Effects of caudate nuclei or frontal cortex ablations in cats. II. Sleep-wakefulness, EEG, and motor activity

ESPERIMENTAI,

Effects II. JAIME

R.

lIc@rtrrlrnt

NE’CTROI.OGY

53, 31-50

of Caudate Nuclei Sleep-Wakefulness, VILLABLANCA,

ROBERT

(1976)

or Frontal Cortex Ablations in Cats. EEG, and Motor Activity 1 J.

MARCUS,

AND

CIIARLES

of Psychiatry and Ncrltal Rctnrdutiott Rcsrnrch Celctcv, Califomin, Los &-2rlgrlcs, Califovlzia 90023 Rccciwd

Fcbmary

E.

OLMSTEAI)

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of

9, 1976

The effects of caudate nuclei ablation or frontal cortex removal on the percentages of wakefulness and sleep stages, spontaneous motor activity, and the EEG were studied in cats by means of 24-hr polygraphic recordings for a 6-month period. A significant, permanent, reduction of sleep (particularly REM sleep) and an increase in motor activity were observed in cats with removal of most of the frontal tissue in front of the A22 stereotaxic plane. A similar decrease in sleep was also observed in animals with bilateral, almost total, removal of the caudate nuclei, but this reduction almost fully recovered after the second postlesion month. Motor hyperactivity was more marked in cats with caudate ablations than in cats with frontal ablations and persisted indefinitely. No marked or lasting effects on the EEG were observed. Sham-operated cats and those with unilateral caudate removal behaved like intact cats. It is concluded that both the frontal cortex and the caudate nuclei are parts of a postulated, complex, forebrain system modulating brain stem activating-deactivating central nervous system mechanisms.

INTRODUCTION We have previously reported (53) a marked decrease in both nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep for “diencephalic” cats. Jouvet (21), however, found a decrease in NREMs only in neodecorticate cats. The main difference between the two preparations was that our diencephalic cats had a more extensive removal of striatal and limbic structures. It appeared appropriate, therefore, to test the hypothesis that striatal participation in sleep-wakefulness control could account for the above discrepancy by removing the caudate nuclei and investigating the effects on sleep-wakefulness. Indeed, it has been pre1 This research was supported by USPHS 04612. We wish to thank D. L. Avery, Ph.D. ysis of the data. 31 Copyright @ 1976 by Academic Press, Inc. All rights of reproduction in any form reserved.

Grants MH-07097, for his assistance

HD-05958, and HDin the statistical anal-

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viously suggested that the caudate exerts an inhibitory control over motor activity and behavioral arousal. On one hand, electrophysiological (1, 12, 16, 30, 40, 41, 47, 48) and biochemical (13, 17) studies have suggested that stimulation of the caudate tends to induce motor relaxation and sleep. Conversely, motor hyperactivity has been shown to follow striatal lesions in several animal species (9, 2.5, 27, 45, 60). In view of all these indications, the lack of studies dealing with the effects of caudate lesions on the sleep-wakefulness cycle is surprising. Furthermore, in cats there is, to our knowledge, only one study (37) reporting the effects of such lesions on motor activity. The studies on the effects of frontal cortex ablation on motor activity and sleep-wakefulness were initiated because of our interest (58) in determining if there are differential effects following caudate versus frontal lesions. There are several reports on the effects of frontal ablations on the amount of motor activity in both cats (28, 29, 35, 59) and monkeys (25, 45, 46). The issue, however, appears not to be settled as yet for the cat (4). The absence of animal studies clarifying the effects of frontal lesions on the cortical areas and five sham-operated cats. This paper reports on the effects of virtually complete bilateral or unilateral removal of the caudate nuclei, as well as on the consequences of bilateral ablation of the frontal cortex, upon the sleep-wakefulness and motor activity percentages in cats. In addition, the electroencephalogram (EEG) was studied because marked EEG changes have been reported in monkeys with caudate lesions (24). Two preliminary reports have been published (34, 56). METHODS The experiments were performed in 23 adult cats (20 males and three females) ; eight with bilateral removal of the caudate nuclei, five with removal of one caudate nucleus, five with bilateral removal of the frontal cortical areas and five sham-operated cats. Surgical Procedures. The surgical ablation and postoperative care procedures were already described (58). In all animals, under anesthesia, recording electrodes were implanted stereotaxically [for the subcortical placements (49)] d uring the same surgical session as follows: bilateral epidural screws in frontal, parietal, and occipital areas ; tripolar electrodes (twisted, 0.25-mm stainless-steel wires, insulated except for the tips) unilaterally, in the ventral hippocampus, pontine reticular formation and/or lateral geniculate body. In addition, bipolar silver wires were implanted in the nuchal muscles for electromyographic (EMG) recordings and a unipolar screw lead was affixed in the roof of each orbit for monitoring eye movements. Finally, one screw was affixed in the midline of the frontal

