Nocturnal sleep of narcoleptics

Nocturnal sleep of narcoleptics

ELECTROENCEPHALOGRAPHYAND CLINICALNEUROPHYSIOLOGY NOCTURNAL 599 SLEEP OF NARCOLEPTICS t ALLAN RECHTSCHAFFEN,PH.D., EDWARD A. WOLPERT, M.D., PH.D.S...

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ELECTROENCEPHALOGRAPHYAND CLINICALNEUROPHYSIOLOGY

NOCTURNAL

599

SLEEP OF NARCOLEPTICS t

ALLAN RECHTSCHAFFEN,PH.D., EDWARD A. WOLPERT, M.D., PH.D.S, WILLIAM C. DEMENT, M.D., PH.D. s, STEPHAN A. MITCHELL, M.D. AND CHARLES FISHER,M.D., PH.D. Departments of Psyeldatry and Psychology, The University of Chicago, Ill. (U.S.A.) and Departments of Psychiatry and Neurology, Mount Sinai Hospital, New York, N.Y. (U.S.A.)

(Received for publication: October 4, !962) (Resubmitted: January 2, 1963)

INTRODUCTION Dement and Kleitman (1957a) described th= cycles of EEG activity which can be expected in the course of a typicmlnight of sleep in normal subjects. Against this background of increased sophistication about normal sl=ep, we have compar~)d the characteristics of nocturnal sleep in narcolepties with those of normals, Dement and Kleitman divided EEG patterns during normal sleep into four stages: (1) a low voltage, irregular, relatively fast pattern conraining slow components in the 4-6 c/see range; (2) 12-14 c/see sleep spindles against a low voltage background; (3) a moderate amount of large (over 100 pV) slow wave activity intermixed with sl~p spindles: (4)at least half of the record composed of large slow waves. At approximately 90 rain intervals during the night, stage I periods appear in conjunction with rapid eye movement& These periods have come to be known as ItEM (rapid eye movement) periods, The rapid eye movements do not appear during stages 2, 3, or 4, which have come to be known as NItEM (no rapid eye movement) periods, Aserinsky and Kleitman (1953) found that subjests are more likely to report that they have been dreaming if they are awakened from REM periods than if they are awakened from NREM periods. This reset has been subsequently ohrained by several investigators (Dement 1955; Dement and Kleitman 1957b; Wolpert and t This rmear~ was supported by grants M-4151and MY-3267from the National Instituteof Mental Health, U.S. Public Health Service. s Now at l~yc,hmonmti¢ end Psychiatric Institute, Midlael Reeu Hmpital, Gl~i~go, IlL ' Now at Department of Psychiatry, Stanford Unicertify, Stanford, Calif.

Trosman 1958; Goodenough etal. 1959; Jouvet el al. 1960; Kamiya 1961; Foulkes 1962; Rechtschaffenetal., in press). I , normal ~ubjects, sleep commences with a few minutes (typically less than 5 min) of "descending" stage ! (without rapid eye movetaunts) and progresses to a cyclic alternation of NREM and REM periods. The first REM _period of a night of sleep normally does not occur until after about 90 rain of sleep. A prominent feature of narcoleptic EEG records obtained during the day is the episodic appearance of extended stage 1 periods (Pond 1952; Daly and Yoss 1957; Fischgold 1957; Gastaut and Roth 1957; Birchfield el al. 1958; Ganado 1958; Roth 1961; Well 1962). WhilG these stage ! periods ha~, generally been int~rpreted as manifestations of drowsiness or states of lowered vigilance, their behavioral significanoe is not well understood. Sometimes the stage ! periods occur in conjunction with narcoleptic sleep attacks, while at other times the narcoleptics appear behaviorally alert during the stage I p~riods (Gastaut and Roth 1957; Ganado 1958; goth 1961). in their early work on EEG recordings during extended daytime and nocturnal sleep pcHods of narcoleptics, Blake et al. (1939) and Dynes and Finley (1941) reported no sisni~c,ant deviations from normal patterns. However, re-examination of the Dynes and Finley data reveals that several of their patients showed much longer stage 1 sleep onset perle as than is generally observed in normals. Vogel (1960), in discussing t~-~ dream i eports of one of the subjects in our series, noted the early appearance of a REM period in the sleep record anti specuL lated that "the narcoleptic patient makes use Eiectroenceph. olin, NeurophysloL, 1963, 15:599-609

