Internal Structure of Sleep Cycles in a Healthy Population

Transcription

1 Sleep 9(4): , Raven Press, New York 1986, Association of Professional Sleep Societies Internal Structure of Sleep Cycles in a Healthy Population H. Merica and J.-M. Gaillard Institutions Universitaires Psychiatriques de Geneve, Clinique de Bel-Air, Geneva, Switzerland Summary: A large body of data has been gathered on the sleep characteristics of normal subjects. The evolution of each sleep stage within each NREMI REM cycle is presented in detail, showing stage intensities minute by minute. There is a three-phase pattern in each stage intensity diagram: an initial phase of rapid change; a central phase of relative stability; and a terminating phase, again, of rapid change. The details of this pattern change progressively during the night. Throughout all cycles, there is a complementary relationship between the intensities of stage 2 sleep and the other stages that underlines the central role of stage 2 sleep in all stage transitions. Stage intensity diagrams for two groups, one group with and one group without stage 4 sleep, were compared. Subjects without stage 4 sleep tended to have a shorter duration and greater latency of stage 3 sleep. Surprisingly, cycles interrupted by abnormally long periods of continuous wake showed a negative correlation between the intensities of wake and slow wave sleep, and these interruptions did not appear to reset the cycle clock to zero. Sleep stage intensity diagrams may be useful to study the sleep patterns of populations of insomniac and depressive patients, as well as the effect of drugs on sleep. Key Words: Human sleep-temporal organization-cycle structure-stage intensities. The cyclic organization of sleep, characterized by the repeated alternation of REM and NREM episodes, has long been established, but little is known of the details of this organization. Most sleep researchers have used total sleep time, i.e., the time between the start of recording and waking in the morning, as the basic unit for discussing the total duration of the various sleep stages, their percentage of total sleep time, their latencies, and other variables such as the sleep efficiency index. Gaillard (1) studied the evolution of sleep stages throughout the night, obtaining the general trends with the polynomial fitting technique. Again, individual cycles were not analyzed, and the basic unit was total sleep time, which provides only a macroscopic view of the process of sleep and could mask interesting phenomena. Any study of the architecture and essential characteristics of sleep would be stronger for taking into account the two essential features of a hypnogram: (a) the cyclic nature Accepted for publication February Address correspondence and reprint requests to Dr. H. Merica at Institutions Universitaires, psychiatriques de Geneve, Clinique de Bel-Air, CH-I225 Chene-Bourg, Geneva, Switzerland. 502

2 INTERNAL STRUCTURE OF SLEEP CYCLES 503 of sleep (alternating NREM/REM episodes) and (b) the temporal organization of the sequence of events that constitutes the cycle. A first step in this direction is to study the sleep cycle as a fundamental unit rather than as a percentage of total sleep. Feinberg (2) and Feinberg and Floyd (3) have conducted a series of studies based on the total duration of slow wave sleep (SWS) and REM sleep within cycles that demonstrated general systematic trends of cycle structure in human sleep. Using a large body of data, this article further analyzes the temporal organization of the elements composing the cycles. The transition probability analysis of these stages within the cycles was reported elsewhere (R. Merica and J.-M. Gaillard, unpublished observations). METHODS This is a retrospective study of 399 nocturnal recordings monitored in 147 healthy adults. Subjects were volunteers, screened for good health on the basis of their history and a clinical examination, who participated in studies testing the effect of psychotropic drugs on sleep. After 1 habituation night, each subject was recorded in the laboratory, following as closely as possible that person's normal sleep schedule. Data for this study were obtained from those nights when no medication or only placebo was administered (excluding placebo nights following a medicated night). For some subjects, there were several nocturnal recordings. The recordings were separated into two separate groups depending on the presence or absence of stage 4 sleep, which disappears with age, and analyzed. Group 1 consisted of 352 recordings with stage 4 sleep present (mean age of subjects within this group was 28.3 ± 10.7 years). The remaining 47 recordings constituted Group 2 (mean age of subjects within this group was 39.3 ± 10.0 years). Sleep was monitored on magnetic tape, using standard techniques: three bipolar electroencephalographic (EEG) leads (F4-CZ, T4-CZ, 02-PZ); one horizontal electrooculogram (EOG); submental electromyogram (EMG); electrocardiogram (ECG), monitored by derivations placed on both shoulders; and monitoring of respiration by thermistors taped under the nostrils. The tapes were analyzed with an electronic scoring system (4) according to the criteria of Rechtschaffen and Kales (5). The results given by this system are similar to those obtained by visual scoring (6). The data were then condensed by a specially written FORTRAN program into digital hypnogram form, a sequence of three-digit numbers, where the unit's digit represents the stage code and the upper digits the number of minutes of that stage. This sequence was then divided into NREM/REM cycles, according to the criteria described below, and stored on disk. The first cycle (Cl) was defined as the interval between sleep onset and the end of the first REM episode, where sleep onset was defined as the first minute of the first episode of sleep lasting> 1 min and containing at least 1 min of a sleep stage other than stage 1. The following cycles (C2 through C5) were defined as beginning at the end of one REM episode and ending at the completion of the next. A REM episode, however, may be interrupted by a short phase of NREM sleep, making it difficult to determine when REM ends and a new cycle begins. Therefore, to avoid ambiguity, we adopted a I5-min empirical rule that considered two REM episodes separated by a NREM period lasting <15 min to be a single episode. Only complete cycles were included in the study; the period between the last REM episode and final waking was therefore excluded. The average number of complete Sleep. Vol. 9, No.4, 1986