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bone and another in the bone overlying the cerebellum as reference and ground leads, respectively. The electrodes were brought together in an Amphenol strip connector and secured with dental cement. Recording and Scoring Procedures. Recordings were done with the animals in a sound-attenuated chamber with a one-way observation window aud under dim, uninterrupted illumination. The freely moving cat was connected to a polygraph through a standard counterweighted cable system and slip ring assembly. The animals had free access to water and food. Sleep-wakefulness and overt motor activity were evaluated by means of 24-hr recording sessions commencing on or about the fifth postoperative day and continued every 10 to 15 days during the first 3 months and every 10 to 30 days thereafter for up to 6 months. Shorter recording sessions were conducted on the first few postoperative days to evaluate early EEG changes. Additional recordings were performed both in the early and late postoperative period in several cats with bilateral or unilateral caudate ablations in order to test the reactivity of the EEG to thiopental (10 to 15 mg/kg, iv) and D-amphetamine (0.5 to 2 mg/kg, intraperitoneally). For the latter purpose the EEG was recorded for more than 1-hr baseline period, thereafter one of the drugs was administered and the recording continued for 2 to 3 more hours. To calculate the time of each 24-hr session spent by each cat in wakefulness, and NREM and REM sleep, the records were scored according to the well defined polygraphic features pertaining to each of these stages in the cat (50). Drowsiness was not considered as a separate stage because it was felt that without continuous behavioral and ocular-pupilar monitoring by the investigator (53), this stage could not be easily distinguished from NREM sleep. The criteria used to identify motor activity during wakefulness were: a desynchronized EEG, highly active EMG, abundant nonpatterened eye movements and movement artifacts in the records. Moreover, the cats were frequently observed, both during the day and during parts of the night, particularly in the early postoperative period, to detect any EEGbehavioral dissociations (54 j. The time spent in quiet wakefulness (ocular movements and active EMG) was not considered as motor activity. For each recording session the time in minutes spent by each animal in wakefulness, NREM and REM sleep, or in motor activity was expressed as a percentage of the 24-hr period. These percentages were used to calculate the mean percentages of time spent in each sleep-wakefulness stage or in motor activity by four combinations of animals. (i) All cats of each group for each 24-hr recording session performed on the days specified above, or sessions Incans (Figs. 2, 3, 68). The latter were used to evaluate the time course of the changes in each group and to compare

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the experimental groups with the sham-operated cats at different postoperative dates. (ii) All cats of each group studied across all recording sessions or grand ?lzealls (Figs. 3, 4, 9). These means were used to compare the experimental with the sham-operated groups across the total duration of the study. (iii) All cats of each group studied during the three recording sessions of the first postoperative month (Days 5, 15, and 25) and third postoperative month (Days 60, 75, and 90) or partial grand means. The latter were used (Figs. 5, 10) to compare (a) late versus early values in each experimental group (to evaluate recovery), and (b) the experimental with the sham-operated groups at these two postoperative stages. (iv) Each individual cat across all sessionsor cat means to compare the sleep-wakefulness changes with the extent of the lesions in the cats with caudate ablations. For statistical analysis of the data a two-tailed t test, corrected for small H and for multiple comparisons ( 15)) was used throughout. For simplification, the statistics of the sessionsmeans are not presented. It was considered that the statistical comparison between the partial grand means conveyed basically the same information and was simpler and more reliable. All pertinent P values are provided in the figure captions. Histology Procedures. The extent of the lesion and placement of the electrode tips were evaluated by procedures already described (58). RESULTS Survival. All cats were studied for a 6-month period except for three cats with bilateral and one with unilateral caudate ablations and one shamoperated cat which were followed for only 3 months. Intercurrent diseases or poor recordings due to deteriorating electrodes justified these deletions. Anatomy. In the bilaterally operated brains the median amount of caudate ablated was 81% (range 27 to 100%) with only one brain exhibiting lessthan 50% removal (27%). F our brains sustaining a virtually complete caudate removal had minimal damage to additional structures (except for the midline, cortico-callosal, penetration sites). In the other four brains additional damage was unilateral, slight (except for two cases with a slight to moderate injury to the fornix-septal regions and another with bilateral moderate lesions of the white matter in front of the caudate head) and not systematically repeated. The amount of caudate tissue removed in unilaterally ablated cats was larger (median SS.Oo/,,range 52 to 100%) than in the bilaterally operated animals. Except for one brain with moderate damage to the frontal capsular area, additional lesions were small and always unilateral. The extent of the frontal ablation of all five cat brains was fairly constant and fits the pattern previously described (58). The caudate nuclei were not damaged and the lateral ventricles were not

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opened. The brains of three sham-operated cats were examined. Midline cortical lesions and callosal penetration with no additional damage were found. Histological examples of these lesions have been presented (58). Electroencephalogram. The EEG was essentially normal in all cats. In some cats with bilateral caudate ablations, during the first two to four postoperative days, isolated bursts of high-voltage slow waves occasionally interrupted the desynchronized cortical EEG during arousal, particularly over frontoparietal areas. Each burst lasted for 1 to 2 set and occurred sporadically enough so as not to constitute an EEG-behavioral dissociation (54). No such abnormal bursts were observed in cats of the other groups. Thereafter in all bilateral acaudate cats both the cortical and subcortical EEG appeared to be entirely normal. This was demonstrated by an adequate display of all EEG events characteristic of the sleep-wakefulness stages including pontine-geniculate-occipital spikes and hippocampal theta during REM sleep (Fig. 1C). The reactivity of the EEG (Fig. 1D) to thiopental (abundant spindle-bursts) and to n-amphetamine (marked, sustained EEG clesynchrony) was also normal.