600

A. RECHTSCHAFFENet

aL

of his sleep for the projection of fantasy which is gratified in a dream in a way unacceptable during waking life",

by at least 4 sec of EEG record containing no trace of muscle tension artifact were counted as separate body movements; (e) periods of muscle tension and amplifier blocking as described summers AND mrrHoDs above which occurred at the junction of sleep Nine narcoleptics, six men and three women, and wakefulness, i.e., a sleeping EEG pattern slept in the laboratory for one to t~ee nights before and a waking EEG pattern following the each for a :ota" of eighteen nights. Six of the muscle tension sigr;s, were counted as body narcoleptics had a history of cataplexy and five movements occurring during sleep. had a history of sleep paralysis with hypnagogic hallucinations in addition to sleep attacks. The RESULTS clinical history of the one subject who showed Since the normal subjects slept in the laboraonly sleep attacks was carefully examined to rule tory for one night each, only the first night of out hypersomnia and other disorders. All but sleep in the laboratory for each of the narcoone of the narcoleptics consented to take no lepti:s was used in quantitative comparisons medication for approximately 48 h prior to with the normals. The narcoleptics averaged sleeping in the laboratory. 6 h, 16.6 min of sleep in their first night in the Nine normal comparison subjects, selected laboratory, and the normals averaged 6 h, 51 for maximum comparability to the narcoleptics rain of sleep. Differences in amount of sleep in age, slept in the laboratory for one night in the laboratory were determiner, by practical each. The mean age of the narcoleptics was considerations as well as by individual differ38.7 years, with a rantle of 26--53 years. The mean ences in sleep habits. age of the normals was 37.9 years, with a range of 26-60 years. I. The occurrence of R E M periods at sieep onset The procedures for monitoring E~Gs and The most striking result of this study was eye movements continuously through the night tile fact that the narcoleptics tended to have have been described by Dement and Kleitman REM periods at sleep onset instead of first (1957a). In the present study, a minimum ofthree showing them at approximately 90 rain after cbannel~ of information per subject was gathered, ~leeponset as is characteristic of normal~. TI~¢ one for eye movements and two for EEG. Most REM periods which began at sleep onset in frequently, two eye movement and two or more the nareoleptics were indistinguishable by inEEG channels were recorded, and on occasion, s~¢tion from the REM periods w~s~h normals as many as eight channels of information on a have later in the night. The EEG during these eubject were recorded. The most frequently periods was a low voltage, irregular, relatively utifized electrode placements were prefrontal, fast pattern containing low voltage slow cornvertex, occipital, and outer canthi leads. Both ponents in the 4-6 c/see range; binocularly bipolar and ear reference EEG recordings were synchronous rapid eye movements of varying made. In general, the number, type, and place, magnitudeappearedatirregularintervalsthrough. ment of leads did not affect the results that were out the period. The transition from wakefulness obtained, to a sleep onset REM period in a narco.leptie Body movements were scored when all of the is illustrated in Fig. 1. following criteria were met: (a) fast muscle Seven of the nine nareolepties showed sleep potential of at least 30 ~,V had to be present on onset REM periods; in one of these subjects a at least half the number of EEG and eye move. sleep onset REM period followed a prolonged merit tracinge of the subject being recorded at interval of wakefulness after a short initial the time; (b) the burst of muscle potential had period of sleep earlier in the night. Of the seven to be at least 4 see in duration; (c) amplifier narcoleptics who showed sleep onset REM bloc~ng of I sec duration or longer on at least periods, two slept in the laboratory for three one of the channels was required; (d) periods nights each and showed sleep onset REM pcof muscle tension artifact which were s~parated riods on all three nights, one slept in the iaboraElcetroem'el~. c/in. Newol~ysiol., 1963, I$: 599-609

NOCTURNAL SLEEP OF NARCOLEPTICS

J~aVAKE

DESCENDING STAGE I

601

REM PE

O

Fpl ~2

C$ ,M~

OI

INc

A2

I

,

TIME 2 4 . 2 3

T~ME 2 4 , 2 6

TIME 2 4 , 2 5

Fig. ! Progressive stages in the development of a sleep onset REM period in a narcoleptic. The record progressed from wakefulness at 0 : 23 to a characteristic descending stage I with sleep transients on the central lead 2 min later. However, instead of a normal pattern of progression from descending stage I to sleep spindles and large slow waves, I min later there was a REM period with typical low voltage random EEG and rapid eye movements. (The frontal tracing was recorded with a 0.1 sec time constant; the other tracin~ were recorded with a 0.3 sec time constant.)

