866
BIOL PSYCHIATRY 1992;31:866-880
Aging of Core and Optional Sleep A+ Wauquier and B. van Sweden
Two consecutive 24-hr ambulatory recordings of 14 healthy elderly persons (7 women, 7 men, ages 88-102) and : f 19 healthy young adults (10 women, 9 men, ages 25-35) were e~,aluated. In addition to the c~+~ssical~'leepparameter analysis, sleep structure was also analyzed in terms of a proposed distinction between "core" and "optional" sleep (Home 1989). Core sleep is the essential part of the sleep and is mainly slow wave sleep. This type of sleep is composed of stages 3 and 4 on non-REM sleep (NREM 3-4). Core sleep is obtained during the first three sleep cycles and the remainder of the night sleep is considered optional sleep. Optwnal sleep is more altered than core sleep. However, in both optional and core sleep, NREM sleep and REM are reduced. There is also an increase in drowsiness and in the time spent awake after sleep onset; however, the extent of these effects are more obvious in elderly men. Aging effects of slow wave sleep probably represent an amplification of the c,~nges as observed in awake electroencephalic (EEG) patterns in healthy seniors. The decrease in slow wave sleep (stages NREM 3-4) is gender relatt,d and prevails in elderly men. REM sleep diminishes with increasing age. In the elderly, most REM sleep occurs at the beginning of the night. This contrasts to younger persons where the duration of REM sleep is longer at the end of the night. Furthermore, a decrease in REM sleep latency is particularly obvious in elderly men and probably secondary to the curtailment of slow wave sleep. The ultradian NREM-REM cycle rhythm (as defined by the periodic occurrence of REM sleep) shows a monophasic trend suggesting a diminished adaptive function of aged sleep. The informative value of true, continuous ambulatory recordings in the assessme~t of sleep-wakefulness patterns in normal and pathological aging is stressed.
Introduction Sleep as a cerebral function is profoundly affected by aging (Blois et al 1983; Reynolds et a11985a 1985b; Webb 1982, 1987). One of the prevailing characteristics is the increased variability evident in some sleep parameters. This increased variability lessens the differential diagnostic significance of polygraphic recordings in pathological aging and sleep disorders, particularly the insomnias. The variability of sleep function also depends on a combination of exogenous and endogenous factors such as sleep demand, circadian tendencies, behavioral facilitators and inhibitors, and pathological conditions. Experi-
From the Department of Neurology, Medical College of Ohio, Toledo, OH (Aw); and the E ~panment of Clinical Neurophysiology, Universityof Leiden, The Netherlands (BVS). Received November20, 1990; revised Janumy 13, 1992. Address reprint requests to Albert Wauquier, Ph.D., Depamnent of Neurology, Medical College of Ohio, 3000 Arlington Avenue, P.O. Box 10008, Toledo, OH 43699-0008. Part of ~ results were presented at the 5th Annual Meeting of the Association of Professional Sleep Societies. Toronto, Ontario, Canada on June 17, 1991. © 1992 Society of BiologicalPsychiatry
0006-3223/92/$05.00
Aging of Core and Optional Sleep
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mental and developmental studies emphasized the adaptive capacity of some segments of the sleep process, in particular, the first sleep cycle (Feinberg 1989) and the last part of the night. Home (1989) hypothesized that night sleep is composed of two parts: "core" sleep and "optional" sleep. Core sleep is the essential first part of the night and contains the majority of the slow wave sleep (stages 3-4 of non-REM sleep). The remainder of the night, which mainly consists of light sleep (stages 1-2 NREM sleep), is considered optional. Home's hypothesis implied that core sleep is an essential and necessary part of the sleep required for optimal daytime functioning. Optional sleep, however, is flexible, that is, the duration is variable and its prolongation (sleeping iu during weekends for example) or its decrease (e.g., getting up earlier than usual) does not necessarily affect optimal functioning and may be considered to have a safety function. It may be anticipated that variability in sleep structure and composition is mainly due to physiological variations of these sleep segments as mentioned above. The topic of the present study is how these apparent "safety valves" of the sleep ftmction are affected by aging and if these alterations have implications at a functional or even diagnostic level. Part of the source of the variability of physiological sleep parameters is bound to the recording technique. In fact, most normative data related to aging, both physiological and pathological, are recorded in a laboratory setting. Even long-term EEG monitoring is often semicontinuous. However, true continuous ambulatory sleep-wakefulness monitoring in healthy seniors is scarce (Wanquier et -,d 1991a). The study used the continuous monitoring technique because it has important, practical advantages and allows recording sessions during one or several days in the habitual environment with minimal disturbance of usual sleeping habits and comfort (Ebersole 1989). Hence, an additional problem addressed in this article is whether. ambulatory sleep data are comparable with aging effects observed in laboratory recordings with respect to total sleep and individual sleep cycle parameters.
Methods Two consecutive 24-hr sleep-wake polygraphic recordings were obtained in 19 young adults (ages 25-35; 10 women, 9 men) and 14 elderly persons (ages 88-102; 7 women, 7 men). The young adults were screened for general good health and were without a medical, psychiatric, or sleep disorder history. The elderly persons were selected on the basis of the "Sanieur" protocol (Ligthart et al 1984). This protocol served to select persons for studies on immunogerontology. The clinical data concerning this elderly sample and the criteria underlying the Senieur protocol were previously published (Wauquier et al 1991b). The Senieur protocol is a stringent protocol defining admission criteria to ira-. munogerontological studies and was used in this study. It was developed originally by Ligthart et al (1984) with the aim of selecting subjects for immunogerontological studies in order to dissociate disease from aging° In summary, the protocol involved exclusion criteria based on clinical information, laboratory data, and pharmacological interference. In edditi~',n, in our study we also used exclusion criteria for cerebral dysfunction. The clinical information we obtained included the following: (1) infection, including bacterial, mycotic, viral, chlomydial, rickettsial, and parasitic infections; (2) inflammation, including all acute and ~hronic inflammatory processes; (3) malignancy, including all malignant neoplasms and borderline tumors; and (4) exclusion of all other overt disorders that might influence the in~nune system. Laboratory information in-:o!,~edJete..~..inatio~ of p~,v..ete~ in b ! ~ a~d -.,'i,.,.a!y~i,~,
868
BIOLPSYCHIATRY
A. Wauquier and B. van Sweden
1992;3 ! :866-880
using reference values es...olished by Landahl et al (1981). With respect to pharmacological interference, two exclusion criteria were applied: prescribed medication for the treatment of a defined disease (e.g., diuretics) and medication with known influence on the immune system (e.g., inflammatory drugs). We excluded persons with a score of less than 24 on the Mini Mental State (MMS) examination. Since the cutoff score of 24 is not reliable for excluding incipient dementia, the MMS was supplemented by an interview and subjective evaluation of behavior. This was done during a visit to the subjects in their home situation in order to exclude persons with psychiatric/affective disorders. The interviewer was an experienced neuropsychiatrist. From an initial group of 29 subjects who were older than 85 and fulfilled the criteria of the protocol, 17 were eligible to participate. Fourteen of these (7 women, 7 men) completed the study on their sleep-wake patterns. The mean age in women was 91.7 years (range 88-102) and in men 91.6 years (range 88-98). All subjects in the study were living independently and did not require major care. Eight persons lived in their own home and six in a home environment where they were not obliged to cook their own meals. With the exception of two women aged 95 and 102, all were able to prepare their own food. The mobility of the same two women was restricted to the use of a wheelchair; all others showed normal locomotion. All but three male subjects had some hearing or visual loss. Two women and five men reported that they took no medication. The others took vitamins or homeopathic preparations. Two women and one man occasionally took a hypnotic drug, but not during this study. All the men had either high school or higher education, whereas four of the women had less than high school education. There was no indication of present or past affective disorder. All appeared to be in a positive state of mind except for one women who complained of being mildly depressed. Ambulatory monitoring was obtained using a modified four-channel Medilog system. Sleep was evaluated by means of two bipolar EEG leads (Fpz-Cz/Pz-Oz), one electrooculograph (EOG) lead (electrode placement at outer eye canthi), and one submental electromyograph (EMG) lead. No other polygraphic variables (e.g., respiration, core temperature, period leg movement assessment) were recorded. These raw data were transferred to a computer allowing visual scoring of sleep-wakefulness stages by 30-see epochs from the screen. Sleep scoring data were validated with respect to the classical Rechtschaffen and Kales (1968) lead (Van Sweden et al 1990). T&e sleep scoring involved distinguishing between wakef:Jlness, REM sleep, and four stagee o~"non.REM (NREM) sleep. Stage NREM 1 sleep is considered as a transitional stage following sleep o~et, NREM 2 is light sleep, and NREM 3-4 are stages of deep sleep or slow wave sleep. In contrast with other sleep studies in the elderly (Prinz et al 1982; Reynolds et al 1985a), we did not introduce new intermediate sleep stages, nor did we combine sleep stages. Scoring criteria were based on strict Rechtschaffen and Kales rules (1968), with few specifications and inceptions. Deep sleep (stages 3 and 4 NREM) was quantified on the frequency spectrum and not on the amplitude of the slow waves, as suggested by Webb and Dreblow (1982a). REM sleep was mainly scored on the tonic and phasic EEG and EOG aspects because submental muscle tone was often unreliable in the elderly, a finding also stressed by others (Prinz et al 1982). Analysis covered sleep structure continuity paranletcrs (REM and NREM sleep) and parameters indicating sleep disruption. These disruptions include wake after sleep onset (WASO), sleep efficiency, and arousal index defined by the number of transitions to wake characterized by an EEG/EMG activation of at least 20 sec of a 30-see epoch. We also evaluated some chronobiological "~-~L'4e~ ~.~.~-~-~- ~ , ~ " ~ M ultradian rhythm. Data were calculated separately for
Aging of Core and Optional Sleep
BlOt.PSYCHIATRY 1992;31:866-880
869
the total sleep period and for each sleep cycle. Definitions of sleep parameters can be found in the glossary of "The International Classification of Sleep Disorders" (ICSD) (1990). Cycle definition is difficult, but important, particularly in the aged person in whom variability and fragmentation of sleep may be more important (Webb and Dreblow 1982b). Moreover, the recognition of cyclicity is more reliable if several repeated recordings are available showing a consistent sleep pattern. Combined rules (15 min) were used in defining NREM-REM cycles: a cycle ends with a period of !~.EgMsleep, which might be interrupted by other sleep stages, provided that these interruptions are less than 15 rain. However, the duration of the percentage of REM sleep was scored according to classical Rechtschaffen and Kales rules. REM sleep was scored as REM sleep provided that the interruptions were not longer than 2 rain and calculated as such.