Sham-Operated Cats. The grand mean values for the duration of the study were: 37.9 * 8.970 for waking, 46.6 I+ 7.5% for NREM sleep and 15.5 + 2.470 for REM sleep (Fig. 4). The session means (Fig. 2) showed, furthermore, that there were no consistent changes in the sleep-wakefulness percentages from date to date across the 4-month period. Thus, essentially, our sham-operated cats did not differ in their percentages of sleepwakefulness from intact cats studied by others (10, 50, 52) under similar experimental conditions (see Discussion). Bilatcval Acandatc Cats. The percentages of sleep-wakefulness changed in these animals in relation to sham-operated cats. The session means (Fig. 3) demonstrated a reduction of sleep, proportionally more marked for REM sleep, coupled with an increase in wakefulness which lasted throughout the first 2 months. After the second postoperative month, the sleep-waking percentages tended to return to normal values with only a slight reduction of sleep and increase in wakefulness persisting throughout the remaining 4 months. This recovery largely offset the relatively low values for sleep during the initial period ; thus, the 6-months’ grand means for wakefulness, NREM, and REM sleep of bilateral acaudate cats were not significantly different from those of sham-operated cats (Fig. 4). This early hyposomnia and the late sleep recovery were further documented by comparing the partial grand means for the first and third months sessions. Comparison of the partial grand means for the first month with similar means for sham-operated cats (Fig. 5) showed that the differences were

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CATS

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FIG. 2. Mean percentages of W, NREMs, and REMs (see legend of Fig. 1) for each 24-hr recording session conducted in five sham-operated cats during the postlesion days indicated. The last co!umn to the right in this and subsequent figures

shows, for comparative all sham-operated cats

the bars in this and

purposes, the grand mean percentages of the three stages for in all 24-hr recording sessions. The vertical iines on top of following figures represent standard deviations of the means.

significant for the increase in wakefulness as well as for the decrease in REM sleep: wakefulness, bilaterally acaudate cats 58.17* 12.370 and sham-operated cats 37.0 * 9.370 ; REM sleep, bilaterally acaudate cats 10.8 * 4.5 and sham-operated cats 15.7 r+ _3.4%, respectively. In contrast, the values of the partial grand means for the third month’s sessions were practically identical for the two groups (Fig. 5). Moreover, the third month’s partial grand means of bilateral acaudate cats showed a marked increase in sleep and a decrease in wakefulness relative to those for the first month’s session of the same animals with the differences for wakefulness and REM sleep being significant (Fig. 5). In summary, caudatectomy produced a significant reduction of REM sleep at the expense of wakefulness, but these changes were almost entirely recovered by the third postoperative month. Frc. lateral, patterns C-rapid grouped Fr Cx ventral nations myogram.

1. Polygraphic recordings taken postoperative day 17 from a cat with a bi94% removal of the caudate nuclei [see Fig. 2, (SS)] showing normal EEG during : A-wakefulness (W) ; B-nonrapid eye movement sleep (NREMs) ; eye movement sleep ( REMs), (note hippocampal theta rhythm and pontine spikes) ; and D-thiopental action (note abundant spindle burst activity). frontal cortex, Par. Cx parietal cortex, Occ Cx occipital cortex, Hipp (v) hippocampus, Pont RF pontine reticular formation [ (1) and (2) are combibetween leads of a tripolar electrode], EOG electro-oxlogram, EMG electroAll recordings are bipolar.

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r+vAKEq NREMI n REMS IOO90;

80-

;

70a 2= 602 so5 ; AO6 2 30zoIOODAYS

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FIG. 3. Mean percentages of W, NREMs, and REMs (see legend of Fig. 1) for each 24-hr recording session conducted in eight cats with bilateral caudate removal during the postlesion days indicated. Last co!umn to the right, as in Fig. 2.

Unilateral Acaudate Cats. As demonstrated by the session means (Fig. 6) and by the grand means (Fig. 4), no consistent changes in the sleepwakefulness

percentages

were

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in these

cats

relative

to sham-

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FIG. 4. Grand mean percentages of W, NREMs, and REMs (see legend of Fig. 1) for all 24-hr recording sessions of sham-operated (Fig. 2), unilateral acaudate (Fig. 6)) bilateral acaudate (Fig. 3), and bilateral frontal cats (Fig. 7). * P < 0.05 in relation to sham-operated cats.

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SLEEP-WAKEFULNESS

FIG. 5. Partial grand mean percentages of all groups of W, NREMs and REMs (see legend of Fig. 1) for 24-hr recording sessions of the first postlesion month (sessions of Days 5, 15, and 25 of Figs. 2, 3, 6, and 7) and third postlesion month (sessions of Days 60, 75, and 90 of Figs. 2, 3, 6 and 7). * P < 0.05 in relation to 1st month (same group of animals) ; 3 P < 0.05 in relation to sham-operated cats.

operated or bilateral acaudate cats. This was ascertained by comparing the partial grand means of this group with both those of sham-operated and bilateral acaudate cats; the differences between these values were also not significant (Fig. 5). Bilateral Frontal Cats. Following surgery, a reduction of both sleep stagesand an increase of wakefulness were observed (Fig. 7). The reduction was significant for REM sleep, but not for NREM sleep, as demonstrated by comparing the grand means for this group with similar means for sham-operated cats (Fig. 4). However, this was not a large reduction : from 15.5 2 7.470 for control cats to 11.5 * 3.370 for frontal ablated cats. The increase in wakefulness was also significant: from 37.9 * 8.9% in control cats to 48.8 f 7.8% in frontal cats. These changes persisted throughout the 6 months as shown by the sessionsmeans (Fig. 7) and as further documented by comparing the partial grand means for the first and third months of frontal ablated cats with similar partial means of control animals (Fig. 5), i.e., the significance of differences for wakefulness and REM sleep observed during the first month persisted for the third month. Furthermore, no significant changes were observed when comparing the partial means of the third versus those of the first month within the same group (Fig. 5). In summary, a significant reduction of REM sleep at the expense of wakefulness was observed following surgery but, unlike bilateral acaudate cats, there was no recovery in the frontal animals.