3 504 H. MERICA AND 1.-M. GAILLARD NREM/REM cycles per night was 4.4 ± 1.0. Some cycles had longer periods of continuous wake than others, regardless of their sequential position in the night. These "interrupted cycles" appeared to have a different pattern of wake and therefore could not, a priori, be included with the normal cycles. An arbitrary threshold level for wake was set to separate the interrupted and normal cycles: Any cycle with >3 min of Continuous wake was considered to be interrupted. The proportion of interrupted cycles was highest for CI (11.9%), dropping sharply to 7.1% in C2, and rising progressively after that to attain 10.9% in C5. These percentages were higher in group 2, especially for Cl and C2 (17%). Depending on the amount of continuous wake, the cycles were divided into two categories: uninterrupted (A) and interrupted (B). The temporal organization of the sleep stages within each of these cycle types was analyzed separately for 1 and 2. However, because of insufficient sample size, interrupted cycles in group 2, i.e., group 2B, were not analyzed. Cycle durations, like all sleep variables, vary greatly from one night to another. The observed coefficients of variation ranged from -25 to -45%. The mean cycle duration in group la was ± 42.3 min in Cl and dropped to 83.1 ± 22.7 min in C5, with an overall mean for the five cycles of ±?9.5 min. All cycles in group 1B were longer, with an overall mean of ± 49.6 min, whereas those in group 2 were shorter, with an overall mean of95.2 ± 26.7 min. There is no reason to believe that the timing governing the sequences of appearance/disappearance of the different stages is any less variable, although it was not quantified. This variation makes it difficult to get a general picture of the timing sequences for more than 1 night, as is evidenced by a perusal of the hypnograms. Because of this, a probabilistic approach is best suited for studying the temporal evolution of the stages within cycles, enabling one to derive average characteristics for a given population. We therefore calculated the intensity of a given stage in any small interval of time along each of the five cycles in turn. Intensity was defined as the probability for a given stage to be present in that interval: In other words, the probability that an individual randomly selected from a given population will be in stage (i) at time (t), given that he or she is in cycle (x). Intensity, therefore, is given by the ratio: number of times a stage is present in a given interval over total number of recordings. Intensities plotted along the real time scale are more or less distorted by the variation of cycle duration. This problem may be overcome by normalizing all durations by reference to the total cycle duration (CL). The method proposed here, then, represents with binary data 1/0 the presence or absence of a particular stage within a small interval of time /j.t at real time t. Using normalized time T = t/cl, we have for a resolution of 0.2%. /j.t = /j.t/cl = 1/500 The number of binary cells corresponding to T is therefore T/ /j.t = 500t/CL Then, moving along the transformed t scale, a vector was constructed for each stage, with binary 0/1 data for each cell, depending on whether the stage was off or on. The intensities calculated were plotted as a function of the percentage of cycle length. Given the large body of data, the standard errors of the mean of the calculated intensities were small, -2-3% in group 1 and -10% in group 2.

