

intraliminar recruitment of a fringe of neurones, not excited by the first stimulus; the second would excite also these cells, enhancing the response (Clare and Bishop 1952), certainly if the inhibitory process did not act. This type of facilitation must not, however, be confused with that due to diffuse ascending facilitatory influences; it appears rather as a specific process, since it is due to events arising in the primary receiving system. Having in mind the advanced intracortical inhibitory network we may state that none of the facts reported here is inconsistent with this view. In addition, inhibition of a single evoked potential also agrees with this hypothesis. Stimulation of either caudate or pontine RF achieves a strong activation of the inhibitory network, making possible its random excitation by travelling influxes (previously subliminal for this), thus leading to inhibition (and variability) of any cortical response, even of the single evoked potential. The only condition for this phenomenon to be obvious is that no facilitatory influences be simultaneously elicited, which explains the need of an RF, or only central gray, lesion to demonstrate the caudate or pontine RF inhibitory action, as previously reported (Demetrescu and Demetrescu 1962a and b). The view of an intracortical inhibitory network may also be compared with the main data previously reported concerning cortical responses to paired central stimuli. Evarts et al. (1960) found more increased refractoriness during arousal than during natural sleep, although towards a 10 msec delay a higher responsiveness than that reported here was seen (probably intenser LGB stimulation was used - we underline again the necessity of working with intensities near the threshold). The findings of Malis and Kruger (1956), besides the general support given to the present hypothesis, showed that rhythmic (3 sec) pairs of LGB stimuli, separated by less than 20 msec, elicited a second response larger than the first. In fact, each next pair might find the protracted inhibition elicited about 300 msec before it by the second large response of the preceding pair; the first inhibited response had not succeeded in fully exciting the network, thus not braking the second, which was facilitated also by the discussed "specific" phenomenon.

17

III. The tonic arousal and its mechanism t From the great bulk of information so far accumulated on the arousal phenomenon (French 1960; Lindsley 1960) it may be easily inferred that it signifies, first of all, achievement of the conditions of maximal cortical (or brain) efficacy; besides other evidence, peripherally elicited paired evoked potentials (but at delays over 20 msec), have been facilitated during arousal, showing a better receiving ability (Lindsley 1961; Steriade and Demetrescu 1962; Schwartz and Shagass 1963); the same idea is supported by the facilitation of evoked potentials elicited by rhythmic flashes, above a certain frequency (Steriade and Demetrescu 1960). On the other hand, as firmly grounded by the present evidence, arousal must be regarded as a particular state, supported by a balanced blending of facilitatory and inhibitory influences; it can be regarded in no case as a simple rise in cortical excitability, since the largely raised responsiveness of the comatose, disinhibited preparation cannot even tentatively be associated with satisfactory efficacy. It is of interest to note that, long ago, Pavlov (1938) held that good efficacy would be achieved by a medium level of excitability. Thus, qualitatively, arousal consists in activation o f efficao, of the cortical function, achieved by a certain pattern of facilitatory and inhibitory active processes, able also to prevent self-sustained over-activity, as discussed. The second step is the problem of wakefulness, that is, of tonic arousal. Available data show that impairment of some mechanisms which are not indispensable to true arousal may considerably impair or even suppress its maintenance. Thus, the central gray lesion has given sleeping preparations (Bailey and Davis 1942), as well as that of the posterior hypothalamic areas (dynamogenic area of Hess, see Akert 1961); in encephalitis lethargica (von Economo 1926) the lesions affected mainly the periaqueductal and periventricular gray matter. But in all these instances a transitory arousal by strong stimulation was possible. These facts led to the hypothesis that the posterior hypothalamus and the central gray are a driving mechanism for the 1 To make easier the discussion of the circuits implied

in arousal and its tonic maintenance, we have tentatively represented them highly diagrammatically in Fig. 12. Electroenceph. olin. Neurophysiol., 1965, 18:1-24

18

M. DEMETRESCU et

al.

first 1-2 sec of posterior hypothalamic or rostral central gray stimulation, after a caudal central gray lesion ; (2) a tonically acting communication channel, able to sustain prolonged arousal, mainly or exclusively realized at a metencephalic level, in a region lying under the floor of the fourth ventricle, comprised between the levels of the trigeminal roots (midpontine) and the base o f the inferior colliculus, involving the dorsal

maintenance of tonic arousal (Demetrescu and Demetrescu 1962b). By addition of the facts reported here this hypothesis becomes well sustained (Results, point l), giving rise to some supplementary considerations as well. So, the driving mechanism of arousal appears as having two types of connections with the reticular mechanisms proper: (1) a short-acting and probably short latency communication channel, realized