TABLE i Symptoms of narcoleptic subjects and comparison of nocturnal sleep patterns of narcoleptics and normals on first nipht in laboratory

Narrolepsy case number

Sex ABe

46 53 28 26 42 44

Sleep p a ralysis and hallucinosis

Duration (min) of sleep on~t REM I~riods Nt I Nt 2 Nt 3

~t,~ 0 t. . . . + 0 0 + 0 -{-

+ + t~ 0 + 0 0 + ~-

6,0 12.0 22.5 0.0 19.0 0.0 33,0 7.0 10.5

Cata plexy

................................................................

10.0 17.0 ~ --, 13.0 15.5 0.0 0.0 . . . . 0.0 0.0 . . . . --0.0 ~

% REM time on Ist night (incl. sleep onset REMP) 13.8 19.4 19.4 15.6 21.5 14.8 16.9 21.9 25.9

Body 9-11/see me ~rn~nt~ activity in per h on anterior Ist night leads 15,0 I 1.0 9.0 8.7 7.5 I 1.0 5.7 6,0 11.5

I 2 3 4 5 6 7 8 9

~ ~ ~ ~ c~ ~ ~ ~ ~

Summary of narcoleptics

6 .~ ,Y = 3 ~ 38.7

5~t-

6+

,~ = 12.2 S.D. = 10.3

,~ = 18.8 S.D. = 3.7

,Y =~ 9.5 7> N S.D. ~2.9 2 N

7< N 2N

Summary of normals

6 ~' ,~ = 3 .~ 37.9

--

--

X = 0.0 S.D. =: 0.0

X = 18.0 S.D. == 4.5

X = 5.3 I> N S.D. = 1.8 8 N

2< N 7N

Significance level: narcoleptics vs. normals

Not sill.*

<0.01'

Not sig.*

<0.02*

<0.10"*

43 45 31

> N :=, N ~, N N N > N >N > N > N

Large slo~~ wave activity

<0.02*"

< N < N < N N < N < N < N < N N

-t- : Symptom present; 0: Symptom absent; > N: More than normal; N: Normal; < N: Less than normal; *: Evaluated by Mann-Whitney U Test; **: Evaluated by Fisher Exact Probability Test.

Eiectroenceph. e/in. Neu~'~ohysioL, 1963, 13:599-609

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A. RECHTSCHAFFENet al.

tory for two nights and had a sleep onset REM period only on the first night, and the four remaining subjects who showed sleep on~t REM periods slept in the laboratory for one night each. Thus, sleep onset ItEM periods were seen on eleven of the twelve nights that these seven subjects spent in the laboratory. The two narcoieptics who did not show sleep onset REM periods failed to do so on all three nights they each slept in the laboratory. The distribution and lengths of sleep onset REM periods in the narcoleptics is summarized in Table 1. Of the eleven recorded sleep onset REM periods, seven occurred immediately at sleep onset. In the other four instances, "descending" stage I with sleep transi-.nts (V waves) but no rapid eye movements preceded the REM pc. tied by from 0.5-7 rain; in two of these four instances, there was an additional 4 rain of stage 2 prior to the sleep onset REM periods. The mean length of the sleep onset REM periods, averaged across subjects, was 15.6 min. The lengths ranged from 6-33 rain. Three of the Nven nareoleptics who showed sleep onset REM periods also displayed during these pc. riods the "saw-toothed" waves which Berger e~ aL (i962), Jouvet et ai. (1900) and Schwartz (1962) have described as characteristic of the REM periods of some subjects, In addition to the above data, one of the nine nareolep~ics was studied during an aftern c ~ e nap which he voluntarily took in the labo. ratory, and he showed a gEM period at the onset of this nap. He was awakened from this REM period by the experimenter who wanted to inter¢iew him about dream activity. Follow. ing the interview, the subject returned to sleep and once again showed a gEM period at sleep onsetx. t Two additional narcolepti~s were studied who~e