StatisticalAnalysis Data from the young and elderly women and the young and elderly men were compared using sleep cycle parameters for sleep continuity and disruption. The differences between the groups were assessed using a two-factor (age x gender) analysis of variance (ANOVA). Analysis of the sleep structure for the different cycles was done using a threefactor (age x gender x sleep cycle) ANOVA. A p less than 0.05 was considered as the minimal significant level. Although the basic sleep structure parameters obtained in Otis group of elderly persons were previously published (Wauquier et al 1991b), the present analysis provides additional data with respect to sleep cycles. There is also new data from a group of younger persons with which the group of elderly are compared. A three-factm" analysis was applied to the data obtained and a completely new analysis of the data was realized using the concepts of core and optional sleep (see results section).
Results The times of sleep onset and offset are shown in Figure 1. Both sleep onset and offset were more variable in elderly men as compared with young adults. The differences in women were minimal and not significant. There was no significant difference between the first and second night in both the young and elderly group and in none of the sleep parameters analyzed. Therefore, data were combined from the two consecutive nights for each group separately. Some important parameters concerning sleep structure, sleep disruption, circadian pattern, and the results from the ANOVA are presented in Table 1. The data pertain to age- and gender-related effects. Time in bed was both gender and age dependent, mainly because elderly women spent longer time in bed. Differences in total sleep time were related to gender, as total sleep time was substantially reduced in elderly men. The differences in total time spent in the different stages as expressed in percentage are almost exclusively an age-related effect. The gender factor and interaction between age and gender was not significant. WASO was both age and gender dependent. Transitions to wake from NREM sleep was mainly an age-related effect. Awakening from REM sleep was both age and gender related, occurring mostly in elderly men. Sleep efficiency was less in elderly women and more in elderly men. Sleep latency was not significantly different, whereas REM sleep was reduced in the elderly and more so in men than in women. Figure 2 shows the duration of the successive NREM-REM cycles
870
BXOLPSYCHIATRY 1992;31:~66--880
A. Wauquier and B. van Sweden
< .05
Time (h)
I
10,00
09.00
i
08.00 07,00 06.00
D u
05.00
Figure 1. Time of boing to bed and rising for young persons (left part) and elderly persons (right part). Each point indicates an individual recording but due to the overlap not every recording is seen.
04.00 03.00 02.00 01.00 24.00 m
23.00
p
I
22,00
Age (years)
Female Male 25-35
Female
Male 88-102
in young adults and elderly men and women. In young adults the variability of the cycle duration as based on the standard deviations of the mean was small. The second sleep cycle was the longest in both young men and young and elderly women. In elderly men, the first two sleep cycles were considerably shorter than in young adults and elderly women. There is a significant effect in gender (F - 6.44, p = 0.012), in cycles (F - 24.13, p = 0.0001), and there is a significant interaction between age and cycle (F - 4.650, p = 0.001). Data per cycle give an approximation of the evolution and trends in sleep structure parameters in the course of sleep process. Figure 3 a-f shows the evolution of WASO, REM sleep, and the different stages of NREM sleep. The figures document age, gender, and cycle differences. WASO remained relatively constant throughout
Aging o f Core and Optional Sleep
BtOL PSYCHIATRY 1992;31:866-880
871
Table 1. Circadian, Sleep Structure, and Disruption Parameters in Healthy Young Men and Women and Elderly Women and Men Separately Young adults Women Men (ages 25-35) Time in bed (min) 479 460 (14.4) (I !.9) Total sleep time (rain) 420 412 (16.2) (8.44) NRBM ! (%) 7.05 8.10
(0.40) NREM 2 (%) 44.4 (2.14) NREM 3 (%) 8.91 (0.66) NREM 4 (%) 10.1 (1.43) REM (%)
Elderly Women Men (ages 88--102)
Age
ANOVA gender
Interaction (age x gender)
566 (22.8)
462 (14.6)
F = 7.543 p = 0.008
F = 14.92 p = 0.0003
F = 7.111 p ~- 0.01
438 (27.6)
328 (14.1)
F = 3.606 NS (1)
F = 11.73 p ffi 0.001
F = 5.804 p = 0.004
18.9
23.1
F ffi 109.3
F = 3.577
(0.86)
(I.80)
(2.09)
p = 0.0001
NS
F = 1.755 NS
42.5 (1.78)
37.7 (I.89)
33.9 (2.19)
F ffi 14.47 p ffi 0.0003
F ffi 1.588 NS
F ffi 0.357 NS
9.91 (!.24)
9.23 (1.02)
4.96 (0.90)
F = 5.034 p ffi 0.029
F ffi 2.876 NS
F = 6.59 p = 0.012
10.4 (I.40)
4.57 (1.02)
0.37 (0.21)
F ffi 36.57 p = 0.0001
F ffi 2.947 NS
F = 2.635 NS
10.1
10.4
4.57
0.37
b" -- 78.71
F = 0.777
F = 0.014
(!.43)
(1.40)
(I.02)
(0.21)
p = 0.0001
NS
IsiS
17.1 (3.43)
30.4 (3.60)
F ffi 60.31 p = 0.0001
F --- 6.556 p = 0.0129
F = 10.36 p = 0.002
26.8 (2.92)
33,3 (4.37)
F ffi 37.44 p = 0.0001
F = 1.068 NS
F = 2.116 NS
0.86 (0.28)
5.57 (0.99)
F ffi 4.706 p -~ 0.0339
F = 7.919 p = 0.0065
F = 30.38 p = 0.0001
79.0 (3.48)
72.0 (I.82)
F ffi 37,272 p ffi 0.0001
F = 1.146 NS
F = 4.351 p -- 0.041
29.9 (4.59)
28.7 (3.21)
F = 2.584 NS
F = 0.603 NS
F = 0.273 NS
56.2 (6.51)
33.4 (5.70)
F = 27.91 p = 0.0001
F = 0.448 NS
F = 4.677 p = 0.0344
WASO (%) 6.53 5.00 (I.09) (I.00) Transition to wake from NREM (n) 14.6 13.1 (I.63) (I.93) Transition to wake from ItEM (n) 2.75 1.22 (0.51) (0.31) Sleep efficiency (%) 87.8 90.0 (I.97) (I.29) Sleep latency (min) 4.6 18.2 (6.33) (3.19) REM latency (rain) 81.3 93.3 (6.32) (10.8)
NS: not significant(p > 0.05). Significanceof differences assessed by a two-factorANOVA.
the n i g h t in y o u n g adults. I n the elderly, the percentage increased sk, .ficantly after the first sleep c y c l e . T h e m a i n factors o f a g e a n d c y c l e are significant ( F = :51.00, p 0 . 0 0 0 1 and F = 7 . 9 2 7 , p = 0 . 0 0 0 1 , r e s p e c t i v e l y ) , as well as the interaction b e t w e e n a g e a n d g e n d e r ( F = 5 . 7 6 1 , p = 0 . 0 1 7 ) a n d a g e and c y c l e ( F = 5 . 4 5 9 , p = 0 . 0 0 0 3 ) . N R E M 1 gradually i n c r e a s e d o v e r the c o u r s e o f the night in b o t h the y o u n g and elderly. A l l the m a i n factors w e r e significant: a g e ( F = 9 3 . 3 6 2 , p = 0 . 0 0 0 1 ) , g e n d e r ( F =
872
BIOLPSYCHIATRY
A. Wauquier and B. van Sweden
! 992;31:866-880
200 180 160 ~
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CYCLE Figure 2. NREM-REM cycle duration in the course of sleep. Each point indicates the mean (+/-SEM) for the different groups (first and second night combined): in young women (open circles) (n--20), young men (open sq,ares) (n= 18), elderly women (filled circles) (n= 14), and elderly men (filled squares) (n--14). 3ignificant differences between the groups for the different cycles were assessed using a three-factor (age x gender x cycle) ANOVA (results in text).
6.672, p = 0.0102), and cycle (F = 5.78, p = 0.0002), but there was no significant interaction among those factors. In young persons, slow wave sleep (stages NREM 3 and NREM 4) gradually decreased over the course of the night. This progressive decrease was sorer;what steeper for NREM 4 than for NREM 3. In elderly men NREM 3 was relatively well preserved. Therefore, for NREM 3 sleep, there is a significant gender (F - 10.366, p - 0.0014) and cycle (F = 36.741, p -- 0.0001) effect and a significant three-factor interaction (F - 2.659, p = 0.033). On the contrary, NREM 4 was significantly decreased in elderly women and was even absent in elderly men. All main factors were significant: age (F = 43.586, p = 0.0001), gender (F - 6.733, p = 0.01), cycle (F -- 23.34, p = 0.0001), and there was a significant interaction between age and cycle (F -- 12.859, p = 0.0001). The duration of REM progressively increased until the fourth cycle in young women and until the third cycle in young men. Thereafter, REM sleep showed a progressive decline. In contrast, a steady decrease in both elderly men and women was observed. The first REM episode was the longest exceeding the duration in young adults. Age (F - 22.567, p = 0.001) and cycle (F --- 26.82, p = 0.001), and both the interaction between age and gender (F = 4.142, p - 0.042) and age and cycle (F -- 9.422, p = 0.0001) were significant. In the young persons, NREM 2 showed an evolution comparable to REM sleep; there was an initial increase followed by a progressive decline after the first three sleep cycles. This trend was similar for the elderly women, whereas, in elderly men, the
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Figure 3 a-f. Evolution of WASO, NREM I, 2, 3, 4, and REM sleep for successive sleep cycles. Each point indicates the mean ( + / - SlM) for the diferent groups (first and second night combined)-.-young females (open circles) (n -- 20), young males (open squares) (n = 18), elderly females (filled circles) (n= 14) and elderly males (filled squares) (n----14). Significant differences between the groups for the different cycles were assessed using a three-factor (age x gender x cycle) ANOVA (results in text).
