Homeostatic process and sleep spindles in patients with sleep-maintenance insomnia (SMI): effect of partial (21 h) sleep deprivation (PSD)

Electroencephalography and clinical Neurophysiology 107 (1998) 122–132

Homeostatic process and sleep spindles in patients with sleep-maintenance insomnia: effect of partial (21 h) sleep deprivation A. Besset*, E. Villemin, M. Tafti, M. Billiard Service de Neurologie B, Unite´ des Troubles du Sommeil et de l’e´veil, Hoˆpital Gui de Chauliac 34 295 Montpellier, Cedex 5, France Accepted for publication: 16 March 1998

Abstract Objectives: A low level of process 5 at bed time would be responsible for a reduced amount of slow-wave activity (SWA) leading to increased alpha activity and awakenings at the end of the night. Methods: Following a base-line night (BLN) recording, 7 sleep-maintenance insomnia (SMI) subjects and 7 sex- and age-matched controls were maintained on 21 h of sleep deprivation. Thereafter, a recovery night (RN) was performed from 2300 h until spontaneous awakening. SWA (power density of the EEG delta band between 0.75 and 4.5 Hz) was monitored by means of spectral analysis (FFT). Sleep spindles and the occupation ratio of Rechtschaffen and Kales EEG bands were observed by integrated digital filtering analysis. Results: SWA was lower in SMI subjects than in controls during RN but was higher than in BLN indicating that the homeostatic process was operating, but weaker in SMI subjects. On the other hand in SMI subjects the sleep spindle index (SSI) did not decrease during slowwave sleep and was significantly lower than in controls. Moreover during RN the SSI decreased significantly during the first sleep cycle in controls and not in SMI subjects. The existence of an inverse relationship between SWA and SSI was therefore not observed in insomniacs. Finally the mean duration of alpha frequency significantly increased in SMI subjects. Conclusions: It is hypothesised that in SMI subjects, an alteration of the homeostatic process is responsible for insufficient sleep pressure leading to an inability to maintain sleep for an extended period.  1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Insomnia; Sleep deprivation; Homeostasis; Sleep spindles; Slow-wave activity

1. Introduction Insomnia appears to be one of the most frequent sleep complaints with 20% of the population in France (Ohayon, 1996) and in North America (Bixler et al., 1979; Coleman, 1983; Mellinger et al., 1985; Gallup Organization, 1991) reporting dissatisfaction with their sleep or relying an medication. This widespread sleep disorder is above all heterogeneous, and numerous diagnostic algorithms have been proposed within internationally-recognised classification systems: the International Classification of Sleep Disorders (ICSD; Diagnostic Classification Steering committee and Thorpy, Chairman, 1990), Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV, 1994), the Manual of the international classification of the diseases, injuries and causes of death, 1993) (ICD 10). Specific symptoms (sleep-onset insomnia (SOI), sleep-maintenance insomnia (SMI), early-awakening insomnia or a combina* Corresponding author.

0013-4694/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0013-4694 (98 )0 0048-0

tion of the 3) are not specified within these classifications, and their evaluation is thus left to the clinical judgement. SOI is the most researched form whereas studies of SMI without other associated sleep disorders are rare. Women appear to have more sleep-onset difficulties than men, and younger subjects tend to have frequently more trouble falling asleep, whereas in older subjects difficulty in maintaining sleep is more commonly reported (Kales et al., 1984; Ohayon, 1996). The stability of these different specific symptoms is very low, especially for SMI with less than 20% (Hohagen et al., 1994). Nevertheless, it is possible that subjects presenting stable SMI may exist even though the phenomena may be rare. Studying subjects with permanent, typical sleep abnormalities as subjects with SMI may lead to a better understanding of the mechanisms underlying high intervening wakefulness during sleep episodes. It has been suggested (Gaillard, 1976, 1978) that some insomnia subgroups with SMI may manifest a chronic slowwave sleep (SWS) deficiency. New insights into the regulation of SWS are provided by recent computer-based EEG