None of the nine normal comparison subjects had sleep onset REM periods. The difference in occurrence of sleep onset REM periods between the nine narcoleptics and the nine norrnals is significant beyond the 0.01 level as evaluated by the Fisher Exact Probability Test. (All significance levels reported in this paper are for two-tailed tests.) The normals showed the typical sleep onset pattern of about 2-5 min of "descending" stage 1 without rapid eye movements. In the two instances in which narcoleptic subjects awakened spontaneously from sleep onset REM periods at the beginning of the night, and in the two instances in which a subject was awakened by the experimenter from sleep onset periods at the beginning of an afternoon nap, the subjects said they had been dreaming and were able to give reports of dreams. These reports were distinguishable from reports following episodes of sleep paralysis with hypnagogic hallucinations. After awakening from sleep onset REM periods, the subjects unambiguously reported that they had been asleep and dreaming. No subject reported on the REM awakenings that he had felt paralyzed. II. The sleep cycle and amount of R£M time Apart from the sleep onset gEM periods, the narcolcptics did not differ from the nine normal comparison subjects or from other normals we have studied in our laboratories with regard to the major cyclical variations of sleep stages during the night. There was a more or less regular alternation of NREM and REM periods. Each complete cycle of a NREM and REM period lasted approximately 90 rain, with REM periods o~upyin8 greater amounts of cycle time as the night progressed. The narcoleptics did not differ significantly from the normal comparison subjects in proper. tion of sleep time spent in REM periods (time spent in REM periods divided by total sleep time) on the first night in the laboratory. Mean

results were not included with those of the nine subjects in the narcoleptic lroup. The first of these two subjects was studied for two nillhts at Atkinson-MorleyHc~qpital London, by one of the authors (S.M.); the results for this subje~ were not included because complete records percentage gEM time was 18.8 per cent for the oi' his nocturnal sleep EEG could not be obtained. This nine narcoleptics (including sleep onset REM subject showed sleep onset REM periods on both nights, periods) and 18.0 per cent for the normals. second subject was a nisht shift worker who slept Calculations to determine whether the sleep

in the laboratory i()r a few hours on eachof two morninss f o l ~ s a nijht of work. This subject showed a sleep onset R E M periods added to an otherwise cram ItEM ixgind on the smond morning in the labore, normal percentage I t E M time or whether they

tory.

served to complement an otherwise sub-normal Eleetroeneeph. olin. Neurophvsiol., 1 ~

13:599-609

NOCTURNAL SLEEP OF NARCOLEPTICS

percentage REM time indicated that the total amount of sleep onset REM time was not great enough to cause a statistically significant differenee in one direction or the other. The first night percentage REM time of the seven narcoleptics who showed sleep onset REM periods was 19.8 per cent when the sleep onset REM periods were included and 15.4 per cent when

603

movements per h of sleep was 5.3 (S.D. 1.8) for the normals. The difference in number of body movements between the two groups was significant at the 0.02 level by the Mann-Whitney U test. Only three of the nine narcoleptics had body movement rates lower than the normal comparison subject who had the greatest number of body movements.

Fig. 2

Monopolar recording from a narcoleptic during a large slow wave sta~ of sleep. Promi~nt .tO/s~ sinusoida! a~:tivityis intermixed with large slow waves on the frontal and central tracings. Unlike alpha activity,this IO/secactivity is relativelyabsent on the occipitaltracing. The 14/seesleepspindles at the end of the recording appear prominently on the central and occipital tracings but not on the frontal tracing. The activity on the eye movement tracing represents EEG activity recorded in the vicinity of the outer canthi rather than eye movements. these were excluded from both sleep and REM time. Neither of these percentage REM times was significantly different from the 18.0 per cent REM time of the normal comparison group, as evaluated by the Mann-Whitney U test. III. Amount of body movement A statistical comparison of narcoleptics and normals with respect to number of body movements per h of sleep was carried out for first night data only. Inspection of number of body movements on second and third nights for the five narcoleptics who spent more than one night in the laboratory indicated that the number of body movements per h cf sleep w ~ relatively similar across nights for those subjects, The narcoleptics had more body movements during sleep than normals. Mean number of body movements per h of sleep was 9.5 (S.D. 2.9) for the narcoleptics. Mean number of body

IV. EF,G manifestations All the observations of EEG wave forms cited in this section were based upon an impressionistic evaluation of the records. More definitive conclusions require further investigation utilizing frequency analyzers and integrators to insure reliability of the data and provide more refined quantification. Seven of the nine narooleptics showed large amounts of 9-11 c/see sinusoidal waves during sleep, especially during the relati,~ely short periods when large slow waves were also prominent in the narcoleptic records (Fig. 2). These were not alpha waves, because they appealed more often and with greater amplitude in "monopolar" anterior leads (frontal and vertex) than in "monopolar" occipital leads; these waves may be related to the 10/sec frontal activity described by Gibbs and Gibbs (1941). Only one of the nine normal comparison subElectroenceph. olin. Neurophysiol., 1963, 15:599.-609