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FIG. 6. Mean percentages of W, NREMs, and REMs (see legend of Fig. 1) for each 24-hr recording session conducted in five unilateral acaudate cats during the postlesion days indicated. Last column to the right as in Fig. 2.

In the first cats of each group the length of REM sleep episodes and the duration of the sleep cycle were studied; because no gross change in relation to values from studies of normal cats (50) was found, the systeFRONTAL

CATS

,oo90BOSJ ;

TO-

m 2

60-

2 a

.50-

n

40-

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3020lo-

5 90 115 DAYS

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FIG. 7. Mean percentages of W, NREMs, and REMs (see each 24-hr recording session conducted in five bilateral afrontal lesion days indicated. Last column to the right as in Fig. 2.

legend of Fig. 1) for cats during the post-

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i

FIG. 8. Mean percentages of spontaneous motor activity for each 24-hr recording session conducted during the postlesion days indicated.

matic analysis of these parameters was not pursued. Finally, no relationship was found between the sleep-wakefulness changes for each cat (cat means) and the amount of caudate tissue removed. Motor Activity. Following surgery there was a marked increase in mean motor activity for all three experimental groups when compared with sham-operated controls (Fig. 8). This increase persisted, except for unilaterally caudate ablated cats (see below), throughout the study: Differences between the grand means of the three experimental groups and the controls were significant (Fig. 9). However, the increase in motor activity was larger for bilateral acaudate cats (27.3 -t 10.1%) than for frontal (25.1 * 5.9%) and unilateral acaudate (33.6 * 5.6% ) animals (see also P values in Fig. 9). After the second postoperative month there was a tendency for the hyperactivity to decrease.Thus, a comparison of the partial grand meansfor the sessionsof the first month with the partial grand means of the sessions of the third month (Fig. 10) showed that such reduction in hyperactivity was slight for bilateral frontal cats, moderate for unilateral acaudate cats, and more marked for bilateral acaudate animals. Indeed, during the first

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postoperative month the percentage of time spent in motor activity by bilateral acaudate cats (31.1 * 6.8%) was almost double that of shamoperated controls (16.8 f 4.1%)) whereas during the third month it was only about 30% larger (24.0 2 7.5% for bilateral acaudate cats and 15.6 + 2.7% for controls). However, during the third postoperative month, the differences between the partial grand means of bilateral acaudate and frontal cats as compared to control animals were still significant, whereas the values for unilateral acaudate cats were not (Fig. 10). In summary, there was a moderate-about 55% in relation to the sham-operated catsbut sustained overall increase in motor activity for the bilateral frontal cats ; a larger-about 68%---but declining increase for bilateral acaudate cats; and a smaller rise, particularly manifested during the first two postoperative months-about 37%--for unilateral acaudate cats.

38-

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MEANS

FOR

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ACTIVITY

3634323028Zb24 -

FIG. 9. Grand mean percentages of spontaneous motor activity for all 24-hr recording sesions of cats operated as indicated (Fig. 8). * P < 0.05 and ** P < 0.01 in relation to sham-operated cats.

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FIG. 10. Partial grand mean percentages of spontaneous motor activity groups for Whr recording sessions of the first postlesion month (sessions 15, and 25, Fig. 8) and the third postlesion month (sessions of Days 60, Fig. 8). + P < 0.05 in relation to first month (same group of animals). and $3 P < 0.01 in relation to sham-operated cats.

of all four of Days 5, 75, and 90, $ P < 0.05

DISCUSSION Electroencepkalogvnlrl. The EEG findings in the present cats depart sharply from those in the only other study (24) we are aware of which examined the effects of extensive bilateral caudate lesions upon the EEG.2 In that study persistent changes in the EEG consisting of intermittent high amplitude bursts, marked slowing with “uneveness” and “diminution of amplitude” of the EEG patterns, were reported in monkeys with combined ablations of the head of the caudates and cortical areas 4 or 6. Seizure activity was a common postoperative occurrence in those animals. Although the author did not provide a detailed account of the extent and characteristics of striatal and cortical lesions, it is conceivable that the cortical involvement plus the epileptogenic nature of the seizures may explain such abnormal EEG patterns. Our results suggest, instead, that the caudates are not conspicuously involved in the control of spontaneous EEG events. Furthermore, the normality of polygraphic patterns in our caudateablated cats is additional proof (58) that noncaudate structures which are 2A recent study in the rat (8) reported no gross changes in the EEG following caudate-putamen lesions. However, the size of the lesions was not specified and, most probably, they were small (produced electrolytically through the tip of OIW fixed bipolar electrode in each caudate).