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analysis using period amplitude analysis (Church et al., 1975) or fast Fourier transform (FFT) (Borbe´ly, 1982). The most relevant contribution of these new methods is probably the concept of SWS intensity which may be quantified by the level of slow-wave activity (SWA = power density of the EEG delta band between 0.75 and 4.5 Hz). Based on this concept, a model of sleep regulation has been proposed, in which the interaction of a circadian and a homeostatic process together determine sleep propensity (Borbe´ly, 1982). The homeostatic process, termed process S, increases gradually during waking, resulting in an elevated initial level of SWA, which then decreases exponentially during sleep (Dann et al., 1984). In accordance with the two-process model of sleep, the time-course of SWA has been shown to be a monotonic function of prior wakefulness in various experimental conditions (Dijk et al., 1987a,b, 1990a,b; Dijk and Beersma, 1989; Beersma et al., 1990). Moreover, SWA is not influenced either by the circadian phase of sleep onset or its time-course correlated to that of core body temperature (Dijk et al., 1990b, 1991a,b, 1992). The sleep of insomniac patients is generally described as poor sleep with frequent intrusions of wakefulness during sleep (Frankel et al., 1976). However this description of the architecture of sleep is insufficient for the satisfactory estimation of sleep continuity. This requires specific information relating to spindle density and occupation ratio of the EEG bands according to Rechtschaffen and Kales (R & K) criteria per epoch of 30 s. Such studies in normal subjects or in insomniac patients are rare. This is undoubtedly due in part to the considerable difficulties of performing this kind of study with conventional analysis. New computerised techniques such as integrated digital filtering analysis (IDFA) permit the assessment of sleep spindle density and the occupation ratio of EEG bands, especially the alpha band which indicates intrusion of wakefulness during sleep. We postulated that in some insomniac subjects a low level of process S at bedtime is accompanied by a reduced amount of SWS and/or SWA in the first part of the night leading to increased alpha activity and awakenings during the second part of the night. In order to demonstrate this hypothesis and according to the above propensity postulate, it was decided to restrict the sleep of SMI patients to the first 3 h of sleep. It was predicted that this partial sleep restriction would not be sufficient to increase the amount of SWS/SWA on recovery night. In addition it was assumed that this partial sleep deprivation could not prevent the intrusion of an important intra-sleep alpha activity in the second part of the night.

2. Materials and methods 2.1. Subjects Insomniac subjects were recruited from the sleep disorders outpatient clinic of the Neurology B department in a general hospital in Montpellier. Control subjects were nor-

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mal volunteers recruited through public advertisement. All subjects (insomniac and control) were remunerated for their participation. Selection criteria for insomniac subjects were complaints of poor sleep for more than 1 year with awakenings occurring during the second part of the night and normal self-estimated sleep-onset latency. Thirty-seven subjects were investigated. Eight subjects were excluded. Five subjects reported SMI associated with irregular sleep-onset difficulty and 3 were currently taking central nervous system (CNS) active drugs. Twenty-nine subjects were given the Minnesota Multiphasic Personality Inventory (MMPI) and underwent a selection polysomnographic (PSG) night. PSG criteria were: sleep-onset latency (SOL) less than 15 min, waketime after sleep onset (WASO) more than 45 min and apnoea and periodic leg movement indices less than 5/h. Twenty-two subjects were excluded, with 9 having a WASO less than 45 min, 7 exhibiting PLM disorder, 3 having an SOL more than 15 min and 3 having obvious abnormal EEG patterns or sleep architecture (pharmacological rhythms and/or REM rebound). Thus, only 7 subjects, out of 37 (18.91%), 6 male and one female, aged 22–53 years (mean = 35.17 ± 9.96 years) without any deviant MMPI scales fulfilled our inclusion criteria for SMI. All selected subjects were free of psychotropic drugs for at least 3 weeks. None of the subjects was obese (body mass index (BMI) ,26). Seven normal subjects, good sleepers, selected with the same procedure, sex- and age-matched to the insomniac patients, served as controls. None was obese (BMI ,26) nor had any taken psychotropic drugs for at least 1 month. 2.2. Experimental procedures Following the selection night (7000 h), subjects were required to stay in the laboratory for the duration of the experimental procedure. A PSG base-line night (BLN) was performed from 2300 h to 7000 h and was followed the next night by a further PSG starting at 2300 h and ending 3 h after sleep onset (curtailed night, CN). Finally, subjects were recorded during a recovery night (RN) from 2300 h to spontaneous awakening. During the 16 h daytime period, subjects were not allowed to sleep. Training for performance tests was carried out on the first day and somnolence and performance tests were performed on the second and third days (this data is reported elsewhere). 2.3. Spectral analysis (FFT) EEGs were derived from C3–A2 and C4–A1. EEGs were low-filtered at 40 Hz and high-filtered at 0.5 Hz and on-line digitised at a sampling rate of 128 Hz by an STC-PC card (SMII, France) on a personal computer (PC). FFT was performed on-line by means of a WE DSP32 digital processor card (AT & T). The epoch length was 4 s and a Hamming window was applied. Power spectra were calculated by Welch’s method (i.e. 9 epochs overlapping every 2 s) and