604

b,. RECHTSCHAFFENel

jeers showed similarly large amounts of 9-11 c/sec activity. The difference in the number of subjects in the two groups who displayed prominent 9-11 c/see activity was significant at the 0.02 level as evaluated by the Fisher Exact Probability Test. The distributimt oi" the 9-i~ +/see activity in the total EEG pattern appeared to be erratic. At times there were continuous trains of the 9-11 c/sec activity of a few seconds duration which interrupted the slow wave background activity. At times the ~-11 c/see activity occurred within seconds of 12-14 c/see sleep spindles; the occurrence of one type ofactivitydidnotappear to preclude the other. Most frequently the 9-11 c/see activity was diffusely distributed among the background slow waves, The secondmostprominentdistinctive feature of the narcoleptic EEG records was the paucity of large slow wave activity. Seven of the narcoleptics and only two of the normal comparison subjects showed a paucity of large slow wave activity; however the difference between the two groups was significant at only the 0.i0 Ivvei of confidence as evaluated by the Fisher Exact Probability Test. Therefore, the data on amount of large slow wave activity should be considered only as a trend subject to further 0valuation. Two other trends which did not attain statistical signilicance in differentiating the narcolep, tics and normals, but which might profitably be examined in future studies are the following: (I) In the sleep records of five of the narcoleptics, spontaneous K complexes were almost absent or were very poorly formed; only one of the normals showed a comparable deficiency in K complex activity. (2) Two of the natcoleptics showed a scarcity of 12~14 c/see sleep spindles. None of the normal comparison sub. jects showed a deficiency in sleep spindle activity, Two of the nine narcoleptic subjects had attacks of sleep paralysis with hypnagogic hallucinations in the laboratory prior to falling asleep. One subject showed a fast, low voltage, desynchronized, waking EEG pattern during her attack. The other subject showed a stage I pattern during his two episodes, but with the sporadic occurrence of rapid eye movements in only one fragment of one episode, An examination of the EEG patterns of the

al.

narcoleptics during the periods of wakefulness which preceded, interrupted, or followed sleep showed no prominent pattern of deviation from normal records. This finding is in agreement with the results of previous investigations (Blake et al. 1939; Dynes and Finley 1941; Pond 1952; Dalyand Yoss 1957; Fischgold 1957). D~SCUSS~ON The results clearly show that narcoleptics have a special susceptibility to the occurrence of REM periods at the beginning of nocturnal sleep. Dynes and Finley (1941) were probably observing the same phenomenon when they recorded especially long stage I periods at sleep onset in narcoleptics. However, without the simultaneous measurement of eye movements and without the current knowledge of EEG cycles during sleep, they had no way of appreelating the significance of these periods. The occurrence of sleep onset REM periods at the beginning of the night seems so distinctive of narcoleptics that its occurrence may be a diagnestle aid in doubtful cases, in addition to the fact that we did not observe a sleep onset REM period in any of the nine normal comparison subjects of this study is the fact that, in our combined laboratory experience of monitorlng nocturnal EEG records of several hundred presumably normal subjects, we have never observed a sleep onset REM period at the beginning of the night. REM periods occasionally occur at "sleep onset" in normals following very brief awakenings later in the night, but not following prolonged awakenings, in addition, we have not observed sleep onset REM periods at the beginning ofthe night in a wide variety of pathological conditions, including: psychoneurosis, strokes, peptic ulcer, cancer, multiple sclerosis, and a wide variety of less serious disorders such as the common cold. There is only one instance recorded in our laboratories of a REM period occurring in a normal subject at initial sleep onset following prolonged wakefulness. Of 23 subjects who slept in the laboratory for daytime naps (March and Wolpert, unpublished data), one showed a REM period at the onset of the nap. We do not know enough about this subject to know whether he had any tendency toward narcolepsy. The only Electroencepk. clin. Neuropkysiol., 1963, 15: 599-609