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essential for the generation of normal EEG patterns were not disturbed in our animals. Sleep-Wakefulness. Our grand mean values for REM sleep and NREM sleep of the sham-operated and unilateral frontal cats were identical to or within one standard deviation of the values for the same stages reported by others (10, 50, 52) for intact cats studied under similar conditions. This has two implications for the present experiments. (i) It further justifies our use of sham-operated cats as a control group, and (ii) it indicates that in cats, a major surgical removal, such as unilateral caudate ablation, can be effected without producing significant sleep-wakefulness effects. A decrease in the amount of REM sleep to 10% in sham-operated cats was reported previously (22). The only long-lasting, practically permanent, sleep-wakefulness change found in the present study was in bilateral frontal cats which manifested a moderate but significant hyposomnia (particularly for REM sleep) and a concomitant wakefulness increase. We do not know of any other animal ablation studies exploring the role of frontal areas in the percentage of sleep-wakefulness. However, several stimulation experiments (2, 6, 39, 43) have shown that low-frequency electrical pulses applied to the pericruciate, orbital, and/or mesial frontal cortical areas induce EEG and behavioral manifestations of sleep suggesting that frontal areas may be involved in sleep-wakefulness control. Studies of the effects of prefrontal lobotomy on human sleep-wakefulness are relevant although also scarce. In their one case study, Hauri and Hawkins (14) reported that following leucotomy there was an increase in the amount of wakefulness and in the time to fall asleep with a decrease in delta sleep lasting for several months. This hyposomnia was interpreted as due to derangement of similar mechanisms as in the hyposomnia observed in cats with basal forebrain lesions (36). Hosokawa et al. (19) observed a decrease in REM sleep in two lobotomized patients ; however, there was no hyposomnia in three other patients who, in addition to leucotomy, received other shock-type treatments. No reduction of sleep percentages was observed (20, 23) in lobotomized schizophrenic patients studied many years after surgery ; thus, if such a reduction had occurred immediately following surgery, it had recovered at the time of the studies. The above reports suggest that in man a frontal lesion also decreases, although temporarily, the amount of sleep (particularly REM sleep). One could speculate that because leucotomy, in contrast with the complete ablation performed in our animals, is a procedure involving only a partial separation of the frontal lobes [see also the description of the procedure in (14) 1, this difference might account for the more permanent disturbance observed in our experiments. The hyposomnia of the bilaterally acaudate cat was only transitory be-

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cause it was almost nonexistent after the second postoperative month; it was also less marked than that exhibited by bilateral frontal cats. This raises the issue of the meaning of sleep recovery following an insomniaproducing lesion and of the time course for such recovery. Unfortunately. there are no established criteria to decide about such issues. Some authors [see (38) ] apparently have little regard for the recovery process, and so decide that a structure is important for sleep-waking control if a significant change in sleep-wakefulness percentages occurs following its destruction, even though the reduction may last for only a few days or weeks. We have adopted the viewpoint that in order to claim a significant disruption of sleep-wakefulness by a brain lesion, either a quantitative change in the sleep-wakefulness stages and/or changes in other sleep-wakefulness parameters should remain more or less permanently (53, 54). The available evidence documenting hyposomnia in our bilateral acaudate cats would probably pass the less stringent criterion mentioned above but it would not comply with our own. Moreover, in evaluating the present results the following facts cannot be overlooked. First, there was a permanent hyposomnia in bilateral afrontal cats. Second, although no direct damage to frontal subcortical fibers was inflicted in most of our bilateral acaudate cats, indirect alterations of the frontal-cortical projections (edema, irritation, destruction of frontal-caudate terminals and of the relatively scarce frontal-subcortical fibers traversing the caudate in cats) most probably occurred in all our preparations and these could have contributed to the transitory hyposomnia of bilateral acuadate cats. Because of the above considerations we believe that the present results suggest that if the caudate plays any functional role in the control of sleepwakefulness in the cat, such a role is not of major importance and is compensated for by other forebrain areas (probably the frontal cortex). For similar reasons, it follows that the differences between the results in the sleep-wakefulness study by Jouvet (171) in neodecorticate cats and by ourselves in diencephalic cats (53) cannot be accounted for by the mere absence of the caudates in the latter animals. We have not found any reports concerning the effects of striatal lesions upon sleep-wakefulness in cats. In rats, two such studies have been published (8, 51). Unfortunately, the rat is not appropriate for caudate ablation experiments because in that species many cortical-subcortical fibers cross the nuclei. Because of this fact and due to other methodological drawbacks of those studies, we are unable to compare them with the present experiments. There are several reports concerning effects of caudatal electrical stimulation on sleep-wakefulness. Although three studies (5, 18, 30) did not report the occurrence of sleep (although “caudate spindles” were pro-