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the resulting spectra were averaged every 20 s if more than 5 epochs were artefact-free. For synchronising spectra and visual scoring of paper recording, a time-code signal was generated and recorded both on PC and EEG. Epochs with artefact were suppressed after visual inspection. NREM– REM sleep cycles were defined according to Feinberg and Floyd’s criteria (Feinberg and Floyd, 1979), by the succession of an NREM sleep episode of at least 15 min duration and a REM sleep episode of at least 5 min duration. No minimum REM sleep duration was required for the first and last cycle.

expressed as a percentage of the average of the sleepnight recording. Values of SWA were then plotted against time at cycle midpoint (CMP). CMPs were defined as the time elapsed from sleep onset until the middle of the cycle. An exponential decay function with a horizontal asymptote was fitted to the data by a non-linear regression procedure. The fitted function was SWAt = SWA0 × e − t/t + SWA∞ where SWA0 represents the intercept with the ordinate; t is the time of the CMP; t is the time constant of the exponential function; SWA∞ represents the horizontal asymptote if t approaches infinity.

2.4. Integrated digital filtering analysis (IDFA) 3. Results IDFA was performed through an automatic sleep analyser (Neurop-CEA-INSERM) in which specific filtering functions have been implemented. This system allowed for the assessment of the occupation ratio of EEG bands and the number of spindles per epoch (Besset, 1994). DFA was set on R and K EEG bands (delta 0.5–2 Hz, theta 3–7 Hz, alpha 8–12 Hz, beta 17–30 Hz and sigma 13–17 Hz). Sleep-stage visual scoring was carried out using a computerised assisted method (IDFA), (Besset, 1994) according to R and K criteria. This method allowed for more steadiness in sleep-stage scoring, especially for SWS. 2.5. Time-course of SWA SWA power density in sleep cycles was averaged per cycle. For each subject, the cycle value of SWA was

3.1. Polygraphic data Tables 1 2 summarise parameters derived from visual scoring for BLN, RN and CN and ANOVA results comparing insomniac and control subjects (factor group) and the different sleep recordings (factor night). As expected, the only differences between insomniacs and controls were a significant reduction of total sleep-time and sleep efficiency, and a significant increase of WASO and number of awakenings. These results were observed during BLN as well as during CN. During CN (expressed as a percentage of BLN) total sleep time (TST) was similar in both groups (39% of BLN value in SMI subjects and 40% in control group); WASO was also similar in both groups (12% of BLN value in SMI and 13.28% in controls); stage 1 was higher

Table 1 Sleep stages and waking during base-line and recovery nights in SMI and control subjects Sleep parameter

Total sleep time (min) Time in bed (min) WASO (min) No. of awakenings Stage 1 (min) Stage 2 (min) SWS (min) REM sleep (min) MT (min) % WASO % Stage 1 % Stage 2 % SWS % REM sleep % MT Sleep latency (min) SWS latency (min) REM latency (min) Sleep efficiency (min) REM efficiency (min)

Base-line night

Recovery night

P value

Insomniacs

Controls

Insomniacs

Controls

Group

Night

383.50 481.93 79.00 19.14 21.21 206.14 80.21 75.93 1.07 17.17 5.71 54.06 20.25 16.69 0.28 18.36 23.00 96.57 0.79 0.83

445.71 469.21 9.71 7.57 22.57 223.29 106.71 93.14 2.00 2.01 5.06 49.89 23.80 20.80 0.44 11.79 21.71 55.86 0.95 0.84