,IsivENESS iNCREASE iB[T[ON

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Corlical downward influences as we//as lha/arnlc diffuseinfluences and collo[era/sof spec/'~C ascending pa/hways ore no/

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Fig. 12

A tentative representation of the circuits contributing to the tonic control of cortical responsiveness. The facilitatory RF influences are represented by white arrows arising in the "responsiveness increasing RF"; the inhibitory ones by black arrows activating the advanced intracortical inhibitory network. All these influences act upon the cortical primary receiving complex, which, in its turn, is able to excite the inhibitory network, besides having descending links to the brain-stem, not represented for clarity. The dotted arrow represent the proposed driving mechanism for arousal, closing the circuit maintaining it tonically. The functional damping of this circuit has been represented as a cut marked "Sleep". A.H. - anterior hypothalamic area; P.H. - posterior (medial) hypothalamic area; C.G. - central gray matter; R.G.T. - Weischedel's radiatio grisea tegmenti; P.C. - posterior commissure; I.P. - interpeduncular nucleus; O.Ch. - optic chiasma; Trap.B. - trapezoid body. mainly at a mesencephalic level (Weischedel's radiatio grisea tegmenti), subserving an arousal of urgency (which may also be triggered through collaterals of specific pathways or fibres from the lateral h y p o t h a l a m u s - see N a u t a 1958; N a u t a and Kuypers 1958). It may explain the shortlasting facilitation of the evoked potentials in the

nucleus of G u d d e n (n. latero-dorsalis tegmenti). Its tonic action, however, may not be supported only by neural activity descending in Schtitz's system and going from the central gray to the RF. G o o d anatomical evidence shows that R F fibres also enter the central gray ( R a m 6 n y Cajal 1909; N a u t a and Kuypers 1958) and it is easy to Electroeneeph. olin. Neurophysiol., 1965, 18:1-24

TONIC CONTROL OF CORTICAL RESPONSIVENESS

suppose that an activated RF will discharge also in this structure, besides its ascending output. In addition, RF influences also activate the posterior hypothalamus, that is, the whole extent of the periventricular and periaqueductal gray matter. A circuit with positive feedback is then established: the excited central gray will drive the mechanism for increasing RF responsiveness, which in its turn, will activate the posterior hypothalamus and central gray, which again will discharge into the RF and so on. This short loop for tonic arousal appears as essential (Fig. 12); however, it cannot exclude larger loops, e.g., the one travelling through the cortex itself (Bremer and Terzuolo 1952; Jasper et al. 1952; Livingston et al. 1953). But since the main cortical areas able to activate the RF have been found in the anterior cortex, those areas being the principal ones which project upon the hypothalamus, it is probable that the cortical arousing control goes through the hypothalamocentral gray driving as well. Thus, the process of tonic maintenance of arousal appears to be selfsustained, and only triggered by sensory inputs. Also, the diffuse thalamic system must act mainly by driving the RF (Schlag et al. 1961; Schlag 1962: Schlag and Chaillet 1963). The lesions made by them in the area of the posterior commissure interrupted the fasciculus retroflexus of Meynert, which carries influxes from the habenular area to the interpeduncular nucleus and to the caudal central gray (Nauta 1958), that would explain the more or less advanced blocking of ECoG arousal elicited by stimulation of the diffuse thalamic system (see first point of Results). Apart from its links with the RF, physiological evidence is available on the connections of the central gray with the caudate (Beyer et al. 1962). Thus, it results that the driving mechanism must act tonically on both facilitatory and inhibitory subcortical mechanisms, establishing a certain ratio between the respective strengths of influences displayed there, to achieve finally their balanced blending which supports arousal. On the other hand, wakefulness (or tonic arousal) is defined by contrast with the unaroused state, and thus with sleep. Therefore, it results that during sleep the driving circuit must not act, a view which is consistent with the arguments