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duced), four other papers (I, lG, 40, 41) reported that sleep or some of its behavioral components occurred as a consequence of low-frequency electrical stimulation of the caudate. However, only Heath and Hodes (16) reported deep sleepfollowing such stimulation in one human patient and one monkey. The other studies, all in cats, reported only behavioral inactivation and/or light sleep with preserved responsiveness to esternal stimuli. According to Parmeggiani (40, 41) the latter findings indicate that the caudate participates only in indz&g light sleep, In conclusion, the present ablation studies and the electrical stimulation experiments cited do not support the notion of any powerful influence of the caudate in the control of sleep-wakefulness. In contrast, the frontal cortex appears to serve a more important role, particularly in the control of REM sleep. Motor Activity. A possible difficulty in evaluating the present results is that the sham-operated animals themselves had a brain lesion. Such injury, it could be argued, might on its own alter the amount of motor activity. This seemsunlikely because (i) no obvious difference was noticed between the motor activity of sham-operated cats versus intact cats in their daily laboratory life, whereas such differences were grossly manifested in bilateral acaudate and frontal cats; (ii) the amounts of sleep-wakefulness were entirely normal in sham-operated cats, whereas a reduction in sleep occurred concomitantly with hyperactivity in frontal and acaudate cats; and (iii) we have not found any data in the literature suggesting a change in the amount of motor activity in animals with lesions in or around the region ablated in our sham-operated cats [see (4) 1. Although there are quantitative studies demonstrating motor hyperactivity in monkeys (9, 45) and rats (27, 60) following striatal lesions, the reports of hyperactivity in the cat have been based on nonquantified visual observations (37). The present study is the first to document the presence of motor hyperactivity following caudate lesions in cats. The literature is less clear regarding a possible participation of lesions restricted to frontal cortical areas in producing motor hyperactivity in cats. The only quantitative study in this regard (28) reported a large increase in motor activity in frontal cats in which some additional damage to the striatum was inflicted. Other studies either did not demonstrate any hyperactivity (29) or reported its presence in frontal cats in which, most probably, the caudates had also been damaged (35, 59). Thus, Brutkowski concluded (4) that hyperactivity has not been reported in cats with frontal lesions. In contrast, but in coincidence with some of the studies just mentioned (28, 35, 59), the present data demonstrated the participation of frontal areas in the control of motor activity in cats. This result extends and renders more significant the findings of hyperactivity following frontal lesions in monkeys (25, 45, 46) and rats (33).

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Although the increase in motor activity in our animals was demonstrated in the relatively stimulus-poor environment of the recording cage, the possibility that hyperreactivity to natural stimuli could contribute to the enhanced activity of these cats should be considered. Our gross behavioral observations (SS), as well as our findings (3) in cats receiving frontal or caudate lesions as kittens, suggested that the latter is the case for bilaterally acaudate cats. We are presently studying this possibility in adult operated animals. The problem of hyperreactivity versus hyperactivity in animals with caudate lesions has been previously discussed by others (27, 37). A further increase in motor activity in caudate-ablated rats (27) and cats (37) was observed following enviromnental darkening for the rats or blindfolding for the cats, respectively. The authors interpreted the change as a reaction to the decrease in illumination since these species naturally display more activity during darkness. The resuIts of our motor activity studies fit well with our data on sleepwakefulness to indicate that both the frontal cortex and the caudate are involved in controlling the level of central nervous system activation. Such role is manifested for both sleep-waking and motor activity in the case of the frontal areas and mainly for motor activity in the case of the caudate. We previously postulated (53, 55) the existence of an inhibitory forebrain system balancing the influence of a powerful ventral diencephalic mechanism for arousal and motor activity. We also proposed that the striatum and the frontal cortex may be a part of such inhibitory system (57). The results from the present experiment support this hypothesis. This postulated forebrain inhibitory system appears to be complex (7, 11, 31, 32, 42, 44) because several other telencephalic regions, i.e., the basal forebrain (30, 31, 36, 47, 48), the hippocampus (7, 26, 32, 44) and diencephalic areas (43, 53, 54), have also been found to have modulatory influences on central nervous system arousal and motor activity levels. Moreover, recent evidence suggests that some of these areas might possess controlling properties acting independently on different manifestations of both sleep-wakefulness (11, 31) and spontaneous behavioral activity (32, 44). REFERENCES B. ANDERSON. 1951. Experimenteller beitrag zur p!lysiologie des Pltysiol. Scafbd. 22: 281-298. 2. ALNES, E., B. R. KAADA, and K. WESTER. 1973. EEG synchronization and sleep induced by stimulation of the medial and orbital frontal cortex in cat. Actn Plqsiol. Scaled. 87( 1) : 96-102. 3. AVERY, D. L., C. E. OLMSTEAD, and J. VILI.ABLANCA. 1976. Behavioral hyperreactivity in cats with caudate nuclei ablation. Fed. Proz. 35(3095) : 768. 4. BRUTKO~SKI, S. 1965. Functions of prefrontal cortex in animals, Physiol. RN. 45 (4) : 721-746. 1. AKERT,

K.,

and

nucleus caudatus. Acta

48

VILLABLANCA,

MARCUS

AND

OLMSTEAD

N. A., E. J. WYERS, C. W. LAUPRECHT, and G. HEUSER. 1961. The “caudate-spindle.” IV. A behavioral index of caudate-induced inhibition. Electroenceph. Clin. Neurophysiol. 13 : 531-537. BURNS, N. M. 1957. Apparent sleep produced by cortical stimulation. Canad. J. Psychol. 2 : 171-181. CAMPBELL, B. A., P. BALLANTINE, II, and G. LYNCH. 1971. Hippocampal control of behavioral arousal: Duration of lesion effects and possible interactions with recovery after frontal cortical damage. Exp. Neural. 33: 159-170. CORSI-CABRERA, M., J. GRINBERG-ZYLERBAUM, and L. S. ARDITTI. 1975. Caudate nucleus lesion selectively increases paradoxical sleep episodes in the rat. Physiol. Behav. 14: 7-11. DAVIS, G. 1958. Caudate lesions and spontaneous locomotion in the monkey. Neurology 8 : 135-139. DELORME, F., P. VIMONT, and D. JOUVET. 1964. Etude statistique du cycle viellesommeil chez le chat. C. R. SOL. Biol. (Paris) 158: 2128-2130. DEMENT, W. C., and J. VILLABLANCA. 1974. Clinical disorders in man and animal model experiments, pp. 317-331. In “Basic Sleep Mechanisms.” 0. Petre-Quadens and J. Schlag [Eds.]. Academic Press, London. FORMAN, D., and J. W. WARD. 1957. Responses to electrical stimulation of caudate nucleus in cats in chronic experiments. J. Neuropltysiol. 20: 230-244. GADEA-CIRIA, M., H. STADLER, K. G. LLOYD, and G. BARTHOLINI. 1973. Acetylcholine release within the cat striatum during the sleep-wakefulness cycle. Nature (Lolldolz) 243 : 518-519. HAURI, P., and D. R. HAWKINS. 1972. Human sleep after leu:otomy. Arch. Gen.