874
BIOLPSYCHIATRY
A. Wauquier and B. van Sweden
1992;31:866-880
trend was more reminiscent of aged REM sleep (i.e., a steady decline). Also, age (F = 4.852, p = 0.0284) and cycle (F = 13.038, p 0.0001) were significant. To evaluate sleep structure using the concepts of core and optional sleep we subtracted the first three sleep cycles in the young adults and took a comparable duration of sleep aftei° sleep onset i~ elderly men (CI + C2 + C3 + C4 = 370 min) and women ( e l + C2 + C3 = 380 min.) The remaining section was considered optional sleep and the first part as core sleep. We compared the structure and disruption parameters of both sections in the four groups. Figure 4a shows the structure of core sleep. In young males and females the core sleep section was strikingly similar. In both elderly men and women slow wave sleep (NREM 3-4) and ItEM sleep were significantly decreased, whereas wakefulness and drowsir~css were significantly increased. This effect was more conspicuous in elderly males than in females. NREM sleep, however, was strikingly similar. Accordingly, there were significant factors (age and gender) for all stages except for NREM 2. The interaction age × gender was significant, except for NREM 2 and NREM 4 (see statistical data in figure legends). Figure 4b shows optional sleep for the four groups. There was a significant age and gender effect for wakefulness, NREM 1 and 2, and REM sleep, but not for NREM 3 and 4 sleep, and a significant interaction for only NREM I and NREM 3 sleep (see statistics in figure legends). The optional sleep is shorter in young men than in women. The duration of this optional sleep in the elderly paralleled the values observed in the young persons. However, there was a proportional decline in REM sleep and increased signs of sleep disruption (WASO and NREM 1 sleep). Discussion The data document that ambulatory sleep-wakefulness monitoring yields comparable aging effects of the sleep function as obtained in laboratory recording settings by other researchers (Blois et al 1983; Reynolds et al 1985a, 1985b, 1987; Webb 1982, 1987). The recording quality was excellent and the technique was well tolerated in the investigated elderly persons. This supports the idea that this technique can be useful for both clinical screening and research purposes. The conclusions may become stronger when a direct comparison is made using the two different techniques in the same population. We have discussed the influence of the recording technique and age on sleep patterns in a previous report (Wauquier et ai 1991a). However, in the present study there was no first night sleep effect in the young adult population or in the selected elderly population. The present findings add more trends over time of sleep structure and disruption parameters as recorded in the conventional home setting. With respect to sleep disruption, it is interesting to note that in young persons, awakening is rather evenly distributed over the night and is lowest during the first sleep cycle. Awakening from sleep is more conspicuous in the elderly and more so in men than in women. The increasing trend over time for NREM 1 (by some considered as drowsiness, by others as part of the sleep, i.e., a transition of sleep) is similar in young adults and the elderly. However, this stage becomes more significant in elderly women and even more so in elderly men. This may have clinical relevance for the subjective evaluation of sleep as hypnagog:~; .'xctivitymay be a prominent feature of this stage. The eventual relationship with psychopathology in the aged persons might be an interesting subject of investigation. The data regarding slow wave sleep are in accord with the literature. The elimination of the delta amplitude criterion for scoring slow wave sleep is based on suggestions by
Aging of C~re and Optional Sleep
nzot. PsXCmATRY 1992;31:866-880
875
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Figure 4a and b. Figurecorresponds to Table 2a and b. Webb and Dreblow (1982a) and recent data by Ehlers and Kupfer (1989). Indeed, there is a decreased slow wave sleep in the elderly, but apparently there is also a dissociation between the age-related evolution of stages NREM 3 and 4. Stage NREM 4 is more affected by aging than stage NREM 3. There was no significant age effect for NREM 3 sleep. The reason for the difference between stages NREM 3 and 4 might be the scoring
876
BIOL PSYCHIATRY 1992;31:866-880
A. Wauquier and B. van Sweden
Table 2a. (See also Figure 4a.) The Structure of Core in Sleep in Percentage (Comparable Duration: Cycle 1 to Cycle 3 in Young Adults and Elderly Women and Cycle 1 to Cycle 4 in Elderly Men) Significant Differences Using a Two-factor (Age × Gender) ANOVA Stage
Age
Gender
Int e ra c t i on
Wake
F = 45.333 d
F = 4.943 °
F = 6.513 b
NREM !
F = 98.91 d
F -- 5 . 3 6 2 °
F -- 4 . 0 5 °
NREM 2 NREM 3
F = 3.867 F = 7.72 b
F = 0.655 F = 8.519 b
F -- 0 . 1 9 7 F = 6.157 °
NREM 4
F --- 39.44~ d
F = 5.016a
F =
!,579
REM
F = 37.712 d
F = 0.263
F =
1.349
Table 2b. (See also Figure 4b.) Th¢~Structure of Optional Sleep in Mean Minutes. Significant Differences Using a Two-factor (Age × Gender) ANOVA Stage
Age
Gender
Int e ra c t i on
Wake
F = 7.987 b
F ffi 5.23 a
F -- I . I 1 7
NREM I
F =
F -- 6 . 9 0 5 b
F = 5.142 a
NREM 2
F = 5,134 °
F = 14.108 c
F -- 0,091
NREM 3
F = 0.008
F = 5.632 a
F -- 4 , 3 7 7 a
NREM 4 REM
F = 1.65 F -- 17.297 't
F = 0.821 F = 6.783 °
F = 0.071 F ffi 3 . 8 9
10,28 b
op < 0,05; bp < ,Ol; ~'p < 0.001; dp < O,O(N)I,
criteria; the delta activity appears less continuous and is more fragmented in the elderly and thus promotes the scoring of stage NREM 3. Some data suggest that the age-related decline in slow wave sleep might be a scorings artefact due to the physical difference~ in skull conductance (Dijk et al 1989). The reported differences in power in young women and men are more convincing for slow frequencies than for higher frequency rhythms. One would, however, expect a more uniform power increase or reduction if only physical factors were involved. Moreover, physical recording factors cannot be held responsible for the differences in sleep duration correlating with the amount of slow wave sleep. Finally, one would expect that osteoporosis of old age wouk~ induce an amplitude increase rather than the observed decrease. A similar trend has been emphasized for rhythmic waking EEG activity in normal aging (Christian 1984). Amplitude reduction is a normal characteristic of the waking EEG and normal aging. As mentioned by ot~lers, a loss of NREM 4 sleep is particularly obvious in elderly men. Gender differences have been reported in routine EEG screening in the elderly, particularly regarding beta frequencies (Busse 1983). The data suggest that at least some of the age-related changes of slow wave sleep might represent an amplification of the waking EEG characteristics in normal aging. REM sleep shows that there is a significant interaction between age and gender. Furthermore, in both elderly men and women, although total REM is decreased, it is consistently highest during the first part of the sleep period. Our ambulatory recording findings are less ambiguous than some data (Hayashi and Endo 1982). ItEM sleep timing is dependent on the circadian pacing. According to Weitzmann et ai (1982) a forward REM shift might be related to a phase advance of the circadian rhythms in aging processes. As pointed out earlier by Webb (1982, 1987), chronobiological aspects are important for aging sleep. The above-mentioned advanced REM shift and the increased variability of
Aging of Core and OptionalSleep
BIOLPSYCHIATRY 1992;31:866-880
877
the NREM-REM cycle duration are compatible with the phase advance and reduced amplitude of a circadian oscillation (Wever 1985). A similar phase advance has been noted in free running conditions without alteration of the NREM-REM cycle duration (Weitzman et al 1980) As there is no data concerning core body temperature, we cannot relate the observed gender differences in sleep structure to this important circadian pacemaker (Campbell et al 1989). In contrast with current findings in young adults documenting a biphasic course (Home 1989), the NREM-RF.~ cycle shows a monophasic evolution in the elderly; this may also result from this forward REM shift. According to the current sleep hypothesis (Borbely 1982) and an earlier recovery model of Feinberg (1974), ItEM displacement may depend on a circadian process, and a decline in slow wave sleep could result from an insufficiency in sleep pressure. Apparently both systems (referred to respectively as "process C" and "process S") are affected by aging, although it is obviously hazardous to indicate what dysfunction is primary or secondary. Although the data support the phase advance theory to explain the early ItEM episodes of advanced age (Weitzman et al 1980), both the ItEM sleep-slow wave sleep interaction hypothesis and circadian amplitude hypothesis cannot be refuted by our findings. The study suggests an inverse relation between REM latency and slow wave sleep duration and a direct correlation with total sleep time, a measure for a putative circadian arousal cycle (Schulz and Lund 1985). What might be the functional significance of our findings and their implications7 How can we translate polygraphic data into clinical language? Our findings will be related to cognitive function and affective disorder using the dichotomy between core and optional sleep put forward by Home (1989). Core sleep as defined by Home involves predominantly slow wave sleep as it is recorded in the early three sleep cycles. However, in humans this sleep type cannot be separated from its associated ItEM segment. In fact, our findings would suggest that ItEM sleep in the elderly is more or less transferred or shifted to the core section of sleep and exponentially decreases thereafter It is probably no coincidence that the first sleep cycle, showing the least sleep disruption, also contains the longest REM episode. This REM saving effect might he important for cognitive functioning in normal or successful aging, as defined by Rowe and Kahn (1987). In dementia of the AIzheimer type, a REM decline and an increased REM latency have been reported (Prinz et al 1982; Vitiello et al 1984). In addition, cholinergic transmission, important for REM sleep timing and induction, is reduced in cortical dementia. One may wonder to what extent of pathophysinlogical significancein subcortical and cortical dementia a disturbance of this "physiological" REM shift mechanism might be. Optional sleep (the remaining sleep section) is curtailed and disrupted in the elderly, which appears not to be associated with excessive daytime napping (Carskadon et al 1982). This last sleep section contains less stage NREM 2 and REM sleep, diminishing its internal compensation function when sleep is disrupted in its core section, suggesting a physiological "atrophy" of this adaptive sleep section. Some of the age-related sleep alterations are similar to the sleep dysfunction in affective disorders (Reynolds and Kupfer 1987). Indeed, a shortened first sleep cycle diminished slow wave sleep and shallow last sleep segment are prominent in severe depression. REM latency is an important polysomnographic variable in clinical psychiatry (Kupfer 1976). Although REM sleep t'arameters remain the most reliable differentiating criteria between the elderly demented and depressed patients (Reynolds et al 1985b, 1988), a polysomnographic classification may be difficult, particularly in elderly mt;n. Furthermore, caution with respect to the diagnostic value of ItEM latency has recently been expressed (Pressman 1989).