4 INTERNAL STRUCTURE OF SLEEP CYCLES 505 RESULTS Group la, from which our principal results were derived, is reported in greatest detail: Fig. I gives the intensity of the sleep stages and of wake after sleep onset as a function of the percentage of cycle duration for CI and C2. Figure 2 summarizes results from all five cycles in a combined intensity diagram. For groups 1B and 2A, only the combined intensity diagrams are given (Figs. 3 and 4). Errors are presented as standard errors of the mean. Group la Figures I and 2 f;how the temporal structure of a given stage within the cycle. There are three focal points for each stage: first, the onset time (or latency) and the initial intensity; second, the time of disappearance from the cycle; and third, the evolution within the cycle. These points are considered here for each stage in turn. Wake and stage 1. The general pattern of wake in C2-C5 consisted of a maximum intensity at the beginning of each cycle, dropping rapidly to nearly zero, and followed l(~) lc~) l(~) BO Be ' BO WAKE,., STAGE STAGE 3 Q STAGE 4 D OJ.:0 D'",:10) OJ (l OJ OJ OJ DClIOlDD"'''Qil EI "",," " ". REM Ol STAGE BO BO BO 1 (~) 1 (~) 1 (~) BO BO "DIiJ Iil""'". BO WAKE D STAGE STAGE 3 '" STAGE REM. STAGE 2 "D ilqd """,[ld"",iol(ild[jdd""d" [I1ilD",.,o BO BO BO C1 (~) FIG. 1. Left: Group la: stage intensity diagrams for cycle 1 (C\). 1(%) = Stage intensity = probability for a given stage to be present in a given interval of time. Cl (%) = time expressed as the percentage of Cl total duration. Superimposition of stages 1 and 2 sleep shows a perfect complementarity between the drop in stage 1 sleep and the first rise in stage 2 sleep. Stage 2 sleep intensity then decreases to give way to SWS. Again, perfect complementarity is seen between stage 2 and stage 4 sleep and then between stage 2 and REM sleep: to the two maxima in stage 4, correspond two minima in stage 2; to the dip between the two peaks in 4, corresponds a rise in stage 2; and to the final rise in REM, corresponds the final drop in stage 2. Stage 2/REM complementarity is, however, replaced by SWSIREM complementarity in the first part of REM up to the stage 2/REM crossover. Right: Group la: stage intensity diagrams for cycle 2 (C2). C2(~) Sleep. Vol. 9, No.4, 1986

5 506 H. MERICA AND J.-M. GAILLARD l 4(33.4%) 1<%) 3<12.3%) so W (0.5%) 2(35.0%) 1<%) CI (%) ~~ =-~~ , so 4( 16. 6%) N=327 3(11.5%) 2(48.5%) (1.9:0 wed.7%) R(.B%) C2(%) r-~~~-----=~~ , 4(6.1%) 1(%) N=310 3(7.9%) SO 2(57.1%) \t3.1:!o ~ we 1.0%) R(24.9%) C3(%) C4<!IP 40 CS(%) FIG. 2. Group la: combined intensities (I) of wake (W), stages 1,2,3,4, and REM sleep (R) as a function of the percentage of cycle duration for uninterrupted cycles I to 5 (CI-C5). Area bounded by a given stage represents the average proportion (indicated in brackets) of that stage in the cycle. Evolution of the stages throughout the night is clearly depicted and shows that the greatest change takes place in the first cycles. by a bout of wake recurring later in the cycle. The higher intensity at the start of the cycles indicates that some individuals wake after a REM episode. However, the proportion of such individuals is low, though increasing slightly with the later cycles: 3.~ ± 0.9% after the first REM episode (REMl), 5.2 ± 1.1% after the second REM episode (REM2), 6.6% ± 1.3% after the third REM episode (REM3), and 6.0 ± 1.9% after the fourth REM episode (REM4). CI, by definition, never begins with an episode of wake but did, however, contain a bout of wake in the early portion of the cycle. If we consider this bout to be similar in nature to those already mentioned for C2-C5, we see a systematic progression of the bout occurrence time, this bout falling in the middle of C2 and C3 and in the latter part of C4 and C5. The intensities during these bouts were, nevertheless, very low. The pattern of stage I sleep was generally similar to that of wake, with the highest intensity at the beginning of the cycle. A low level of intensity was reached rapidly after ~ 10-% of the cycle duration and was more or less constant throughout the remainder of the cycle, finally disappearing in the last 5% of the cycle. The pattern of stage 1 sleep in Cl differed from that in the other cycles by the magnitude of its initial intensity. This indicates that although the majority of individuals (80%) start sleep (Cl) in stage I, only a small fraction begin the following cycles in stage 1. This fraction increases gradually with the later cycles, increasing from 11.3 ± 1.8% in C2 to 21.6 ± 4.8% in C5. In the later cycles there was also a gradual increase in the constant intensity level attained after the drop. Although this level was never high, it more than doubled from Cl (1.5%) to C5 (3.5%).