455.07 (26.83) 505.21 (30.37) 41.93 (20.97) 16.57 (4.82) 22.0 (5.36) 239.36 (27.10) 97.57 (17.75 96.14 (5.26) 3.29 (1.37) 7.87 (3.74) 4.77 (1.26) 51.54 (3.68) 21.94 (4.41) 21.06 (0.60) 0.69 (025) 5.07 (2.13) 14.36 (4.86) 90.00 (9.48) 0.91 (0.04) 0.84 (0.03)

541.86 (19.26) 565.29 (19.21) 11.21 (3.89) 8.29 (2.53) 29.8 (4.17) 266.29 (12.30) 134.57 (14.56) 111.14 (5.86) 7.79 (2.33) 1.97 (0.64) 5.39 (0.68) 48.64 (2.26) 24.34 (2.03) 20.20 (0.69) 1.43 (0.45) 4.57 (l.52) 11.14 (1.63) 61.79 (6.67) 0.96 (0.01) 0.81 (0.03)

0.001 n.s. 0.001 0.01 n.s. n.s. 0.05 0.05 n.s. 0.001 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. 0.001 n.s.

0.005 0.005 n.s. n.s. n.s. 0.05 n.s. 0.01 0.01 n.s. n.s. n.s. n.s. n.s. 0.05 0.005 0.05 0.01 0.05 n.s.

(23.34) (10.93) (17.96) (3.91) (1.60) (12.85) (16.81) (8.22) (0.32) (4.07) (0.66) (2.75) (4.05) (1.57) (0.08) (5.71) (6.04) (21.79) (0.04) (0.03)

(4.29) (4.59) (2.85) (1.70) (3.24) (13.49) (11.45) (8.54) (0.78) (0.61) (0.74) (3.05) (2.49) (1.92) (0.17) (2.21) (4.36) (2.47) (0.01) (0.03)

Percentages of sleep stages are referred to total sleep time. Values in parentheses represent SD. WASO, wake time after sleep onset; SWS, non-REM sleep stages 3 + 4; MT, movement time.

A. Besset et al. / Electroencephalography and clinical Neurophysiology 107 (1998) 122–132 Table 2 Sleep stages and waking during curtailed night in SMI and control subjects Sleep parameter

Total sleep time (min) WASO (min) No. of awakenings Stage 1 (min) Stage 2 (min) SWS (min) REM sleep (min) MT (min) %WASO % Stage 1 % stage 2 % SWS % REM sleep %MT Sleep latency (min) SWS latency (min) REM latency (min) Sleep efficiency (min) REM efficiency (min)

Curtailed night Insomniacs

Controls

P

149.51 9.43 7.00 8.86 72.00 48.36 19.93 0.36 6.91 5.91 48.16 32.34 13.33 0.24 7.83 20.71 67.43 0.90 0.81

181.56 (5.77) 1.29(0.45) 1.67 (0.33) 6.93 (1.61) 70 93 (5.52) 70.50 (8.62) 32.36 (2.38) 1.14 (0.52) 0.71 (0.23) 3.81 (0 96) 39.00 (3.13) 38.77 (4.20) 17.79 (1.52) 0.63 (0.29) 6.86 (1.77) 16.21 (2.26) 65.07 (04.04) 0.96 (00.01) 0.83 (00.01)

0.001 0.001 0.01 n.s. n.s. 0.01 0.005 0.05 0.001 n.s. n.s. n.s. n.s. 0.05 n.s. n.s. n.s. 0.01 n.s.

(17.00) (3.85) (2 64) (3.19) (14.47) (10.07) (03.92) (0.14) (2.11) (1 83) (8.06) (09.12) (02.28) (0.08) (03.82) (04.65) (04.88) (00.02) (00.07)

Percentages of sleep stages are referred to total sleep time. Values in parentheses represent SD. WASO, wake time after sleep onset; SWS, non-REM sleep stages 3 + 4; MT, movement time.

in SMI (41.77 of BLN value) than in controls (30.70% of BLN value); stage 2 was similar in both groups (35% of BLN value in SMI and 32% of BLN value in controls); SWS was lower in SMI (54.68% of BLN value) than in controls (66.06% of BLN value), and finally REM sleep