878
BIOLPSYCHIATRY
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Normal aging is characterized by a decreased transmitter turnover without a simultaneous functional loss. The brain,has important functional reserve capacit~ based on an increased activity (up-regulation of the remaining neurons). The relationship between the clinical state and the sleep pattern, of which the REM latency is only one parameter of the first sleep cycle, may be raised. The notion of a decreased adaptive function of the first and last sleep segments may also be of considerable interest for the biology of depressive states. A decreased turnover and/or dysregulation of transmitter systems has been postulated in depression (Siever and Davis 1985). The dysfunction could be stressinduced resulting from exhaustion (state parameter) or could represent a genetic vulnerability (trait parameter) (Gold et al 1988). Our findings in healthy elderly also show that this sleep pattern is not necessarily associated with clinical psychopathological signs. In fact, this could reflect a nonspecific expression of a dysregulated neurochemical state. Considering the important interactions between the different transmitter systems, a comparable polysomnographic pattern is perhaps not surprising and could help to explain similar sleep data in schizophrenia (Hiat et al 1985; Zarcone et al 1987). Many features defy all clinical interpretation, and speculation as to the underlying mechanisms are not understood. They will probably only be accessible through other techniques of investigation. The age-related decline in slow wave sleep undoubtedly remains most intriguing (Wauquier et al 1989). Based on the previous findings, it might be suggested that at least some aspects of the NREM sleep alterations in aging might be gender dependent. References Blois R, Feinberg I, Gaillard JM, Kupfer DJ, Webb WB (1983): Sleep in normal and pathological aging. Experientia 39:551-586. Borbely AA (1982): A two process model of sleep regulation. Human Neurobiol 1:195-204. Busse EW (1983): Electroencephalography. In Reisberg B (ed), Alzheimer's Disease. London: The Free Press, p 231. Campbell SS, Gillin JC, Kripke DF, Erikson P, Clopton P (1989): Gender differences in the circadian temperature rhythms of healthy elderly subjects: Relationships to sleep quality. Sleep 12:529-536. Carskadon MA, Brown ED, Dement WC (1982): Sleep fragmentation in the elderly: Relationship to daytime sleep tendency. Neurobiol Aging 3:321-327. Christian W (1984): Das Elektroencephalogram in hoheren Lebensalter. Nervenartz 55:517-524. Dijk DJ, Beersma DGM, Bloem GM (1989): Sex differences in the sleep EEG of young adults: Visual scoring and spectral analysis. Sleep 12:500-507. Ebersole J (ed) (1989): Ambulatory EEG Monitoring. New York: Raven Press, p 365. Ehlers CL, Kupfer DJ (1989): Effects of age on delta and REM sleep parameters. Electroencephal Clin Neurophysiol 72: ! 18-125. Feinberg I (1974): Changes in sleep cycle patterns with age. J. Psychiatr Res 10:283-306. Feinberg ! (1989): Effects of maturation and aging on slow wave sleep in man: Implications for neurobiol,3gy. In Wauquier A, Dugovic C, Radulovacki M (eds), Slow Wave Sleep: Physiological, Pathophysiological and Functional Aspects. New York: Raven Press, pp 31-48. Gold PW, Goodwin FK, Chmnisos GP (1988): Clinical and biochemical manifestations of depression--relation to the neurobiology of stress. N Engl J Mud 319:413-420. Hayashi Y, Endo S (1982): All night sleep polygraphic recordings of healthy aged persons: REM and slow-wave sleep. Sleep 5:277-.283. Hiat JF, Floyd FC, Katz PH, Feinberg I (1985): Futher evidence of abnormal NREM sleep in schizophrenia. Arch Gun Psychiatry 42:797-802.
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Home J (1989): Why We Sleep. Oxford: Oxford University Press. ICSD (1990) International Classification of Sleep Disorders: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee, Rochester, Minnesota: American Sleep Disorders Association, 1990. Kupfer DJ (1976): REI~Alatency: A psychobiologic marker for primary depressive disease. Biol Psych 11:159-174. Landahl S, Jagenburg K, Svanborg M (1981): Blood components in a 70-year old population. Clin Chem Acta 112:301. Ligthart GJ, Corberand JX, Fournier C, et al (1984): Admission criteria for irnmunogerontological studies in man: The Senieur protocol. Mech Ageing Dev 28:47-55. Pressman R (1989): Interpreting the polysonmogram: 10 questions to consider concerning nocturnal REM sleep latency. APSS Newsletter 4:9-15. Prinz PN, Peskind ER, Vitaliano PP, et al (1982): Changes in the sleep and waking EEGs of nondemented and demented elderly subjects. J Am Gerontol Soc 30:86-93. Rechtschaffen A, Kales A (I 968): A Manualof Standardized Terminology, Techniquesand Scoring System for Sleep Stages of Human Subjects. Washington DC: Public Health Service, U.S. Government Printing Office, Reynolds CF III, Kupfer DJ (1987): Sleep research in affective illness: State of the art circa 1987. Sleep 10:199-215. Reynolds CF III, Kupfer DJ, Taska IS, Hoch CC, Sewitch DE, Spiker DF (1985a): Sleep of healthy seniors: A revisit. Sleep 8:20-29. Reynolds CF IH, Kupfer DJ, Taska IS, et el (1985b): EEG sleep in elderly depressed, demented and healthy subjects. Biol Psychol 20:431-442. Reynolds CF I11, Kupfer DJ, Month PR, et el (1988): Reliable discrimination of elderly depressed and demented patients by electroencephelographic sleep data. Arch Gen Psychiatry 45:258264. Rowe JW, Kahn RL (1987): Human aging: Usual and successful. Science 237:143-149. Schulz H, Lund R (1985): On the origin of early REM episodes in the sleep of depressed patients: A comparison of three hypotheses. Psychiatry Res 16:65-77. Siever LJ, Davis KL (1985): Toward a dysregulation hypothesis of depression. Am J Psychiatry 142:1017-1031. Van Sweden B, Kemp B, Kamphuisen HAC, Vet der Velde A (1990): Alternative electrode placement in (automatic) sleep scoring. Sleep 13:279-283. Vitieilo MV, Bokan JA, Kukull W, Muniz RL, Smallwood AG, Prinz PM (1984): REM sleep measures of the Alzheimer's type dementia patients and optimally healthy aged individuals. Biol Psychiatry 19:721-734. Wauquier A, Dugovic C, Radulovacki M (1989): Slow Wave Sleep. Physiological, Pathophysiological and Functional Aspects. New York: Raven Press, p 330. Wauquier A, Van Sweden B, Kerkhof GS, Kamphuisen HAC (1991a): Ambulatory first night sleep effect recording in the elderly. Behav Brain ~qes42:7-11. Wauquier A, Van Sweden B, Lagaay J, Kemp B, Kamphuisen HAC (1991b): Antbulatory monitoring of sleep-wakefulness patterns in healthy elderly males and females (>88 years). The "senieur" protocol. J Am Geriatr Soc. Webb WB (1982): The measurement and characteristics of sleep in older persons. NeurobiolAging 3:311-319. Webb WB (1987): Disorders of aging sleep. In yon Hahn HP (ed), lnterdisc Topics in Gerontology. Basel: Karger, pp 1-12. Webb WB, Dreblow LM (1982a): A modifiedmethod for scoring slow wave sleep in older subjects. Sleep 5:195-199. Webb WB, Dreblow LM (1982b): The REM cycle, combining rules, and age. Sleep 5:372-377.
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Weitzman E, Czeisler CA, Zimmerman JC, Ronda JM (1980): Timing of REM and stages 3 + 4 sleep during temporal isolation in man. Sleep 2:391-407. Weitzman E, Molire M, Czeisler C, Zimmerman J (1982): Chronobiology of eging temperature, sleep-wake rhythms and entrainment. Neurobiol Aging 3:299--304. Wever RA (1985): Models of interaction between ultradian and circadian rhythms: Toward a mathemathical model of sleep. Exp Brain Res (Suppl) 12:309-317. Zarcone VP, Benson KL, Berger PA (1987): Abnormal REM latencies in schizophrenia. Arch Gen Psychiatry 44:45-48.