NOCTURNAL SLEEP OF NARCOLEPTICS

other possible instance of an initial sleep onset REM peliod we know of, occurred inan acute, hallucinating schizophrenic (Fisher and Dement, in press). In this instance, however, the resemblance of the EEG pattern to typical stage 1 patterns was questionable. The occurrence of REM periods at the onset of nocturnal sleep in narcoleptics provides a basis for a possible reappraisal of the significance ofthe typical EEG pattern during daytime narcoieptic attacks. Many investigators have noted the frequent appearance of stage I periods in EEG recordings of narcoleptics during the day. These stage 1 periods have most frequently been interpreted as representing drowsiness, largely on the basis of their resemblance to the drowsy "descending" stage I patterns usually seen at sleep onset in normals. However, stage I patterns may have different behavioral, and presumably physiological, correlates at different times. For example, Dement and Kleitman (1957a) demonstrated that auditory thresholds are much lower duriag deaceading stage I periods thaa during stage I associated with lapid eye movements, and that subjects aroused from descending stage I periods tend to report having had hypnagogic-like experiences in contrast to the organized dreams they report on REM period awakenings. Thus, there seem to be at least two different behavioral states associated with stage I periods. Four considerations prompt us to postulate that the daytime stage I periods of narcoleptics may be, at least in part, more closely related to gEM periods than to the descending stage I periods of norreals: (I) The results of the present study demonstrate that narcoleptics are susceptible to precocious triggering of REM periods at night; this susceptibility may exist throughout the day. (Recall that in normals, REM periods do not occur except following extended periods of prior NREM sleep.) (2) The observation of Daniels (1934) that narcoleptic sleep attacks are at times accompanied by dream phenomena is suggestive of REM period activity during the attacks. (3) The duration of the daytime stage I periods of narcoleptics approximates the duration of REM periods more closely than it approximates the duration of descending stage ! periods at sleep onset in normals. Daly and ¥oss

605

(1957) reported that the narcoleptic stage 1 patterns were protracted for periods up to 30 min or more, and that for many narcoleptics 5 or 10 rain in stage 1 were sufficient to relieve the impulse to sleep. Dement and Kleitman (1957a~ reported that REM period durations in normals range from an average of 9 min early in the night to 34 min late in the night. Descending stage 1 patterns in normals rarely last more than a few minutes. (4) The observations that daytime stage 1 patterns in narcoleptics rarely progress to NREM sleep (Daly and Yoss 1957) is congruent with the hypothesis of a precociously triggered REM period which is relatively independent of a more general need for sleep. To date, we have only two pieces of direct data indicating that the narcoleptic attack itself may resemble or be a variant of REM periods. One narcoleptic, the night shift worker mentioned earlier, had a history of invariably falling asleep within a few minutes of starting to read. We asked this subject to read from a magazine while his EEG was recorded and his behavior observed. After I rain of reading, the magazine slowly dropped to his chest and behaviorally he seemed to be dozing or asleep for I rain, at the end of which he aroused spontaneously. As the subject passed from alertness to the sleeplike state, the EEG changed from a low voltage fast, waking pattern to a mixed, low voltage pattern which contained bursts of 12 c/see spindles, some 3-6 c/se¢ activity, 15ml8c/see spindles, and traces of 9 c/see alpha activity against a desynchronized, moderately fast background. The E EG record during the behavioral loss of contact could not be described as typical of either wakefulness, sleep, dozing, or REM periods. However, it was very clear that rapid eye movements, not of the type associated with reading, were abundant during this period. After he was aroused, the subject said he had blacked out while reading and could not remember anything of the period. On one occasion we observed a routine EEG examination of another narcoleptic patient. During those portions of the examination when the patient appeared to be behaviorally asleep, the EEG pattern was stage I. No electrodes were placed near the outer canthi to record eye movements. However, rapid Electroenceph. clin. Neurophysiol., 1963, 15:599-699

606

A. RECHTSCHAFFENel aL

eye movement activity was reflected on the prefrontaltracing, andbydirectobservationwecould see his eyes moving rapidly under his closed lids. It is possible that both descending and REM period stage I patterns are included in narcoleptic attacks, with short, initial, descending stage I periods progressing to more extended REM periods. This could explain the fact, cited in the introduction, that narcoleptics seem close to wakefulness during some stage 1 attacks and behaviorally asleep during others, These speculations lead to specific research suggestions. The narcoleptic "attacks" of stage I during the day should be re-examined to evaluate the extent to which they resemble REM periods a~ compared with other stages of sleep, Naturally the focus of attention should be on variables which distinguish REM periods from other sleep stages, e.g., rapid eye movements, reports of having been dreaming, diminution of background muscle tonus (Jouvet 1960; Berger 1961), increase in discrete bursts of muscle potential from the limbs (Wolpert 1960), increase in respiratory and heart rates (Aserinsky and Kieitman 1953). There is also reason to suspect that other aspects of narcoleptic pathology, apart from the sleep attacks, are related to REM periods, Cataplexy, for example, may parallel the profound loss of muscle tone observed during REM periods in cats by Jouvet (1960) and in humans by Berger (1961). Oillespi (cited by Daniels 1934) reported the occurrence of dream experiences during some cataplecti¢ attacks, With rejard to sleep paralysis with sleep haliucinosis, we can only speculate that some features of REM period a~tivity, i.e., loss of voluntary motor control and visual hallucinations, occur in narcoleptics even while they are, in some sense, still awake. Thus, in the narcoleptic symptoms of cataplexy and sleep paralysis with hypnagogic hallucinations we may be witnessing some or all of the attribates of REM periods during the waking state, Although the normal circumstances for the occurrence of REM ~riods m~y ~ a pr~,~dlng period of N ~ M sleep, in narcoleptics the propensity for their on~t may be so great that REM periods occur not only at the initiation of sleep but during wakefulness itself,