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was lower in SMI (26.24% of BLN value) than in controls (34.66% of BLN value). Thus the sleep debt was stronger in SMI in comparison with controls with regard to both SWS and REM sleep. Comparison of sleep parameters between insomniacs and controls during RN and BLN showed that sleep restriction resulted in significantly more TST (18% in SMI and 21.57% in controls), more SWS (21.64% in SMI and 26.10% in controls, values were significant for controls only and not for SMI), more REM sleep (26.61% in SMI and 19.32% in controls), a significantlyreduced REM sleep latency and a significantly-reduced SWS latency. 3.2. SWA In CN the time of integral SWA was significantly reduced in both groups, expressed as a percentage of BLN, integrated SWA was 43.17 ± 7% in insomniac patients and 46.60 ± 5% in control subjects. In RN (Fig. 1) when calculated according to the sleep cycles and expressed as a percentage of the BLN mean values, the SWA was significantly increased in SMI during the first 3 sleep cycles and in control subjects during the 4 sleep cycles. This SWA increase was significantly higher in control subjects than in SMI subjects, especially during the first sleep cycle (24% ± 11% in SMI subjects versus 68% ± 9% in control subjects). 3.2.1. Time-course of SWA Values of SWA% were plotted in Fig. 2 at cycle midpoints. In BLN and RN, SWA% declined exponentially from the onset to the end of sleep in both groups. An expo-

Fig. 1. Values of SWA in NREM and REM sleep per NREM–REM sleep cycle during base-line night (hatched bars) and recovery night (black bars) in SMI patients and control subjects. Values are expressed as percentages of the average SWA in the total sleep during the base-line night of each subject. *Significant difference (P , 0.05) between nights. °Statistically-significant difference (P , 0.05) between groups.

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Table 3 Summary of the non-linear regression analysis on the time-course of mean SWA in non-REM and REM sleep over successive sleep cycles Base-line night

Recovery night

Insomniacs SWA0 (%) t(min) SWA∞ r2

Controls

180.11 (8.09) 220.55 (30.81) 20.48 (10.59) 0.7139

Insomniacs

Controls b

178.05 (5.97) 226.33 (24.63) 23.10 (7.93) 0.7488

291.70 (5.18)a 137.46 (6.87)a 46.88 (3.42) 0.7487

208.4 (7.14) 232.67 (24.92) 32.34 (8.61) 0.5556

Values in parentheses represent 1 SD. Statistically-significant difference (P , 0.05) between recovery night and base-line night and between control recovery night and insomniac recovery night. b Statistically-significant difference (P , 0.05) between recovery night and base-line night. a

nential decaying function with a horizontal asymptote was fitted to the data (the regression equation yielded significant correlation coefficients P , 0.01 in both insomniacs and controls). Values of r2 were significant in both groups but smaller in insomniacs during RN. SWA0% values did not differ between the two groups in BLN and were significantly increased (P , 0.05) in RN in both groups. Moreover, in RN normal subject SWA0% values were significantly increased in comparison with insomniac subjects values: 15.70% in insomniacs versus 63.83% in controls when the SWA0 % increase was expressed as a

percentage of the BLN values. Finally, the value was significantly shorter (P , 0.05) in controls than in insomniacs in RN (Table 3). 3.3. EEG bands EEG bands were expressed as a percentage of the time occupied by the band during the epoch (Table 4). In BLN delta % was significantly lower (P , 0.05) while theta % was significantly higher (P , 0.05) in insomniacs in comparison with controls during SWS. Moreover in RN dur-

Table 4 Percentage of occupation of EEG bands per sleep stages during baseline night and recovery night Sleep parameter

Base-line night

Recovery night

Statistics

Insomniacs

Controls

Insomniacs

Controls

Group

Night

Delta % Stage 1 (min) Stage 2 (min) SWS (min) REM sleep (min) TST (min)

2.10 11.41 51.14 3.13 19.26

(0.47) (0.81) (6.83) (1.53) (3.61)

1.01 (0.44) 9.97(0.82) 58.36 (1.28) 2.53 (0.68) 20.62 (2.14)

2.12 10.36 52.48 2.67 18.34

(0.39) (0.88) (1.28) (1.12) (3.94)

3.73 9.97 65.64 1.67 21.39

(2.05) (0.82) (2.92) (0.17) (1.65)

n.s. n.s. 0.05 n.s. n.s.

n.s. n.s. 0.05* n.s. n.s.