6 INTERNAL STRUCTURE OF SLEEP CYCLES 507 ~~ ~ , [ClI) [CI:> 1'1= (7.7~) I<Z) J(Z) CI<Z) ~~ "' ' ~-- ~ , [<Z) C2<Z) C5<Z) C3<Z) C4<Z) FIG. 3. Group IB: combined intensities (I) of wake (W), stages I, 2, 3, 4, and REM sleep (R) as a function of the percentage of cycle duration for interrupted cycles I to 5 (CI-C5). SWS. Stages 3 and 4 of SWS had a similar temporal structure, which was almost uniform in all cycles. Both occupied the central portion of each cycle and formed a symmetrical disposition with a gradual rise to peak intensity, followed by a gradual fall. There were, nevertheless, several features that varied from one cycle to another: The portion of the cycle during which SWS stages were in evidence decreased with succeeding cycles, finally occupying only the middle of the cycle. This shrinkage was the result of both a delayed stage onset and an earlier disappearance of the stage from the cycle. The maximum intensity attained within the cycle also decreased in the later cycles. Although both stages 3 and 4 conformed to this general pattern, stage 3 was more constant throughout the night than stage 4. Figure 1 shows that the lengthening in stage 3 sleep onset was more gradual (onset after 4% of C1, after 8% of C2 and of C3, after 18% ofc4 and ofc5) than that in stage 4 sleep (onset after 8% ofc1, 12% ofc2, 16% of C3, 26% of C4, and 28% of C5). The decrease in intensity during the night was also much less dramatic in stage 3 sleep (dropping from 23 ± 2% in C1 and C2 to 15 ± 3% in C4 and C5) than during stage 4 (55 ± 3% in C1, 34 ± 3% in C2, 17 ± 2% in C3, 8 ± 2% in C4, and 5 ± 2% in C5). Further, the intensity of stage 4 sleep in C1 formed a symmetrical, double-peaked disposition constituting two distinct bursts. The dip between peaks, though small, was significant, since its magnitude was greater than the measurement error. There was no clear evidence of a similar evolution of stage 4 sleep in the later cycles nor of stage 3 sleep in any cycle. In this comparison of the two SWS stages, it is noteworthy that in C1 and C2 the

7 508 H. MERICA AND 1.-M. GAILLARD IOD 1(%) I!'t=33 l 50 1 (9.4~O so WCO.3%) J(%) CI (%) ~~----~ , N= C2(%) r--~~==~-~ ' N= (%) 50 N=23 \3CO.3%) C4<:1:l 2C57.4%) RC27.2%) C5(%) FIG. 4. Group 2A: combined intensities (I) of wake (W). stages 1, 2, 3, 4, and REM sleep (R) as a function of the percentage of cycle duration for uninterrupted cycles 1 to 5 (Cl-CSJ. overall intensity ()f stage 4 sleep was greater than that of stage 3 sleep, that in C3 the two stages were of equal intensity, and that in C4 and C5 stage 3 sleep was of greater intensity than stage 4 sleep. Stage 3 sleep systematically appeared eariler than stage 4 sleep in all cycles, indicating that the transition to stage 4 sleep takes place essentially via stage 3 (7). REM sleep. REM sleep, by definition, occupies the latter part of the cycle. The temporal organization was similar in all cycles, although the latency became progressively shorter in later cycles. A more precise measure of REM onset was the stage 2/REM crossover point, during which the intensity of REM sleep became greater than that of any other stage. The figures show that this point, too, was earlier in the later cycles. Another phenomenon observed in C2 and succeeding cycles was a plateau in the REM curve, well after the stage 2/REM crossover point. This could correspond to interrupted REM episodes as defined in Methods. Stage 2. Stage 2 is the most abundant stage in all cycles. While its initial intensity is relatively low in Cl (on only % of nights does sleep onset occur with stage 2 sleep), this intensity in later cycles is much greater. This percentage was highest in the C2 at 84.5 ± 1.9% and dropped gradually overnight to 71.0 ± 5.0% in C5, as the probability to wake or pass into stage 1 sleep from REM rose. The characteristic temporal organization of stage 2 sleep tends to reflect its pivotal role, which has been discussed in a previous work (7). At different times within a cycle there was a complementary relationship between stage 1 and stage 2 sleep, SWS and stage 2 sleep, and REM and stage 2 sleep. This was most dramatically evident in Cl Sleep. Vol. 9, No.4, 1986