19

regarding sleeping sickness, the animals with central gray and posterior hypothalamic lesions mentioned above, and with the spindle ECoG following central gray transection (the functional cut of the positive feedback circuit supporting arousal has been tentatively represented in Fig. 12). In addition, the "deactivation" (Bremer 1954; Dell et al. 1961) supposed as underlying sleep would be rightly regarded as a global impairment of the activation of cortical efficacy, but the intimate phenomenon seems to be rather a change of the pattern of diffuse influences supporting arousal into another, as Hebb (1949) had tentatively advanced. (In a report in preparation we shall return to this matter.) It is probable that the mechanism displaying ascending inhibition may be independently driven by other mechanisms, e.g., by those lying in the anterior hypothalamic and more rostral basal areas, in order to damp the positive feedback circuit maintaining wakefulness, thus to elicit an active onset of sleep. This would explain the strong behavioral inhibition and onset of sleep obtained by Sterman and Clemente (1962) when stimulating the mentioned areas, as well as the old and much discussed evidence of Hess (1949) concerning sleep (tentatively represented in Fig. 12 as a link going caudalwards to the posterior bulbar nuclei and giving there collaterals returning to the inhibitory RF). This type of link would explain also the imbalance in the direction of weaker ECoG synchronization obtained by Bonvallet and Bloch (1961; Dell et al. 1961) as a result of prebulbar transection. In this connection, the results of Cordeau and Mancia (1959) are highly significant, demonstrating homolateral ECoG desynchronization as following hemi-sections of the lower brain-stem from the bulbar caudal third up to the midpontine level. Driving of the ventral pontine, inhibitory RF (Demetrescu and Demetrescu 1962b) by cortical descending influences is sustained by the evoked potentials found by Moruzzi and Magni (see Moruzzi and Pompeiano 1962) in the medio-ventral pontine and bulbar R E as a result of pyramidal stimulation (they disappeared after a cut of the pyramids at the level of the caudal pons). In this way the problem of inhibition of the "activating" RF by a bulbar mechanism (see Moruzzi 1964) would be shifted to the Eleetroeneeph. olin. Neurophysiol., 1965, 18:1-24

20

M. DEMETRESCUel al.

level of the damping of larger circuits travelling up and down between the cortex and the medulla. As regards the problem of ECoG pattern alteration by diffuse influences, it can be shortly stated that: (1) The presence of sufficiently strong facilitatory influences is systematically associated with "activated" ECoG patterns, as seen during arousal or in the midpontine pretrigeminal preparation (Batini et al. 1959), irrespective of active inhibition, displayed more or less strongly. (2) Cortical responsiveness, and thus excitability, may be very large (maximal) without necessary arrest of ECoG spindles, as was seen in the RF and caudate lesion preparations. Consequently, the ECoG picture appears to be directly affected only by the facilitatory influences and not by the actual responsiveness, of course when no drugs are administered and when the integrity of the diffuse thalamic system is conserved (see Chow et al. 1959). Thus taking only the ECoG as criterion of cortical excitability it was legitimate to accept the presence or absence of "activation" as supporting arousal and sleep respectively, not taking into consideration active inhibition actually displayed at the cortical level. However, these conclusions may be critically compared with those of the comprehensive survey of data concerning the ECoG made by Moruzzi (1964); this evidence, classical now, is not discussed here. Now, if all the preceding considerations are valid, a question arises: are we still entitled to speak of an "activating" second sensory system, acting tonically on the neothalamo-cortical complex to maintain wakefulness? Or does this function represent only a part of the more extensive functions of a diffuse regulating system, able to display intrinsic braking as well as complex arousing influences? Undoubtedly, both views are as yet conventional representations of some important brain functions but the second appears to be better supported by the experimental evidence. The function of the first order, proper to this regulating system, appears to be the braking of overresponsiveness and self-sustained activity. The complex negative feedback which does this implies no continuous sensory input; thus this function may be regarded as mainly self-sus-

tained. It undoubtedly also prevents eventual harm to the cortical tissues. It is also credible that this same system achieves and maintains the activation of efficacy of cortical function characterizing arousal; at first sight it seems a sensory-maintained function, but a large part of it appears to be self-sustained and only triggered by sensory events. Thus, on a firm experimental basis, the view begins to develop of a diffuse regulating system, including the RF and caudate inhibitory mechanisms, the RF facilitatory one, their driving mechanisms, the intracortical inhibitory network and perhaps others; owing to it the brain is able to maintain some patterns of natural activity, even with a discontinuous sensory inflow. SUMMARY