Although narcoleptics show a propensity for precocious triggering of REM periods, it is doubtful that narcolepsy is simply a condition of excessive need to spend large amounts of time in REM periods, because the nocturnal sleep records of narcoleptics do not resemble those of normal subjects recovering f, om experimentally induced REM period deprivation. Subjects who have been deprived of REM pcriods but not other stages of sleep show above normal percentage REM times on recovery nights (Dement 1960). it could be argued that if the daytime sleep attacks of narcoleptics are REM periods (this possibility has been discussed more fully above), then considering the entire 24 h day, narcoleptics might prove to have supranormal percentage REM times. However, if this were the case, narcoleptics would still differ from subjects recovering from REM period deprivation. The REM period deprived subjects occasionally show sleep onset REM periods, but these occur only following awakenings later in the night and have never been observed to occur at the beginning of the night in these subjects. An additional note of interest regarding the relatedness of narcoleptic pathology and REM periods is the fact that dexedrine, a drug used in the treatment of narcolepsy, had been found by Maron and Rechtschaffen (unpublished study} to inhibit the appearance of REM periods, even when it does not interfere with the other stages of sleep, One possible source of artifact in our results which deservescarefulconsiderationistbepotentiai contribution of amphetamine withdrawal to the appearance of sleep onset REM periods. Oswald and Thacore (in press) found that amphetamine addicts tend to have normal percentage REM times while on the drug. Upon withdrawal of the drug, however, percentage REM time increased dramatically, and there was a reduction in delay time (amount of NREM time prior to the first REM period). Becausethe narcoleptics in the present study who were taking amphetamines were asked to stop taking drugs 48 h prior to sleeping in the laboratory, the possibility is raised that the sleep onset REM periods of the narcoleptics resulted from amphetamine withdrawal. Several considerations E.lectroes~'eph. clin. Neueophy$iol,, I ~

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NOCTURNAL SLEEP OF NARCOLEPTICS

render this possibility extremely unlikely: (1) Three of the narcoleptics who showed sleep onset REM periods had taken only small doses of amphetamine for short periods of time and had discontinued the medication either because it was not helpful or because of the side effect of agitation. According to the best available records, these three subjects had not received amphetamines for about a month or longer prior to sleeping in the laboratory. A fourth subject was hospitalized and received dexedrine for the first time while in the hospital. The medication was given for only three days and then discontinued for six days prior to the first of his three nights in the laboratory, in the above four subjects, the amount of amphetamine taken seems too small and the time between drug withdrawal and sleeping in the laboratory seems too long to have produced shortening of delay times approximating sleep onset REM periods, in an unpublished study by Maron and Rechtschaffen, the shortest delay time recorded on three normal subjects who were withdrawn from dexedrine after three or four days on the drug was 48 min. Another narcoleptic who showed sleep onset REM periods had only minimal drug withdrawal by virtue of the fact that he consented only to eliminating his evening dose of the drug, and he maintained his regular dosage until 3 p.m. on days of recordings. (2) The early appearance of REM periods was much more pronouced in the narcoleptics than in the addicts subjected to drug withdrawal. There was almost no o,lerlap in the two distributions of delay time. The minimum delay time of the addicts following withdrc',~,al was 4 min. In most of the sleep onset REM periods of the narcoleptics, delay time was zero, and the maximum delay time of a narcoleptic sleep onset REM period was 4 min. (3) All of the addicts showed a phenomenon upon drug withdrawal whicn was not seen in any of the narcoleptics, Following drug withdrawal, the addicts showed markedly elevated percentage REM times which frequently approximated twice normal values, All of the narcoleptics showed percentage REM times within or slightly below the normal range, This difference in the two groups suggests that their deviations from normal patterns are based upon different mechanisms,