8 INTERNAL STRUCTURE OF SLEEP CYCLES 509 (Fig. 1). This pattern was observed in all the cycles. However, as SWS decreased in the later cycles, the first drop in stage 2 intensity became gradually less pronounced, forming a more or less distinct plateau at a high intensity level before dropping to give way to REM sleep. This dynamic complementarity, stage 2/stage x, persisting almost continuously over each part of each cycle throughout the night as shown by a comparison of the intensity diagrams is an aspect of sleep structure clearly illustrated by the new technique. Group 1B In all cycles, regardless oftheir position in the night, there were occasional abnormal amounts of wake. Brezinova (8) has shown that the mean duration of these interrupted cycles is longer than that of the uninterrupted cycles, even when the time occupied by wake is subtracted. Our results confirm this finding, showing an increased length of 44% for CI, falling progressively to ~3% for CS. The temporal organization of the sleep stages for interrupted cycles is given in Fig. 3. The wake pattern is irregular and difficult to characterize, probably because the sample sizes were relatively small. Nevertheless, the temporal organization of wake was clearly different from that of the uninterrupted cycles. Wake appeared to intrude during specific portions of each cycle related to the cycle's position in the night. In CI and CS, wake was most likely to occur at the beginning of the cycle; the probability of its occurring dropped gradually to a fairly constant, though relatively high, level. In C2 and C3, wake tended to occur during the span between and 80% of the cycle length, with the highest intensity in the second half of the cycle. In C4, the probability for wake to occur was greatest in the first three-quarters of the cycle. In the last 10% of all the cycles, wake intensity dropped to zero. With the exclusion of CI, the initial intensity of wake was significantly higher than that observed in group la, suggesting that waking after a REM episode predisposes the cycle to a certain fragility that persists throughout its entire length. The temporal organization of stage I sleep appeared to follow the pattern set by wake rather than that observed in group IA. This could be expected, since wake and stage 1 sleep are positively correlated (7). The characteristics of SWS in group 1B are similar to those in group IA. The portion of the cycle over which SWS is active was essentially the same in both groups, but in group 1B there was a slight predominance in the earlier part of the cycle. Figure 3 shows that increased wake in the cycle is accompanied by a perturbation in the temporal organization of SWS, particularly in stage 4 sleep: The symmetrical arrangement of stage 4 sleep in the cycles of group IA is gone, and the characteristic overnight decrease of stage 4 sleep is accentuated. Modifications in the other stages were less pronounced and appeared only in the later cycles. REM latency in CI was the same as that of group la, but it was significantly longer in C2-C4, suggesting that wake in the second half of the cycle tends to suppress REM sleep. The characteristics of stage 2 sleep remained generally unchanged, again exhibiting the complementarity of stage 2 sleep and the other stages. Group 2A Stage 4 sleep tends to disappear with age, causing modifications in the cycle structure (2,9). On the average, cycles were shorter and the proportion of stage I sleep was greater than when SWS was intact (Fig. 4). The proportions of the other sleep stages were also modified, but these changes did not affect all cycles uniformly. In CI, C2,