BIOL PSYCHIATRY 1992;31:866-880
Aging of Core and Optional Sleep A+ Wauquier and B. van Sweden
Two consecutive 24-hr ambulatory recordings of 14 healthy elderly persons (7 women, 7 men, ages 88-102) and : f 19 healthy young adults (10 women, 9 men, ages 25-35) were e~,aluated. In addition to the c~+~ssical~'leepparameter analysis, sleep structure was also analyzed in terms of a proposed distinction between "core" and "optional" sleep (Home 1989). Core sleep is the essential part of the sleep and is mainly slow wave sleep. This type of sleep is composed of stages 3 and 4 on non-REM sleep (NREM 3-4). Core sleep is obtained during the first three sleep cycles and the remainder of the night sleep is considered optional sleep. Optwnal sleep is more altered than core sleep. However, in both optional and core sleep, NREM sleep and REM are reduced. There is also an increase in drowsiness and in the time spent awake after sleep onset; however, the extent of these effects are more obvious in elderly men. Aging effects of slow wave sleep probably represent an amplification of the c,~nges as observed in awake electroencephalic (EEG) patterns in healthy seniors. The decrease in slow wave sleep (stages NREM 3-4) is gender relatt,d and prevails in elderly men. REM sleep diminishes with increasing age. In the elderly, most REM sleep occurs at the beginning of the night. This contrasts to younger persons where the duration of REM sleep is longer at the end of the night. Furthermore, a decrease in REM sleep latency is particularly obvious in elderly men and probably secondary to the curtailment of slow wave sleep. The ultradian NREM-REM cycle rhythm (as defined by the periodic occurrence of REM sleep) shows a monophasic trend suggesting a diminished adaptive function of aged sleep. The informative value of true, continuous ambulatory recordings in the assessme~t of sleep-wakefulness patterns in normal and pathological aging is stressed.
Introduction Sleep as a cerebral function is profoundly affected by aging (Blois et al 1983; Reynolds et a11985a 1985b; Webb 1982, 1987). One of the prevailing characteristics is the increased variability evident in some sleep parameters. This increased variability lessens the differential diagnostic significance of polygraphic recordings in pathological aging and sleep disorders, particularly the insomnias. The variability of sleep function also depends on a combination of exogenous and endogenous factors such as sleep demand, circadian tendencies, behavioral facilitators and inhibitors, and pathological conditions. Experi-
From the Department of Neurology, Medical College of Ohio, Toledo, OH (Aw); and the E ~panment of Clinical Neurophysiology, Universityof Leiden, The Netherlands (BVS). Received November20, 1990; revised Janumy 13, 1992. Address reprint requests to Albert Wauquier, Ph.D., Depamnent of Neurology, Medical College of Ohio, 3000 Arlington Avenue, P.O. Box 10008, Toledo, OH 43699-0008. Part of ~ results were presented at the 5th Annual Meeting of the Association of Professional Sleep Societies. Toronto, Ontario, Canada on June 17, 1991. © 1992 Society of BiologicalPsychiatry
0006-3223/92/$05.00
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mental and developmental studies emphasized the adaptive capacity of some segments of the sleep process, in particular, the first sleep cycle (Feinberg 1989) and the last part of the night. Home (1989) hypothesized that night sleep is composed of two parts: "core" sleep and "optional" sleep. Core sleep is the essential first part of the night and contains the majority of the slow wave sleep (stages 3-4 of non-REM sleep). The remainder of the night, which mainly consists of light sleep (stages 1-2 NREM sleep), is considered optional. Home's hypothesis implied that core sleep is an essential and necessary part of the sleep required for optimal daytime functioning. Optional sleep, however, is flexible, that is, the duration is variable and its prolongation (sleeping iu during weekends for example) or its decrease (e.g., getting up earlier than usual) does not necessarily affect optimal functioning and may be considered to have a safety function. It may be anticipated that variability in sleep structure and composition is mainly due to physiological variations of these sleep segments as mentioned above. The topic of the present study is how these apparent "safety valves" of the sleep ftmction are affected by aging and if these alterations have implications at a functional or even diagnostic level. Part of the source of the variability of physiological sleep parameters is bound to the recording technique. In fact, most normative data related to aging, both physiological and pathological, are recorded in a laboratory setting. Even long-term EEG monitoring is often semicontinuous. However, true continuous ambulatory sleep-wakefulness monitoring in healthy seniors is scarce (Wanquier et -,d 1991a). The study used the continuous monitoring technique because it has important, practical advantages and allows recording sessions during one or several days in the habitual environment with minimal disturbance of usual sleeping habits and comfort (Ebersole 1989). Hence, an additional problem addressed in this article is whether. ambulatory sleep data are comparable with aging effects observed in laboratory recordings with respect to total sleep and individual sleep cycle parameters.
Methods Two consecutive 24-hr sleep-wake polygraphic recordings were obtained in 19 young adults (ages 25-35; 10 women, 9 men) and 14 elderly persons (ages 88-102; 7 women, 7 men). The young adults were screened for general good health and were without a medical, psychiatric, or sleep disorder history. The elderly persons were selected on the basis of the "Sanieur" protocol (Ligthart et al 1984). This protocol served to select persons for studies on immunogerontology. The clinical data concerning this elderly sample and the criteria underlying the Senieur protocol were previously published (Wauquier et al 1991b). The Senieur protocol is a stringent protocol defining admission criteria to ira-. munogerontological studies and was used in this study. It was developed originally by Ligthart et al (1984) with the aim of selecting subjects for immunogerontological studies in order to dissociate disease from aging° In summary, the protocol involved exclusion criteria based on clinical information, laboratory data, and pharmacological interference. In edditi~',n, in our study we also used exclusion criteria for cerebral dysfunction. The clinical information we obtained included the following: (1) infection, including bacterial, mycotic, viral, chlomydial, rickettsial, and parasitic infections; (2) inflammation, including all acute and ~hronic inflammatory processes; (3) malignancy, including all malignant neoplasms and borderline tumors; and (4) exclusion of all other overt disorders that might influence the in~nune system. Laboratory information in-:o!,~edJete..~..inatio~ of p~,v..ete~ in b ! ~ a~d -.,'i,.,.a!y~i,~,
868
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using reference values es...olished by Landahl et al (1981). With respect to pharmacological interference, two exclusion criteria were applied: prescribed medication for the treatment of a defined disease (e.g., diuretics) and medication with known influence on the immune system (e.g., inflammatory drugs). We excluded persons with a score of less than 24 on the Mini Mental State (MMS) examination. Since the cutoff score of 24 is not reliable for excluding incipient dementia, the MMS was supplemented by an interview and subjective evaluation of behavior. This was done during a visit to the subjects in their home situation in order to exclude persons with psychiatric/affective disorders. The interviewer was an experienced neuropsychiatrist. From an initial group of 29 subjects who were older than 85 and fulfilled the criteria of the protocol, 17 were eligible to participate. Fourteen of these (7 women, 7 men) completed the study on their sleep-wake patterns. The mean age in women was 91.7 years (range 88-102) and in men 91.6 years (range 88-98). All subjects in the study were living independently and did not require major care. Eight persons lived in their own home and six in a home environment where they were not obliged to cook their own meals. With the exception of two women aged 95 and 102, all were able to prepare their own food. The mobility of the same two women was restricted to the use of a wheelchair; all others showed normal locomotion. All but three male subjects had some hearing or visual loss. Two women and five men reported that they took no medication. The others took vitamins or homeopathic preparations. Two women and one man occasionally took a hypnotic drug, but not during this study. All the men had either high school or higher education, whereas four of the women had less than high school education. There was no indication of present or past affective disorder. All appeared to be in a positive state of mind except for one women who complained of being mildly depressed. Ambulatory monitoring was obtained using a modified four-channel Medilog system. Sleep was evaluated by means of two bipolar EEG leads (Fpz-Cz/Pz-Oz), one electrooculograph (EOG) lead (electrode placement at outer eye canthi), and one submental electromyograph (EMG) lead. No other polygraphic variables (e.g., respiration, core temperature, period leg movement assessment) were recorded. These raw data were transferred to a computer allowing visual scoring of sleep-wakefulness stages by 30-see epochs from the screen. Sleep scoring data were validated with respect to the classical Rechtschaffen and Kales (1968) lead (Van Sweden et al 1990). T&e sleep scoring involved distinguishing between wakef:Jlness, REM sleep, and four stagee o~"non.REM (NREM) sleep. Stage NREM 1 sleep is considered as a transitional stage following sleep o~et, NREM 2 is light sleep, and NREM 3-4 are stages of deep sleep or slow wave sleep. In contrast with other sleep studies in the elderly (Prinz et al 1982; Reynolds et al 1985a), we did not introduce new intermediate sleep stages, nor did we combine sleep stages. Scoring criteria were based on strict Rechtschaffen and Kales rules (1968), with few specifications and inceptions. Deep sleep (stages 3 and 4 NREM) was quantified on the frequency spectrum and not on the amplitude of the slow waves, as suggested by Webb and Dreblow (1982a). REM sleep was mainly scored on the tonic and phasic EEG and EOG aspects because submental muscle tone was often unreliable in the elderly, a finding also stressed by others (Prinz et al 1982). Analysis covered sleep structure continuity paranletcrs (REM and NREM sleep) and parameters indicating sleep disruption. These disruptions include wake after sleep onset (WASO), sleep efficiency, and arousal index defined by the number of transitions to wake characterized by an EEG/EMG activation of at least 20 sec of a 30-see epoch. We also evaluated some chronobiological "~-~L'4e~ ~.~.~-~-~- ~ , ~ " ~ M ultradian rhythm. Data were calculated separately for
Aging of Core and Optional Sleep
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the total sleep period and for each sleep cycle. Definitions of sleep parameters can be found in the glossary of "The International Classification of Sleep Disorders" (ICSD) (1990). Cycle definition is difficult, but important, particularly in the aged person in whom variability and fragmentation of sleep may be more important (Webb and Dreblow 1982b). Moreover, the recognition of cyclicity is more reliable if several repeated recordings are available showing a consistent sleep pattern. Combined rules (15 min) were used in defining NREM-REM cycles: a cycle ends with a period of !~.EgMsleep, which might be interrupted by other sleep stages, provided that these interruptions are less than 15 rain. However, the duration of the percentage of REM sleep was scored according to classical Rechtschaffen and Kales rules. REM sleep was scored as REM sleep provided that the interruptions were not longer than 2 rain and calculated as such.