5. BUCHWALD,

6. 7. 8. 9. 10. 11. 12. 13. 14.

Psychiat.

26 : 469-473.

15. HAYS, W. L. 1963. “Statistics for Psychologists.” Holt, Rinehart & Winston, New York. 16. HEATH, R. G., and R. HODES. 1952. Induction of sleep by stimulation of the caudate nucleus in macacus rhesus and man. Trafts. Amer. Neurol. Assoc. 77 : 2OC 210. 17. HERNANDEZ-PEON, R., J. J. O’FLAHERTY, and A. L. MAZZUCHELLI-O’FLAHERTY. 1967. Sleep and other behavioral effects induced by acetylcholinic stimulation of basal temporal cortex and striate structures. Brain Res. 4 : 243-267. 18. HESS, R., JR., W. P. KOELLA, and K. AKERT. 1953. Cortical and subcortical recordings in natural and artificially induced sleep on cats. Electrocnceph. Clin. Neurophysiol. 5 : 75-90. 19. HOSOKAWA, K., J. SAWADA, J. OHARA, and K. MATSUDA. 1968. Follow-up studies on the sleep EEG after prefrontal lobotomy. Folia Psychiat. Nezrrol. Jap. 22: 233-243. 20. ITIL, T. M., W. Hsu, J. M. C. HOLDEN, and P. GANNON. 1970. Digital computer sleep prints in lobotomized and nonlobotomized schizophrenics. BioZ. Psychiat. 2 : 141-152. 21. JOUVET, M. 1962. Recherches sur les structures nerveuses et les mCchanismes responsables des diffCrents phases du sommeil physiologique. Arch. Ital. Biol. 100 : 125-206. 22. JOUVET, M. 1974. Discussion, pp. 78-79. Of: Role of the thalamus in sleep control: Sleep-wakefulness studies in chronic diencephalic and athalamic cats. J. Villablanca. IIZ “Basic Sleep Mechanisms.” 0. Petre-Quadens and J. D. Schlag [Eds.]. Academic Press, New York and London. 23. Jus, A., K. Jus, A. VILLENEUVE, A. PIRES, R. LACHANCE, J. FORTIER, and .R. VILLENEUVE. 1973. Studies on dream recall in chronic schizophrenic patients after prefrontal lobotomy. Biol. Psychiat. 6: 275-293.

CAUDATE

OR

FRONTAL

ABLATIONS

AND

SLEEP

49

M. A, 1943. Effects on EEG of chronic lesions of basal ganglia, thalamus, and hypothalamus of monkeys. 1. Neztrophysiol. 6: 405-416. 25. KENNARD, M. A., and J. F. FULTON. 1942. Corticostriatal interrelations in monkey and chimpanzee. Res. Publ. Assoc. New. Melst. Dis. 21 : 228-245. 26. KIM, C., H. CHOI, C. C. KIM, J. K. KIM, M. S. KIM, H. J. PARK, and S. T. AHN. 1975. Effect of hippocampectomy on sleep patterns in cats. Electromcrph. 24. KENNARD,

Clir~. Ncwopkysiol. 38 : 235-243 27. KIRKBY, R. J. 1973. Caudate nucleus and Psychol. 85 : 82-96. 28. LANGWOKTAY, 0. R., and C. P. RICHTER.

29. 30. 31. 32. 33. 34. 35.

36. 37.

38. 39. 40. 41. 42.

arousal

in the rat. J. Cornp. Plqsiol.