9 510 H. MERICA AND J.-M. GAILLARD and C3, where stage 3 sleep accounted for ~3.9% of the cycle, stage 2 and REM sleep increased and wake decreased, and this occurred as a function of the proportion of stage 3 sleep. In the later cycles, the inverse phenomenon was observed. SWS, represented by stage 3 sleep only, generally decreased. Although the proportion of stage 3 sleep in CI was ~40% greater than that observed in the same cycle of group la, it represented only 37.5% of the total SWS observed in that group. Moreover, from C2 op., the proportion of stage 3 sleep decreased rapidly. The temporal organization of the sleep stages also differed from that in group IA: Wake appeared in bouts scattered throughout the cycles rather than peaking at cycle onset and then dropping to zero intensity, suggesting that in this group a smaller proportion of people wake from a REM episode. This is especially true in the early cycles (CI ± 1% wake from REMI and from REM2). This proportion increased in later cycles. The proportion of individuals who passed from a REM episode into stage I sleep, on the other hand, was much larger than in group IA (32.3 ± 5.2% from REMI, 37.1 ± 5.8% from REM2, 23.5 ± 8.4% from REM3, and 30.7 ± 4.5% from REM4). The earlier cycles ec2, C3), as opposed to the later cycles in group la, were most affected by this phenomenon. The disposition of stage I sleep was similar in both groups, but intensity in group 2A, after dropping from its initial level, rose to a higher level from which it oscillated throughout the cycle. The onset of stage 3 sleep was very much delayed in this group. In CI, the average stage 3 sleep latency was five times greater than that in group IA. This long latency persisted in the following cycles but was only about twice as long as that in group IA. The maximum intensity of stage 3 sleep decreased rapidly in successive cycles, resembling stage 4 sleep rather than stage 3 sleep. REM onset also differed. Although the average latency decreased systematically in successive cycles, as in group la, it was shorter in the first two cycles and longer in the last three cycles. Modifications observed in stage 2 sleep correspond essentially to the changes in the other stages, thus accentuating the pivotal role of this stage. Figure 5 summarizes the evolution during the night of the proportion of each stage for the three groups. DISCUSSION As well as giving a general picture of the structure of individual cycles, our results give new insight into the effect of stage 4 sleep deficiency and into the relation between 80 GROUl' la 80 GROUP IB 80 GROUP 2A , /' ~ 30:::::---- R_. I : ~_==,,_ l--~~~: ~.,,",::::::=-::: Cl C2 C3 C4 CS Cl C2 C3 C4 C5 Ct C2 C3 C4 C5 CYCLE NO. CYCLE NO. CYCLE NO. FIG. S. Evolution during the night of the proportion of each sleep stage in each group.

10 INTERNAL STRUCTURE OF SLEEP CYCLES 5// abnormally long wake periods and the cycle structure. They also present a graphic and quantitative illustration of what have been tentative hypotheses: the pivotal role of stage 2 sleep, the preferential replacement of stage 4 by stage 2 sleep, and the antagonism between SWS and REM sleep. In general, cycle structure may be described in three consecutive phases: an initial phase of rapid stage change, a second phase of relative stability, and a terminating phase, again, of rapid stage change. Although the stage content of each phase is the same throughout the night, both the relative magnitudes of the stages within each phase and the phase durations vary. The principal aspects of this overnight evolution are these. (a) The initial intensity of stage 1 sleep is much higher in C1 than in the later cycles; i.e., the process of failing asleep at the start of C1 is not repeated in later cycles. (b) The duration of the central, more or less stable, phase of the cycle shrinks during the night while retaining its central position. As the night advances, three distinct observations-an increase in the probability of waking from a REM episode, an increase in the probability of interrupted REM periods, and a decrease in SWS-collectively manifest an increasing "pressure to wake." The group without stage 4 sleep appears to have a general deficit in SWS, since stage 3 sleep does not increase; in fact, the proportion of stage 3 sleep actually decreases. In these individuals, the less rapid drop in stage 1 sleep intensity at the beginning of the cycles and the delayed stage 3 sleep onset suggest a difficulty in descending into deeper sleep. The rate of decrease of stage 3 sleep during the night in this group strongly resembles that of stage 4 sleep in group 1A. Cycles interrupted by excessive wake are an enigma. Many researchers, including ourselves, have considered that a spontaneous waking of> 3 min effectively sets that cycle clock to zero. The results presented here, however, support the hypothesis that while excessive wake modifies the cycle, the cycle is not aborted, and the cycle clock is not reset to zero. In fact, interrupted cycles maintain the general pattern of the uninterrupted cycles, and even after high wake intensity do not reproduce the characteristic structure of the typical cycle onset. What is modified is the proportion of the stages within these cycles; there is a general increase in stage 1 sleep and a decrease in the other stages, especially stage 4 sleep. There is also a complementarity between increased wake intensity and decreased stage 4 sleep intensity. We have shown that caffeine also produces a significant increase in the duration of each wake episode and a significant reduction in the total amount of stage 4 sleep, but in a large population of normal subjects (7) and in a population of insomnic subjects (13,14), we found no correlation between the total durations of wake and stage 4 sleep. The previous studies, however, do not account for the temporal disposition of these two stages in the night, and what may be true on an hourly basis may not necessarily be true on a nightly basis. One hypothesis for the mechanisms that give rise to our observations on wakefulness and stage 4 sleep is that stage 4 sleep presents a certain fragility, or tendency to pass to wake, since the proportion of interrupted cycles is highest for the first cycle in which SWS is most abundant. Another explanation for the decrease in stage 4 sleep is that there is a difficulty in transition from stage 2 to SWS, but transition probability analysis has not been performed to confirm this hypothesis. It is interesting to note, from a X 2 analysis, that the quality of sleep SUbjectively evaluated on waking did not appear to be affected by these interrupted cycles.