The responsiveness of the visual neothalamocortical complex in cats has been investigated by single or paired thalamo-cortical evoked potentials (E.P.), to obtain information about: (a) the brain-stem mechanisms able to maintain tonic cortical arousal; (b) the functional picture of the complex when deprived of the main ascending influences, and (c) its alteration by active inhibitory and facilitatory processes elicited by ascending influences, during effective arousal. 1. The E.P. facilitation with after-effect, exerted by posterior hypothalamic or central gray stimulation, has been abolished by a caudal central gray lesion; thereafter direct RF stimulation has again induced facilitation, but without after-effect. These and related previous data show that a driving mechanism, having its main descending circuit in the periventricular and periaqueductal gray matter, interacts with the RF, establishing a positive feedback circuit, to maintain tonic arousal. This would explain the impairment of enduring wakefulness and the occurrence of E C o G spindles in animals with central gray or posterior hypothalamic lesions. 2. Either a caudate or an RF (rostro-pontine to rostral midbrain) lesion induced a strong increase of the single (or first of a pair) E.P., suppressing first the natural variability, which however recovered as time elapsed (2-6 h); the 7-10 msec delayed second E.P. was enhanced as compared with the control before the lesion. 3. The association of caudate and RF lesions Electroenceph. clin. Neurophysiol., 1965, 18:1-24

21

TONIC CONTROL OF CORTICAL RESPONSIVENESS

induces an impressive enduring increase of the first E.P., as well as of the shortly delayed (10-20 msec) second one, which appears to be released from an inhibitory process which has been further increased in latency, since the longer delayed (20-50 msec) second E.P. is strongly inhibited, or absent. In addition, these preparations have often displayed enduring cortical seizures, spontaneous or induced at a very low threshold. A further lesion of the rostral thalamus has not changed this picture. 4. An opposite pattern of responsiveness appears during strong arousal (only intact brain under RF stimulation, inducing facilitation of the first E.P.), since the shortly delayed E.P. (in the first 20 msec) is strongly inhibited, while the longer delayed (30-50 msec) second E.P. is facilitated. (The responsiveness of the animal which is not strongly aroused is not essential for the present investigation.) 5. An intermediary, intracortical inhibitory network of neurones has been tentatively advanced; it would be excited by the first E.P., starting the cycle of inhibition, and only activated by ascending diffuse influences (arising in the caudate and pontine RF) whose impairment explains the proportional release from inhibition of only the shortly delayed second E.P., by increasing the latency of inhibition. The strong inhibition of the same response during arousal has been explained by strong activation of the network, acting also to prevent cortical seizures, like a negative feedback circuit whose impairment would obviously release self-sustained activity (§ 3). 6. Midbrain RF stimulation after rostropontine and caudate lesions has resulted only in facilitating all E.P., at any delay. Some facilitatory influences have been separated; they have occurred spontaneously in the midpontine pretrigeminal preparation, their effect having not been counteracted, as in the aroused intact brain, by a more powerful inhibition exerted on the shortly delayed second responses (§ 4). 7. The ECoG "activation" was seen only in conditions in which facilitatory influences might be inferred, irrespective of the contingent occurrence of active inhibition since the midpontine preparation itself displayed ECoG spindles when its central gray was destroyed. 8. As a comprehensive consequence, a pattern-

ed blending of inhibitory and facilitatory influences is advanced as supporting effective arousal, tonically maintained by brain-stem circuits which would constitute a diffuse regulating system, including inhibitory, facilitatory and driving mechanisms. It would be only triggered by sensory events, since the brain is able to selfmaintain certain patterns of cortical responsiveness through this system. R~SUM~ CONTROLE TONIQUE DE LA RI~ACTIVITI~ CORTICALE PAR DES INFLUENCES DIFFUSES INHIBITRICES ET FACILITATRICES

La rdactivitd du complexe visuel ndothalamocortical a dtd dtudide chez le chat h l'aide de potentiels dvoquds (P.E.) simples ou couplds, pour obtenir des informations sur: (a) l'entretien de l'dveil tonique cortical par des mdcanismes du tronc cdrdbral; (b) l'aspect fonctionnel du complexe ddpourvu de la majoritd des influences diffuses ascendantes et (c) ses modifications par les processus actifs - inhibiteur et facilitateur -, dfis aux influences ascendantes, pendant l'dveil cortical efficace. 1. La facilitation avec post-effet, exercde sur les P.E. par stimulation de l'hypothalamus postdrieur ou de la substance grise centrale (rostrale), a dtd abolie par une ldsion de la portion caudale de la substance grise centrale. Une stimulation subsdquente de la FR mdsencdphalique proprement dite, induisait/~ nouveau la facilitation des potentiels dvoquds, mais cette fois-ci ddpourvue de post-effets. Ces faits, aussi bien que des donndes antdrieures, montrent qu'un "driving" mdcanisme ayant son principal circuit descendant dans la substance grise pdri-ventriculaire et pdri-aqudductielle, entre en action rdciproque avec la FR, rdalisant ainsi un circuit de rdaction positive capable de maintenir l'dveil tonique cortical. Ceci expliquerait l'altdration de l'dtat de veille et les fuseaux ECoG apparus chez les animaux avec ldsions de la substance grise centrale ou de l'hypothalamus postdrieur. 2. La ldsion--soit du noyau caudd, soit de la FR (d'un niveau rostro-pontique jusqu'au mdsencdphale rostral)--a dtd suivie d'une forte augmentation du P.E. (seul ou premier du couple); dans une premi6re phase leur variabilitd Electroeneeph. din. Neurophysiol., 1965, 18:1-24