StatisticalAnalysis Data from the young and elderly women and the young and elderly men were compared using sleep cycle parameters for sleep continuity and disruption. The differences between the groups were assessed using a two-factor (age x gender) analysis of variance (ANOVA). Analysis of the sleep structure for the different cycles was done using a threefactor (age x gender x sleep cycle) ANOVA. A p less than 0.05 was considered as the minimal significant level. Although the basic sleep structure parameters obtained in Otis group of elderly persons were previously published (Wauquier et al 1991b), the present analysis provides additional data with respect to sleep cycles. There is also new data from a group of younger persons with which the group of elderly are compared. A three-factm" analysis was applied to the data obtained and a completely new analysis of the data was realized using the concepts of core and optional sleep (see results section).
Results The times of sleep onset and offset are shown in Figure 1. Both sleep onset and offset were more variable in elderly men as compared with young adults. The differences in women were minimal and not significant. There was no significant difference between the first and second night in both the young and elderly group and in none of the sleep parameters analyzed. Therefore, data were combined from the two consecutive nights for each group separately. Some important parameters concerning sleep structure, sleep disruption, circadian pattern, and the results from the ANOVA are presented in Table 1. The data pertain to age- and gender-related effects. Time in bed was both gender and age dependent, mainly because elderly women spent longer time in bed. Differences in total sleep time were related to gender, as total sleep time was substantially reduced in elderly men. The differences in total time spent in the different stages as expressed in percentage are almost exclusively an age-related effect. The gender factor and interaction between age and gender was not significant. WASO was both age and gender dependent. Transitions to wake from NREM sleep was mainly an age-related effect. Awakening from REM sleep was both age and gender related, occurring mostly in elderly men. Sleep efficiency was less in elderly women and more in elderly men. Sleep latency was not significantly different, whereas REM sleep was reduced in the elderly and more so in men than in women. Figure 2 shows the duration of the successive NREM-REM cycles
870
BXOLPSYCHIATRY 1992;31:~66--880
A. Wauquier and B. van Sweden
< .05
Time (h)
I
10,00
09.00
i
08.00 07,00 06.00
D u
05.00
Figure 1. Time of boing to bed and rising for young persons (left part) and elderly persons (right part). Each point indicates an individual recording but due to the overlap not every recording is seen.
04.00 03.00 02.00 01.00 24.00 m
23.00
p
I
22,00
Age (years)
Female Male 25-35
Female
Male 88-102
in young adults and elderly men and women. In young adults the variability of the cycle duration as based on the standard deviations of the mean was small. The second sleep cycle was the longest in both young men and young and elderly women. In elderly men, the first two sleep cycles were considerably shorter than in young adults and elderly women. There is a significant effect in gender (F - 6.44, p = 0.012), in cycles (F - 24.13, p = 0.0001), and there is a significant interaction between age and cycle (F - 4.650, p = 0.001). Data per cycle give an approximation of the evolution and trends in sleep structure parameters in the course of sleep process. Figure 3 a-f shows the evolution of WASO, REM sleep, and the different stages of NREM sleep. The figures document age, gender, and cycle differences. WASO remained relatively constant throughout
Aging o f Core and Optional Sleep
BtOL PSYCHIATRY 1992;31:866-880
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Table 1. Circadian, Sleep Structure, and Disruption Parameters in Healthy Young Men and Women and Elderly Women and Men Separately Young adults Women Men (ages 25-35) Time in bed (min) 479 460 (14.4) (I !.9) Total sleep time (rain) 420 412 (16.2) (8.44) NRBM ! (%) 7.05 8.10
(0.40) NREM 2 (%) 44.4 (2.14) NREM 3 (%) 8.91 (0.66) NREM 4 (%) 10.1 (1.43) REM (%)
Elderly Women Men (ages 88--102)
Age
ANOVA gender
Interaction (age x gender)
566 (22.8)
462 (14.6)
F = 7.543 p = 0.008
F = 14.92 p = 0.0003
F = 7.111 p ~- 0.01
438 (27.6)
328 (14.1)
F = 3.606 NS (1)
F = 11.73 p ffi 0.001
F = 5.804 p = 0.004
18.9
23.1
F ffi 109.3
F = 3.577
(0.86)
(I.80)
(2.09)
p = 0.0001
NS
F = 1.755 NS
42.5 (1.78)
37.7 (I.89)
33.9 (2.19)
F ffi 14.47 p ffi 0.0003
F ffi 1.588 NS
F ffi 0.357 NS
9.91 (!.24)
9.23 (1.02)
4.96 (0.90)
F = 5.034 p ffi 0.029
F ffi 2.876 NS
F = 6.59 p = 0.012
10.4 (I.40)
4.57 (1.02)
0.37 (0.21)
F ffi 36.57 p = 0.0001
F ffi 2.947 NS
F = 2.635 NS
10.1
10.4
4.57
0.37
b" -- 78.71
F = 0.777
F = 0.014
(!.43)
(1.40)
(I.02)
(0.21)
p = 0.0001
NS
IsiS
17.1 (3.43)
30.4 (3.60)
F ffi 60.31 p = 0.0001
F --- 6.556 p = 0.0129
F = 10.36 p = 0.002
26.8 (2.92)
33,3 (4.37)
F ffi 37.44 p = 0.0001
F = 1.068 NS
F = 2.116 NS
0.86 (0.28)
5.57 (0.99)
F ffi 4.706 p -~ 0.0339
F = 7.919 p = 0.0065
F = 30.38 p = 0.0001
79.0 (3.48)
72.0 (I.82)
F ffi 37,272 p ffi 0.0001
F = 1.146 NS
F = 4.351 p -- 0.041
29.9 (4.59)
28.7 (3.21)
F = 2.584 NS
F = 0.603 NS
F = 0.273 NS
56.2 (6.51)
33.4 (5.70)
F = 27.91 p = 0.0001
F = 0.448 NS
F = 4.677 p = 0.0344
WASO (%) 6.53 5.00 (I.09) (I.00) Transition to wake from NREM (n) 14.6 13.1 (I.63) (I.93) Transition to wake from ItEM (n) 2.75 1.22 (0.51) (0.31) Sleep efficiency (%) 87.8 90.0 (I.97) (I.29) Sleep latency (min) 4.6 18.2 (6.33) (3.19) REM latency (rain) 81.3 93.3 (6.32) (10.8)
NS: not significant(p > 0.05). Significanceof differences assessed by a two-factorANOVA.
the n i g h t in y o u n g adults. I n the elderly, the percentage increased sk, .ficantly after the first sleep c y c l e . T h e m a i n factors o f a g e a n d c y c l e are significant ( F = :51.00, p 0 . 0 0 0 1 and F = 7 . 9 2 7 , p = 0 . 0 0 0 1 , r e s p e c t i v e l y ) , as well as the interaction b e t w e e n a g e a n d g e n d e r ( F = 5 . 7 6 1 , p = 0 . 0 1 7 ) a n d a g e and c y c l e ( F = 5 . 4 5 9 , p = 0 . 0 0 0 3 ) . N R E M 1 gradually i n c r e a s e d o v e r the c o u r s e o f the night in b o t h the y o u n g and elderly. A l l the m a i n factors w e r e significant: a g e ( F = 9 3 . 3 6 2 , p = 0 . 0 0 0 1 ) , g e n d e r ( F =
872
BIOLPSYCHIATRY
A. Wauquier and B. van Sweden
! 992;31:866-880
200 180 160 ~
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CYCLE Figure 2. NREM-REM cycle duration in the course of sleep. Each point indicates the mean (+/-SEM) for the different groups (first and second night combined): in young women (open circles) (n--20), young men (open sq,ares) (n= 18), elderly women (filled circles) (n= 14), and elderly men (filled squares) (n--14). 3ignificant differences between the groups for the different cycles were assessed using a three-factor (age x gender x cycle) ANOVA (results in text).
6.672, p = 0.0102), and cycle (F = 5.78, p = 0.0002), but there was no significant interaction among those factors. In young persons, slow wave sleep (stages NREM 3 and NREM 4) gradually decreased over the course of the night. This progressive decrease was sorer;what steeper for NREM 4 than for NREM 3. In elderly men NREM 3 was relatively well preserved. Therefore, for NREM 3 sleep, there is a significant gender (F - 10.366, p - 0.0014) and cycle (F = 36.741, p -- 0.0001) effect and a significant three-factor interaction (F - 2.659, p = 0.033). On the contrary, NREM 4 was significantly decreased in elderly women and was even absent in elderly men. All main factors were significant: age (F = 43.586, p = 0.0001), gender (F - 6.733, p = 0.01), cycle (F -- 23.34, p = 0.0001), and there was a significant interaction between age and cycle (F -- 12.859, p = 0.0001). The duration of REM progressively increased until the fourth cycle in young women and until the third cycle in young men. Thereafter, REM sleep showed a progressive decline. In contrast, a steady decrease in both elderly men and women was observed. The first REM episode was the longest exceeding the duration in young adults. Age (F - 22.567, p = 0.001) and cycle (F --- 26.82, p = 0.001), and both the interaction between age and gender (F = 4.142, p - 0.042) and age and cycle (F -- 9.422, p = 0.0001) were significant. In the young persons, NREM 2 showed an evolution comparable to REM sleep; there was an initial increase followed by a progressive decline after the first three sleep cycles. This trend was similar for the elderly women, whereas, in elderly men, the
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Figure 3 a-f. Evolution of WASO, NREM I, 2, 3, 4, and REM sleep for successive sleep cycles. Each point indicates the mean ( + / - SlM) for the diferent groups (first and second night combined)-.-young females (open circles) (n -- 20), young males (open squares) (n = 18), elderly females (filled circles) (n= 14) and elderly males (filled squares) (n----14). Significant differences between the groups for the different cycles were assessed using a three-factor (age x gender x cycle) ANOVA (results in text).