11 512 H. MERICA AND J.-M. GAILLARD In regard to the pivotal role of stage 2 sleep, we showed, using transition probability analysis (7), that all stage transitions (other than those between stages 3 and 4 sleep) tend to take place via stage 2 sleep. The present work illustrates this pivotal role by showing the dynamic complementarity between stage 2 sleep and the other stages (Fig. 1). Previous studies (10,7) suggested that as stage 4 sleep disappears in the night, it is preferentially replaced by stage 2 sleep, which this study appears to confirm. Figure 5 (group la) shows that an exponential decrease of stage 4 sleep is accompanied by a complementary exponential increase in stage 2 sleep, whereas in the absence of stage 4 sleep (group 2A), stage 2 sleep stays fairly constant throughout the night. Note that in each group, REM increases in the same manner, suggesting its lesser involvement in the replacement of stage 4 sleep. This result also suggests a certain independence between stages 2 and REM sleep and that the positive correlations previously observed (11,7) between these two stages are a result of their common negative association with SWS rather than their association with each other. The antagonism between SWS and REM found in the same correlation study (7) is confirmed in the present study: As the proportion of SWS decreases across the night, REM latency systematically shortens and REM sleep increases. One would expect, however, that the shortening of REM latency and the increase in proportion of REM sleep would be accentuated in group 2A, which did not exhibit stage 4 sleep, especially since the proportion of stage 3 sleep did not compensate for the absence of stage 4 sleep. This, however, is true only for the first two cycles, which have a higher proportion of stage 3 sleep. In the last three cycles, in which stage 3 sleep almost disappears, REM onset was retarded and the proportion of REM reduced. This could suggest that there is a fine balance between SWS and REM, and that a certain amount of SWS is required to initiate REM. Given the small sample size for group 2A, this observation could be a statistical fluctuation, especially since it is not confirmed by the stage 2/REM crossover point, which systematically occurred slightly earlier than it did in group lao A better characterization of individuals with no stage 4 sleep would be required before this hypothesis can be verified. In conclusion, the probabilistic approach described here makes it possible to study in detail the temporal organization of sleep stages within sleep cycles, thus demonstrating interrelationships that may permit a better understanding of the mechanisms involved in sleep. It is a means to appreciate quantitatively what has been observed qualitatively in the hypnogram diagrams. Here it has been used to provide a more detailed characterization of sleep in healthy adults; if the graphic characteristics were parametrized, the approach could be a useful tool to study sleep patterns of insomnic and depressive patients, as well as the effects of drugs on sleep. The number of observation nights necessary for a useful diagnostic application depends upon the statistical characteristics of the parameters that the new technique has made available. A discriminant analysis of these characteristics is an obvious next step. If the number of observation nights required is not unreasonably large, then individual diagnostic discrimination may be possible. If not, the technique can be applied, as in the present work, to the comparison of populations. REFERENCES 1. Gaillard J-M. Temporal organization of human sleep: general trends of sleep stages and their ultradian cyclic components. L'Encephale 1979;V: Feinberg I. Changes in sleep cycle patterns with age. J Psychiatr Res 1974;10:

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