Theta % Stage 1 (min) Stage 2 (min) SWS (min) REM sleep (min) TST (min)

71.70 (5.10) 76.10 (4.03) 45.46 (6.83) 81.04(5.10) 68.58 (2.80)

86.13 (2.23) 83.51 (2.94) 40.64 (1.48) 94.40(0.61) 74.55 (2.63)

70.64 76.43 43.99 83.96 69.47

(3.41) (3.76) (5.23) (3.56) (2.41)

86.04 82.96 32.92 95.71 71.84

(0.92) (2.79) (2.99) (0.74) (2.58)

0.001 0.05 0.05 0.0001 0.05

n.s. n.s. 05* n.s.

Alpha % Stage 1 (min) Stage 2 (min) SWS (min) REM sleep (min) TST (min)

25.89 12.31 3.41 15.51 12.00

(4.70) (3.72) (1.82) (4.29) (3.89)

10.61 6.26 0.99 2.82 4.55

(1.97) (2.52) (0.58) (0.57) (1.45)

27.46 13.18 3.53 13.22 12.13

(3.53) (4.12) (1.95) (3.05) (3.96)

9.71 (1.33) 6.40 (2.28) 1.43 (0.99) 2.46 (0.70) 4.53 (1.48)

0.0001 0.05 0.05 0.0001 0.005

n.s. n.s. n.s. n.s. n.s.

Beta % Stage 1 (min) Stage 2 (min) SWS (min) REM sleep (min) TST (min)

0.31 0.24 0 0.60 0.20

(0.09) (0.10)

3.45 0.33 0 0.41 0.35

(0.43) (0.12)

0.24 0.05 0 0.19 0.07

(0.12) (0.01)

(0.52) (0.08)

*Statistically-significant difference for the controls only. Values in parentheses represent SD.

(0.21) (0.12)

(0.07) (0.03)

1.48 0.10 0 0.25 0.15

(0.45) (0.04) (0.08) (0.05)

0.0001 n.s. n.s. n.s. n.s.

0.05* 0.05 0.05

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Fig. 2. Time-course of SWA in NREM and REM sleep per NREM–REM sleep cycle during the base-line night and the recovery nights in SMI and control subjects. Values of SWA are plotted at cycle midpoints and are expressed as percentages of the average SWA in the total sleep during the base-line night of each subject.

ing SWS, no percentage increase in delta or decrease in theta were observed in insomniacs in comparison with BLN while a significant difference was observed in controls: 2.62% in insomniacs, versus 12.47% in controls for delta % and −3.23% in insomniacs versus −19% in controls for theta %. In stages 1 and 2 and REM sleep, alpha % was significantly higher and theta % lower in insomniacs than in controls irrespective of night (BLN or RN). There was no difference between RN and BLN in any group. 3.4. Time-course of EEG bands In order to determine the time-course of EEG bands, values of percentage per epoch were calculated according to sleep cycles. Only the first 4 cycles were taken into account (Fig. 3).

3.5. Alpha % In BLN, alpha % was significantly (P , 0.01) higher in insomniacs than in controls in each cycle. In both groups, alpha % increased significantly (P , 0.05) from the first to the last sleep cycle. The same characteristics were observed in RN. 3.6. Theta % In BLN theta % was significantly higher (P , 0.05) in control subjects than in SMI during the two last cycles of the night. A progressive enhancement of theta % throughout the night was seen in both groups, however the differences of the values between cycles were not statistically significant. The same characteristic was observed in RN. In RN, theta % was significantly lower (by 18%) during the first cycle in

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control subjects than in SMI. In control subjects the values of the 4 sleep cycles in RN were however significantly lower (P , 0.01) (by 22%, 14.3%, 9.3% and 5%, respectively) than those of BLN. In SMI only the value of the second cycle was significantly lower (by 13.23%) than that of BLN. 3.6.1. Delta % In BLN, delta % was significantly (P , 0.05) lower (by

34%) during the second sleep cycle in SMI than in control subjects. In both groups, delta % increased significantly (P , 0.05) from the first to the last sleep cycle. The same characteristics were observed in RN. In RN delta % was significantly higher (P , 0.01) in the first and the second sleep cycles (by 63.44% and 25%, respectively) in control subjects than in SMI. In RN, the values of the 4 sleep cycles in controls were significantly (P , 0.01) higher (by 58.18%, 34.51%, 66% and 61.44%, respectively) than

Fig. 3. Time-course of EEG bands (alpha, theta, delta) in NREM and REM sleep per NREM–REM sleep cycle during the base-line night and recovery night in SMI (hatched bars) and control subjects (black bars). Values are expressed as the percentage of occupation per epoch (30 s). *Indicates a statisticallysignificant difference (P , 0.05) between SMI and control subjects, the line indicates a statistically-significant difference (P , 0.05) between cycles, °Statistically-significant difference between nights (base-line night and recovery night).