874
BIOLPSYCHIATRY
A. Wauquier and B. van Sweden
1992;31:866-880
trend was more reminiscent of aged REM sleep (i.e., a steady decline). Also, age (F = 4.852, p = 0.0284) and cycle (F = 13.038, p 0.0001) were significant. To evaluate sleep structure using the concepts of core and optional sleep we subtracted the first three sleep cycles in the young adults and took a comparable duration of sleep aftei° sleep onset i~ elderly men (CI + C2 + C3 + C4 = 370 min) and women ( e l + C2 + C3 = 380 min.) The remaining section was considered optional sleep and the first part as core sleep. We compared the structure and disruption parameters of both sections in the four groups. Figure 4a shows the structure of core sleep. In young males and females the core sleep section was strikingly similar. In both elderly men and women slow wave sleep (NREM 3-4) and ItEM sleep were significantly decreased, whereas wakefulness and drowsir~css were significantly increased. This effect was more conspicuous in elderly males than in females. NREM sleep, however, was strikingly similar. Accordingly, there were significant factors (age and gender) for all stages except for NREM 2. The interaction age × gender was significant, except for NREM 2 and NREM 4 (see statistical data in figure legends). Figure 4b shows optional sleep for the four groups. There was a significant age and gender effect for wakefulness, NREM 1 and 2, and REM sleep, but not for NREM 3 and 4 sleep, and a significant interaction for only NREM I and NREM 3 sleep (see statistics in figure legends). The optional sleep is shorter in young men than in women. The duration of this optional sleep in the elderly paralleled the values observed in the young persons. However, there was a proportional decline in REM sleep and increased signs of sleep disruption (WASO and NREM 1 sleep). Discussion The data document that ambulatory sleep-wakefulness monitoring yields comparable aging effects of the sleep function as obtained in laboratory recording settings by other researchers (Blois et al 1983; Reynolds et al 1985a, 1985b, 1987; Webb 1982, 1987). The recording quality was excellent and the technique was well tolerated in the investigated elderly persons. This supports the idea that this technique can be useful for both clinical screening and research purposes. The conclusions may become stronger when a direct comparison is made using the two different techniques in the same population. We have discussed the influence of the recording technique and age on sleep patterns in a previous report (Wauquier et ai 1991a). However, in the present study there was no first night sleep effect in the young adult population or in the selected elderly population. The present findings add more trends over time of sleep structure and disruption parameters as recorded in the conventional home setting. With respect to sleep disruption, it is interesting to note that in young persons, awakening is rather evenly distributed over the night and is lowest during the first sleep cycle. Awakening from sleep is more conspicuous in the elderly and more so in men than in women. The increasing trend over time for NREM 1 (by some considered as drowsiness, by others as part of the sleep, i.e., a transition of sleep) is similar in young adults and the elderly. However, this stage becomes more significant in elderly women and even more so in elderly men. This may have clinical relevance for the subjective evaluation of sleep as hypnagog:~; .'xctivitymay be a prominent feature of this stage. The eventual relationship with psychopathology in the aged persons might be an interesting subject of investigation. The data regarding slow wave sleep are in accord with the literature. The elimination of the delta amplitude criterion for scoring slow wave sleep is based on suggestions by
Aging of C~re and Optional Sleep
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Figure 4a and b. Figurecorresponds to Table 2a and b. Webb and Dreblow (1982a) and recent data by Ehlers and Kupfer (1989). Indeed, there is a decreased slow wave sleep in the elderly, but apparently there is also a dissociation between the age-related evolution of stages NREM 3 and 4. Stage NREM 4 is more affected by aging than stage NREM 3. There was no significant age effect for NREM 3 sleep. The reason for the difference between stages NREM 3 and 4 might be the scoring
876
BIOL PSYCHIATRY 1992;31:866-880
A. Wauquier and B. van Sweden
Table 2a. (See also Figure 4a.) The Structure of Core in Sleep in Percentage (Comparable Duration: Cycle 1 to Cycle 3 in Young Adults and Elderly Women and Cycle 1 to Cycle 4 in Elderly Men) Significant Differences Using a Two-factor (Age × Gender) ANOVA Stage
Age
Gender
Int e ra c t i on
Wake
F = 45.333 d
F = 4.943 °
F = 6.513 b
NREM !
F = 98.91 d
F -- 5 . 3 6 2 °
F -- 4 . 0 5 °
NREM 2 NREM 3
F = 3.867 F = 7.72 b
F = 0.655 F = 8.519 b
F -- 0 . 1 9 7 F = 6.157 °
NREM 4
F --- 39.44~ d
F = 5.016a
F =
!,579
REM
F = 37.712 d
F = 0.263
F =
1.349
Table 2b. (See also Figure 4b.) Th¢~Structure of Optional Sleep in Mean Minutes. Significant Differences Using a Two-factor (Age × Gender) ANOVA Stage
Age
Gender
Int e ra c t i on
Wake
F = 7.987 b
F ffi 5.23 a
F -- I . I 1 7
NREM I
F =
F -- 6 . 9 0 5 b
F = 5.142 a
NREM 2
F = 5,134 °
F = 14.108 c
F -- 0,091
NREM 3
F = 0.008
F = 5.632 a
F -- 4 , 3 7 7 a
NREM 4 REM
F = 1.65 F -- 17.297 't
F = 0.821 F = 6.783 °
F = 0.071 F ffi 3 . 8 9
10,28 b
op < 0,05; bp < ,Ol; ~'p < 0.001; dp < O,O(N)I,
criteria; the delta activity appears less continuous and is more fragmented in the elderly and thus promotes the scoring of stage NREM 3. Some data suggest that the age-related decline in slow wave sleep might be a scorings artefact due to the physical difference~ in skull conductance (Dijk et al 1989). The reported differences in power in young women and men are more convincing for slow frequencies than for higher frequency rhythms. One would, however, expect a more uniform power increase or reduction if only physical factors were involved. Moreover, physical recording factors cannot be held responsible for the differences in sleep duration correlating with the amount of slow wave sleep. Finally, one would expect that osteoporosis of old age wouk~ induce an amplitude increase rather than the observed decrease. A similar trend has been emphasized for rhythmic waking EEG activity in normal aging (Christian 1984). Amplitude reduction is a normal characteristic of the waking EEG and normal aging. As mentioned by ot~lers, a loss of NREM 4 sleep is particularly obvious in elderly men. Gender differences have been reported in routine EEG screening in the elderly, particularly regarding beta frequencies (Busse 1983). The data suggest that at least some of the age-related changes of slow wave sleep might represent an amplification of the waking EEG characteristics in normal aging. REM sleep shows that there is a significant interaction between age and gender. Furthermore, in both elderly men and women, although total REM is decreased, it is consistently highest during the first part of the sleep period. Our ambulatory recording findings are less ambiguous than some data (Hayashi and Endo 1982). ItEM sleep timing is dependent on the circadian pacing. According to Weitzmann et ai (1982) a forward REM shift might be related to a phase advance of the circadian rhythms in aging processes. As pointed out earlier by Webb (1982, 1987), chronobiological aspects are important for aging sleep. The above-mentioned advanced REM shift and the increased variability of
Aging of Core and OptionalSleep
BIOLPSYCHIATRY 1992;31:866-880
877
the NREM-REM cycle duration are compatible with the phase advance and reduced amplitude of a circadian oscillation (Wever 1985). A similar phase advance has been noted in free running conditions without alteration of the NREM-REM cycle duration (Weitzman et al 1980) As there is no data concerning core body temperature, we cannot relate the observed gender differences in sleep structure to this important circadian pacemaker (Campbell et al 1989). In contrast with current findings in young adults documenting a biphasic course (Home 1989), the NREM-RF.~ cycle shows a monophasic evolution in the elderly; this may also result from this forward REM shift. According to the current sleep hypothesis (Borbely 1982) and an earlier recovery model of Feinberg (1974), ItEM displacement may depend on a circadian process, and a decline in slow wave sleep could result from an insufficiency in sleep pressure. Apparently both systems (referred to respectively as "process C" and "process S") are affected by aging, although it is obviously hazardous to indicate what dysfunction is primary or secondary. Although the data support the phase advance theory to explain the early ItEM episodes of advanced age (Weitzman et al 1980), both the ItEM sleep-slow wave sleep interaction hypothesis and circadian amplitude hypothesis cannot be refuted by our findings. The study suggests an inverse relation between REM latency and slow wave sleep duration and a direct correlation with total sleep time, a measure for a putative circadian arousal cycle (Schulz and Lund 1985). What might be the functional significance of our findings and their implications7 How can we translate polygraphic data into clinical language? Our findings will be related to cognitive function and affective disorder using the dichotomy between core and optional sleep put forward by Home (1989). Core sleep as defined by Home involves predominantly slow wave sleep as it is recorded in the early three sleep cycles. However, in humans this sleep type cannot be separated from its associated ItEM segment. In fact, our findings would suggest that ItEM sleep in the elderly is more or less transferred or shifted to the core section of sleep and exponentially decreases thereafter It is probably no coincidence that the first sleep cycle, showing the least sleep disruption, also contains the longest REM episode. This REM saving effect might he important for cognitive functioning in normal or successful aging, as defined by Rowe and Kahn (1987). In dementia of the AIzheimer type, a REM decline and an increased REM latency have been reported (Prinz et al 1982; Vitiello et al 1984). In addition, cholinergic transmission, important for REM sleep timing and induction, is reduced in cortical dementia. One may wonder to what extent of pathophysinlogical significancein subcortical and cortical dementia a disturbance of this "physiological" REM shift mechanism might be. Optional sleep (the remaining sleep section) is curtailed and disrupted in the elderly, which appears not to be associated with excessive daytime napping (Carskadon et al 1982). This last sleep section contains less stage NREM 2 and REM sleep, diminishing its internal compensation function when sleep is disrupted in its core section, suggesting a physiological "atrophy" of this adaptive sleep section. Some of the age-related sleep alterations are similar to the sleep dysfunction in affective disorders (Reynolds and Kupfer 1987). Indeed, a shortened first sleep cycle diminished slow wave sleep and shallow last sleep segment are prominent in severe depression. REM latency is an important polysomnographic variable in clinical psychiatry (Kupfer 1976). Although REM sleep t'arameters remain the most reliable differentiating criteria between the elderly demented and depressed patients (Reynolds et al 1985b, 1988), a polysomnographic classification may be difficult, particularly in elderly mt;n. Furthermore, caution with respect to the diagnostic value of ItEM latency has recently been expressed (Pressman 1989).