607

What can the occurrence of REM periods at sleep onset in narcoleptics tell us about the neuropathological mechanisms of narcolepsy? Working with cats, Jouvet (1960) has shown that experimental lesions in the pontine reticular formation result in the elimination of REM periods, and stimulation of the intact pontine reticular formation triggers the occurrence of REM periods. If we may extrapolate from the animal experimentation, we can postulate that REM periods in humans result from a triggering of the pontine reticular formation which, in normals, occurs with cyclic regularity but, with rare exception, only following extended periods of other stages of sleep. According to this view, narcoleptics would suffer from precocious triggering of the pontine reticular fo~ation, i.e., the triggering could take place immediately or shortly following periods of wakefulness. The emphasis is on triggering rather than on duration, because narcoleptics do not seem to show more REM time during the night than normals, and because the duration of the sleep onset REM periods of narcoleptics approximates the duration of REM periods during the first half of the night in the sleep of normals. The view that narcoleptic symptoms are mediated by precocious triggering of the pontine reticular system is consistent with the "inhibitory" effects described by Demetrescu and Demetrescu (1962) which result from stimulation of the ventral pontine reticular system. Why should narcoleptics show precocious triggering of the pontine reticular formation? Any attempt to answer this question is necessarily speculative, because we do not know enough about the mechanism which regulates the triggering in normals to know in what way this mechanism might be impaired in nar¢oleptics. Although the pontine reticular formation is implicated as a mediating structure for REM periods because Jouvet has shown it to be necessary for that stage of sleep, th© original site of anatomical disturbance which produces sleep onset REM periods in narcoleptics need not be the pontine reticular formation itself. For example, Karmos and Grastyan (1960) have shown that stimulation of the mesencephalic reticular formatioJ~ during NREM sleep can initiate REM periods and that stimulation of the Eleetroenceph. e/in. Neurophysiol., 1963, 15:599-609

A. RECHTSCHAFFENel aL hippocampus can interrupt REM periods. There= fore, although the pontine reticular formation may be a necessary mediator of REM periods, activity in other anatomical centers may contribute to their control, and the anatomical site of pathology which produces precocious trig= gering in narcoleptics could be in these other centers. There is also a possibility that the source of pathology could be biochemical rather than neuroanatomical. For example, Ruth (1957) found that a high proportion of narcoleptics tend to have low 17-ketosteroid levels, and Di Raimondo and Forsham (1956)have summafized the evidence which indicates that diurnal steroid levels in normals are at their lowest during the first few hours of the night. Because normals usually accumulate all their REM time after the first hour of sleep, it is possible that low steroid levels are in some way associated with the initiation of REM periods, and that the

early appearance of REM periods in narcoleptics

could be associated with their lower steroid levels, Apart from the propensity for sleep onset REM periods, not much can be said about the other nocturnal sleep manifestations in which narcoleptics tend to differ from normals, i.e., number of body movements, presence of 9-11 C/See activity in anterior leads, and possibly a paucity of large slow wave actt• 0Vt~tty, because the functional significance and physiological basis of these manifestations are not well understood. It is a temptation to regard the paucity of large slow wave act v'tty as a sign that narcoleptics do not sleep very deeply, because large slow ac . . . . . wave ,ttvtty has traditionally become mdentiffed with deep sleep. However, although large slow wave activity represents deep sleep in that auditory waking thresholds are generally high during the early part of the night when this activity is most prominent (Blake and Gerard 1937), other measures such as heart rate and basal skin resistance may indicate relatively light sleep at those times (Kleitman 1939; Kamiya 1961). Heightened body movement activity in narcoleptics may be a more direct indi~fion that the restfulness of nocturnal sleep in narcoleptics is impaired. SUMMARY The EEG patterns and eye movements of

nine narcoleptics during nocturnal sleep were compared with those of normals. Seven of the nine narcoleptics showed a distinctive phenomenon which is virtually unknown in other pathological conditions or in normals. The narcoleptics had stage I rapid eye movement (REM) periods at sleep onset rather than approximately 90 mix after sleep onset as most subjects do. This was interpreted as suggesting that narcoieptics are susceptible to "precocious triggering" of the pontiac reticular formation. Other manifestations of narcoleptic sleep which distinguished it from that of normals were" (I) a superabundance of body movements; (2) the presence of 9-11 c/see activity in anterior EEG leads; (3) a tendency to have less than a normal amount of large slow wave activity. REFERENCES ASeRtNSXV,E. and KL~STMAN,N. Regularly occurring

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