A. Besset et al. / Electroencephalography and clinical Neurophysiology 107 (1998) 122–132

those of BLN, while the value of the second sleep cycle only was significantly (P , 0.01) higher (by 44.25%) than that of BLN in SMI subjects.

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the first NREM sleep cycle (176.53 spindles/h ± 9.16 vs. 116.63 spindles/h ± 5.95). This reduction was not significant in insomniacs (119.5 spindles/h ± 14.9 vs. 126.76 spindles/h ± 18).

3.7. Sleep spindles In BLN and RN, the sleep spindle index/h (SSI) was significantly (P , 0.001) lower (by 72% and 66.6%, respectively) in insomniacs than in controls. In controls (Fig. 4, upper part), the SSI was increased in stage 2 in comparison with SWS during both BLN and recovery nights (by 128.56% and 159.93%, respectively). This increase was not significant in insomniacs (by 29.45% and 51.12%, respectively).When averaged according to sleep cycles, the SSI was significantly higher (P , 0.01) during the last sleep cycles of the night in controls irrespective of night (BLN or RN), however for insomniac patients this was only the case for BLN and did not reach significance (Fig. 4, lower part). Furthermore, during the recovery night, the SSI was significantly reduced (P , 0.01) in controls during

4. Discussion Both the number of awakenings and the duration of WASO were increased, while sleep efficiency and TST were decreased, in insomniacs in comparison with controls. Sleep latency did not differ between the two groups on any of the 3 nights (BLN, CN, RN) confirming the specific complaint of sleep-maintenance insomnia reported by these subjects. Due to TST reduction, SWS and REM were decreased in absolute values, but not in term of percentage in insomniacs. A similar reduction of SWS has already been reported (Gaillard, 1976, 1978) and interpreted as a consequence of a deficient sleep mechanism. REM sleep reduction has also been found in other studies (Frankel

Fig. 4. Upper part: sleep spindle index (the SD) per sleep stages for base-line night (hatched bars) and for recovery night (black bars) in SMI and control subjects. * Indicates a statistically significant difference (P , 0.05) between sleep stages. The line indicates that the difference is significant for both nights. Lower part: sleep spindle index (the SD) in NREM and REM sleep per NREM–REM sleep cycle during the base-line night (hatched bars) and recovery night (black bars) in SMI and control subjects. *Statistically-significant difference (P , 0.05) between nights. The line indicates a statistically-significant difference (P , 0.05) between sleep cycles.