878
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1992;31:866-880
Normal aging is characterized by a decreased transmitter turnover without a simultaneous functional loss. The brain,has important functional reserve capacit~ based on an increased activity (up-regulation of the remaining neurons). The relationship between the clinical state and the sleep pattern, of which the REM latency is only one parameter of the first sleep cycle, may be raised. The notion of a decreased adaptive function of the first and last sleep segments may also be of considerable interest for the biology of depressive states. A decreased turnover and/or dysregulation of transmitter systems has been postulated in depression (Siever and Davis 1985). The dysfunction could be stressinduced resulting from exhaustion (state parameter) or could represent a genetic vulnerability (trait parameter) (Gold et al 1988). Our findings in healthy elderly also show that this sleep pattern is not necessarily associated with clinical psychopathological signs. In fact, this could reflect a nonspecific expression of a dysregulated neurochemical state. Considering the important interactions between the different transmitter systems, a comparable polysomnographic pattern is perhaps not surprising and could help to explain similar sleep data in schizophrenia (Hiat et al 1985; Zarcone et al 1987). Many features defy all clinical interpretation, and speculation as to the underlying mechanisms are not understood. They will probably only be accessible through other techniques of investigation. The age-related decline in slow wave sleep undoubtedly remains most intriguing (Wauquier et al 1989). Based on the previous findings, it might be suggested that at least some aspects of the NREM sleep alterations in aging might be gender dependent. References Blois R, Feinberg I, Gaillard JM, Kupfer DJ, Webb WB (1983): Sleep in normal and pathological aging. Experientia 39:551-586. Borbely AA (1982): A two process model of sleep regulation. Human Neurobiol 1:195-204. Busse EW (1983): Electroencephalography. In Reisberg B (ed), Alzheimer's Disease. London: The Free Press, p 231. Campbell SS, Gillin JC, Kripke DF, Erikson P, Clopton P (1989): Gender differences in the circadian temperature rhythms of healthy elderly subjects: Relationships to sleep quality. Sleep 12:529-536. Carskadon MA, Brown ED, Dement WC (1982): Sleep fragmentation in the elderly: Relationship to daytime sleep tendency. Neurobiol Aging 3:321-327. Christian W (1984): Das Elektroencephalogram in hoheren Lebensalter. Nervenartz 55:517-524. Dijk DJ, Beersma DGM, Bloem GM (1989): Sex differences in the sleep EEG of young adults: Visual scoring and spectral analysis. Sleep 12:500-507. Ebersole J (ed) (1989): Ambulatory EEG Monitoring. New York: Raven Press, p 365. Ehlers CL, Kupfer DJ (1989): Effects of age on delta and REM sleep parameters. Electroencephal Clin Neurophysiol 72: ! 18-125. Feinberg I (1974): Changes in sleep cycle patterns with age. J. Psychiatr Res 10:283-306. Feinberg ! (1989): Effects of maturation and aging on slow wave sleep in man: Implications for neurobiol,3gy. In Wauquier A, Dugovic C, Radulovacki M (eds), Slow Wave Sleep: Physiological, Pathophysiological and Functional Aspects. New York: Raven Press, pp 31-48. Gold PW, Goodwin FK, Chmnisos GP (1988): Clinical and biochemical manifestations of depression--relation to the neurobiology of stress. N Engl J Mud 319:413-420. Hayashi Y, Endo S (1982): All night sleep polygraphic recordings of healthy aged persons: REM and slow-wave sleep. Sleep 5:277-.283. Hiat JF, Floyd FC, Katz PH, Feinberg I (1985): Futher evidence of abnormal NREM sleep in schizophrenia. Arch Gun Psychiatry 42:797-802.
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Home J (1989): Why We Sleep. Oxford: Oxford University Press. ICSD (1990) International Classification of Sleep Disorders: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee, Rochester, Minnesota: American Sleep Disorders Association, 1990. Kupfer DJ (1976): REI~Alatency: A psychobiologic marker for primary depressive disease. Biol Psych 11:159-174. Landahl S, Jagenburg K, Svanborg M (1981): Blood components in a 70-year old population. Clin Chem Acta 112:301. Ligthart GJ, Corberand JX, Fournier C, et al (1984): Admission criteria for irnmunogerontological studies in man: The Senieur protocol. Mech Ageing Dev 28:47-55. Pressman R (1989): Interpreting the polysonmogram: 10 questions to consider concerning nocturnal REM sleep latency. APSS Newsletter 4:9-15. Prinz PN, Peskind ER, Vitaliano PP, et al (1982): Changes in the sleep and waking EEGs of nondemented and demented elderly subjects. J Am Gerontol Soc 30:86-93. Rechtschaffen A, Kales A (I 968): A Manualof Standardized Terminology, Techniquesand Scoring System for Sleep Stages of Human Subjects. Washington DC: Public Health Service, U.S. Government Printing Office, Reynolds CF III, Kupfer DJ (1987): Sleep research in affective illness: State of the art circa 1987. Sleep 10:199-215. Reynolds CF III, Kupfer DJ, Taska IS, Hoch CC, Sewitch DE, Spiker DF (1985a): Sleep of healthy seniors: A revisit. Sleep 8:20-29. Reynolds CF IH, Kupfer DJ, Taska IS, et el (1985b): EEG sleep in elderly depressed, demented and healthy subjects. Biol Psychol 20:431-442. Reynolds CF I11, Kupfer DJ, Month PR, et el (1988): Reliable discrimination of elderly depressed and demented patients by electroencephelographic sleep data. Arch Gen Psychiatry 45:258264. Rowe JW, Kahn RL (1987): Human aging: Usual and successful. Science 237:143-149. Schulz H, Lund R (1985): On the origin of early REM episodes in the sleep of depressed patients: A comparison of three hypotheses. Psychiatry Res 16:65-77. Siever LJ, Davis KL (1985): Toward a dysregulation hypothesis of depression. Am J Psychiatry 142:1017-1031. Van Sweden B, Kemp B, Kamphuisen HAC, Vet der Velde A (1990): Alternative electrode placement in (automatic) sleep scoring. Sleep 13:279-283. Vitieilo MV, Bokan JA, Kukull W, Muniz RL, Smallwood AG, Prinz PM (1984): REM sleep measures of the Alzheimer's type dementia patients and optimally healthy aged individuals. Biol Psychiatry 19:721-734. Wauquier A, Dugovic C, Radulovacki M (1989): Slow Wave Sleep. Physiological, Pathophysiological and Functional Aspects. New York: Raven Press, p 330. Wauquier A, Van Sweden B, Kerkhof GS, Kamphuisen HAC (1991a): Ambulatory first night sleep effect recording in the elderly. Behav Brain ~qes42:7-11. Wauquier A, Van Sweden B, Lagaay J, Kemp B, Kamphuisen HAC (1991b): Antbulatory monitoring of sleep-wakefulness patterns in healthy elderly males and females (>88 years). The "senieur" protocol. J Am Geriatr Soc. Webb WB (1982): The measurement and characteristics of sleep in older persons. NeurobiolAging 3:311-319. Webb WB (1987): Disorders of aging sleep. In yon Hahn HP (ed), lnterdisc Topics in Gerontology. Basel: Karger, pp 1-12. Webb WB, Dreblow LM (1982a): A modifiedmethod for scoring slow wave sleep in older subjects. Sleep 5:195-199. Webb WB, Dreblow LM (1982b): The REM cycle, combining rules, and age. Sleep 5:372-377.
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Weitzman E, Czeisler CA, Zimmerman JC, Ronda JM (1980): Timing of REM and stages 3 + 4 sleep during temporal isolation in man. Sleep 2:391-407. Weitzman E, Molire M, Czeisler C, Zimmerman J (1982): Chronobiology of eging temperature, sleep-wake rhythms and entrainment. Neurobiol Aging 3:299--304. Wever RA (1985): Models of interaction between ultradian and circadian rhythms: Toward a mathemathical model of sleep. Exp Brain Res (Suppl) 12:309-317. Zarcone VP, Benson KL, Berger PA (1987): Abnormal REM latencies in schizophrenia. Arch Gen Psychiatry 44:45-48.