1939. Increased spontaneous activity produced by frontal lobe lesions in cats. AUUY. J. Physiol. 126: 158-161. LAWICKA, W., and J. KONORSKI. 1961. The effects of prefrontal lobotomies on the delayed responses in cats. Acta Neurobiol. Exp. 21: 141-156. LINEBERRY, C. G., and J. SIEGEL. 1971. EEG synchronization, behavioral inhibition, and mesencephalic unit effects produced by stimulation of orbital cortex, basal forebrain and caudate nucleus. &airc RPS. 34: 143-161. LUCAS, E. A., and M. B. STERMAN. 1975. Effect of a forebrain lesion on the polycyclic sleep-wake cycle and sleep-wake patterns in the cat. Exp. Nrrtrol. 46(2) : 368-388. LYNCH, G. S. 1970. Separable forebrain system controlling different manifestations of spontaneous activity. J. Cowp. Physiul. Psychol. PO(l) : 48-59. LYNCH, G. S., P. BALLANTINE, II, and B. A. CAMPBELL. 1969. Potentiation of behavioral arousal after cortical damage and subsequent recovery. Exp. Newel. 23 : 195-206. MARCUS, R. J., and J. VILLABLANCA. 1974. Long-term sleep reduction in frontal cats. The Pltysiologist 17: 280. MAGOUN, H. W., and S. W. RANSON. 1938. The behavior of cats following bilateral removal of the rostra1 portion of the cerebral hemispheres. J. Neurophysiol. 1 : 39-44. MCGINTY, D. J., and M. B. STERMAN. 1968. Sleep suppression after basal forebrain lesions in the cat. Science 160: 1253-1255. METTLER, F. A., and C. C. METTLER. 1942. The effects of striatal injury. Brain 65 : 242-255. MORUZZI, G. 1971. The sleep-waking cycle. Ergebrc. Physiol. 64: l-165. PAOLA, D. J. M., M. PISANO, and G. F. COSSI. 1964. Effetti ipnogeni della stimolazione electrica della corteccua sensitivomotrice ne gatto. Boll. Sot. Ital. Biol. Spcr. 40: 833-835. PARMEGGIANI, P. L. 1962. Sleep behaviour elicited by electrical stimulation of cortical and subcortical structures in the cat. Helv. Physiol. Acta 20: 347-367. PARMEGGIANI, P. L. 1964. A study of central representation of sleep behavior. Prog. Braitz Res. 6: 180-190. PARMEGGIANI, P. L. 1968. Telencephalo-diencephalic aspects of sleep mechanisms. Braitz

Res.

7: 350-359.

.

43. PE~ALOZA-ROJAS, J. H., J. H. M. ELTERMAN, and N. OLMOS. 1964. Sleep induced by cortical stimulation. Exp. Neurol. 10: 140-147. 44. PRIBRAM, K. H., and D. MCGUINNESS. 1975. Arousal, activation, and effort in the control of attention. Psychol. Rev. 2 : 116-149. 45. RICHTER, C. P., and M. HINES. 1938. Increased spontaneous activity produced in monkeys by brain lesions. Bra&G 61: l-16. 46. RUCH, T. C., and H. A. SHENKIN. 1943. The relation of area 13 on orbital surface of frontal lobes to hyperactivity and hyperphagia in monkeys. I. NenropA3lsiol. 6 : 349-360.

50

VILLABLANCA,

MARCUS

AND

OLMSTEAD

P. N., K. K. TANGRI, and K. P. BHARGAVA. 1964. An experimental study of the synchronizing system in the brain. Electroencepla. Clin. Neurofhysiol. 17 : 506-512. 48. SIEGEL, J., and R. Y. WANG. 1974. Electroencephalographic, behavioral and singleunit effects produced by stimulation of forebrain inhibitory structures in cats. 47. SAXENA,

Et-p. 49. SNIDER,

50. 51.

52. 53.

54.

55.

56. 57.

58.

59.

60.

Neurol.

42:

28-50.

R. S., and W. T. NIEMER. 1961. “A Stereotaxic Atlas of the Cat Brain.” University of Chicago Press, Chicago. STERMAN, M. B., T. KNAUSS, D. LEHMANN, and C. D. CLEMENTE. 1965. Circadian sleep and waking patterns in laboratory cat. Electroenceph. C&n. Nenrophysiol. 19 : 509-517. SVORAD, D., and W. B. WEBB. 1971. The effect of caudate nucleus lesions on natural sleep in the rat, pp. 82-87. In “The Association for the Psychophysiological Study of Sleep.” First International Congress. Bruges, Belgium. URSIN, R. 1968. The two stages of slow wave sleep in the cat and their relation to REM sleep. Brain. Res. 11: 347-356. VILLABLANCA, J., and R. MARCUS. 1972. Sleep-wakefulness, EEG and behavioral studies of chronic cats without neocortex and striatum: The ‘diencephalic cat.’ Arch. Ital. Biol. 110: 348-382. VILLABLANCA, J., and M. E. SALINAS-ZEBALLOS. 1972. Sleep-wakefulness, EEG and behavioral studies in chronic cats without the thalamus: The ‘Athalamic’ cat. Arch. Ital. Biol. 110: 383-411. VILLABLANCA, J. 1974. The role of the thalamus on sleep control: Sleep-wakefulness studies in chronic ‘Diencephalic’ and ‘Athalamic’ cats, pp. 51-81, In “Basic Sleep Mechanisms.” 0. Petre-Quadens and J. Schlag [Eds.]. Academic Press, London. VILLABLANCA, J., and R. J. MARCUS. 1974. Long-term sleep-wakefulness effects of caudate nucleus ablation in cats. Sleep Res. 3: 36. VILLABLANCA, J., and R. J. MARCUS. 1975. Effects of caudate nuclei removal in cats. Comparison with effects of frontal cortex ablation, pp. 273-311. In Brairz Mechanisms in Melztal Retardation. N. A. Buchwald and M. A. B. Brazier [Eds.]. Academic Press, New York. VILLABLANCA, J. R., R. J. MARCUS, and CH. E. OLMSTEAD. 1976. Effects of caudate nuclei or frontal cortical ablations in cats. I. Neurology and gross behavior. Exp. Neural. 52: 389-420. WHEATLEY, M. D. 1974. The hypothalamus and affective behavior in cats. Arch. Newel. Psychiat. (Chicago) 52 : 296-316. WHITTIER, J. R., and A. ORR. 1962. Hyperkinesia and other physiologic effects of caudate deficit in the adult albino rat. Neurology 12: 529-539.