22

M. DEMETRESCUet al.

naturelle a 6t6 abolie, mais elle revenait entretemps (2 ~t 6 h apr6s la 16sion). Le second P.E. coupl6, ~t un d61ai de 7-10 msec, a 6t6 constamment accru, par rapport au contr61e antdrieur ~t la 16sion. 3. La double 16sion--du caud6 et de la F R - d&ermine une augmentation impressionante et durable des deux P.E. s6par6s par un ddlai de 10-20 msec; le second P.E., ~t court ddlai, apparait donc comme d61ivr6 de sous l'influence d'un processus inhibiteur qui aurait accru sa latence d'action, vu, qu'~t des d61ais plus longs (20-50 msec), il subit une forte inhibition. De plus, ces prdparations ont souvent pr6sent6 des crises corticales de longue dur6e, spontan6es ou induites/t un seuil tr~s bas. Une 16sion additionnelle du p61e rostral thalamique n'a pas modifi6 ce tableau. 4. Un aspect diam6tralement oppos6 appara~t pendant l'6veil tr~s intense (r6alis6 seulement dans le cerveau intact, par stimulation de la FR, induisant facilitation du premier P.E.), car le second P.E. est fortement inhib6 pendant les premi6res 20 msec, tandis qu'il est nettement facilit6/~ des d61ais plus longs (30-50 msec). (La rdactivit6 de l'animal non fortement 6veill6 n'a pas 6t6 essentielle pour cette 6tude). 5. On a hypoth6tiquement avanc6 un r6seau inhibiteur interm6diaire de neurones intracorticaux, qui serait excitd par le premier P.E., d6clanchant ainsi le cycle d'inhibition; il serait seulement activd par les influences diffuses ascendantes prenant naissance dans le caud6 et la F R pontine ventrale; leur alt6ration explique la lib6ration proportionnelle d'inhibition du second P.E. ~t court d61ai, par accroissement de la latence d'action du processus inhibiteur. La forte inhibition de la m~me r6ponse pendant l'6veil est expliqu6e par une forte activation du rdseau, qui para]t prdvenir aussi les crises corticales, actionnant comme un circuit de rdaction ndgative; son alt6ration a 6videmment permis une activit6 critique auto-soutenue (§ 3). 6. AprSs ldsion du caud6 et transection rostropontine de la FR, une stimulation de la FR mdsenc6phalique n'a pu induire que facilitation de toute r6ponse 6voqu6e, ~t n'importe quel d61ai. Certaines influences exclusivement facilitatrices ont 6t6 donc isol6es; l'effet de leur occurrence spontan6e, darts la prdparation

m6dio-pontine pr6trig6minale, n'a pas 6t6 contrecarr6, comme dans l'6veil du cerveau intact, par une inhibition plus puissante excerc6e sur le second P.E./t court d61ai (§ 4). 7. "L'activation" E C o G n'appara~t que dans les conditions exp6rimentales o/t on a constat6 aussi l'existence d'influences facilitatrices, ind6pendemment de l'occurrence 6ventuelle de l'inhibition active; en effet, la pr6paration m6diopontine m~me pr6sentait des fuseaux ECoG lorsque sa substance grise centrale avait 6t6 interrompue par 16sion. 8. En cons6quence, un m61ange d'influences diffuses inhibitrices et facilitatrices, equilibr6es d'une certaine mani~re, est propos6 comme support de l'6veil efficace, toniquement entretenu par des circuits sous-corticaux; ils constitueraient un s y s t k m e diffus de rdglage, comprenant les m6canismes inhibiteur, facilitateur et de "driving". Le cerveau apparait comme 6tant capable d'auto-entretenir certains types de r6activit6 corticale, grace ~t ce syst~me, qui ne serait que d6clanch6 sensoriellement. REFERENCES AKERT,K. Diencephalon. In D. E. SHEER(Ed.), Electrical stimulation of the brain. Univ. Texas Press, Austin,

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