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et al., 1976; Gillin et al., 1979; Hauri and Fisher, 1986). During RN, TST was increased in both groups, but less so in insomniacs than in controls. On the other hand, despite the sleep deprivation, WASO remained at high levels in insomniacs during RN, even if reduced to a non-significant degree in comparison with BLN. Thus PSD had limited effects on sleep continuity in SMI. After the CN, a greater debt of both SWS and REM sleep was observed in SMI in comparison with controls subjects. If in RN the REM sleep increase was greater in SMI than in controls, the SWS increase was lower in SMI than in controls. A normal homeostatic process, as demonstrated by SWS has been shown in poor sleepers (Benoit and Aguirre, 1996) in whom the amounts of stage 4 sleep and SWS were similar to those of controls subjects after a 24 h or 36 h sleep deprivation. Partial sleep deprivation (PSD) is known to decrease REM sleep more than SWS, however a rebound of SWS has been shown in RN after PSD in normal subjects (Brunner et al., 1990, 1993). Due to chronic sleep loss, insomniac patients, would be less sensitive than control subjects to SWS deprivation after PSD but with a similar reaction to REM sleep deprivation. Data derived from spectral analysis supports a weaker response to PSD in SMI subjects than in controls. Previous studies in normal subjects have demonstrated that EEG power density in the delta range (SWA) is a function of prior wakefulness duration (Borbe´ly et al., 1981; Dijk et al., 1987a,b, 1990a,b, 1991a,b; Dijk and Beersma, 1989). An increase of SWA was reported after sleep deprivation, while a reduction of wakefulness was accompanied by a reduced SWA. After PSD (nights of 4 h sleep) SWA increased by approximately 20% in control subjects (Brunner et al., 1993). However, studies using the method of amplitude-derived EEG (Feinberg et al., 1991; Travis et al., 1991) failed to find a significant increase of derived delta EEG (0–3 Hz) after sleep reduction to 4 h. After a sleep reduction to 3 h in normal subjects and to 2.5 h in SMI, an SWA increase was found in RN in both groups. Moreover, the SWA enhancement was less important than in normal subjects and both delayed and shortened: the SWA peak occurring principally in SMI at the second sleep cycle and ending at the third sleep cycle. This suggests that the variations of SWA in SMI may either be the consequence of a change in the homeostatic process underlying sleep propensity in favour of decreased sleep need in insomniacs, or of a deficiency of the mechanisms responsible for the implementation of SWA itself. Observations relating to the percentage of occupation of the delta band obtained by IDFA may clarify this question. In SMI, BLN delta % (representing the lower part of the delta band: 0.5–2 Hz) was reduced during SWS in comparison with controls and theta % (representing the higher part of the delta band and the theta band: 3–7 Hz) was increased in BLN, suggesting a possible SWS deficiency in SMI. Moreover, after PSD no percentage increase in delta or decrease in theta was observed during SWS in SMI for RN in contrast to the control group. The

same trend was observed when delta % was averaged per sleep cycle. It may be that in SMI, too weak a homeostatic process associated with a deficient SWS is responsible for difficulties in maintaining sleep. In SMI alpha % was increased in all sleep stages and during TST in comparison with controls. This increase might be due to micro-arousals (.3 s and .15 s) as defined by The ASDA Atlas Task Force (1992). Several factors may be involved in sleep fragmentation: periodic limb movements during sleep (PLMs), sleep apnoea syndrome (SAS), upper airway resistance syndrome, (UARS), (Guilleminault et al., 1993), and cycling alternating pattern (CAP) in the course of which arousal-dependent phasic events are periodically clustered during CAP, whereas they are isolated during NCAP. (Terzano et al., 1988). However, none of the subjects presented PLMs or SAS and in UARS and CAP, micro-arousals usually occur periodically, which was not the case in our subjects. The alpha % increase observed in SMI could be due to an abnormal CNS activation during sleep, or to an insufficient sleep process. A CNS hyperactivation already revealed during day-time (Monroe, 1967; Sugerman et al., 1985; Stepanski et al., 1988, 1989) might be maintained during sleep, and an insufficient SWS process might be responsible for awakenings. The most interesting result is the reduction of the SSI in insomniacs. A possible function of the spindles may be to block the sensitive afferences to the cortex and thus protect sleep continuity (Glenn and Steriade, 1982). Similarly, a positive correlation has been found in normal subjects between the sleep fragmentation index and the SSI. (Besset et al., 1994). It seems that if the SSI is liable to significant interindividual variations (Gaillard and Blois, 1981) it remains constant in each subject after several registration nights. Moreover there is no first-night effect (Gaillard and Blois, 1981; Azumi and Shirakawa, 1982), so the decrease of SSI in insomniacs which could explain in part the difficulty in maintaining sleep, seems to be due to an alteration of sleep microstructure rather than to reactivity to environmental conditions. A reduction of the SSI during SWS has been found in controls and not in SMI. When averaged per NREM sleep cycle, the SSI progressively increased from the first to the last sleep cycle in controls only. Numerous studies performed in normal subjects using either visual scoring of sleep (Jankel and Niedermayer, 1985; Guazzelli et al., 1986), filtering techniques (Silverstein and Levy, 1976; Azumi and Shirakawa, 1982; Di Perri et al., 1977a,b; Dijk et al., 1993) or FFT analysis (Johnson et al., 1969; Borbe´ly et al., 1981; Dijk et al., 1993) have shown that the spindle number or the power density in the sigma range were higher during stage 2 than during SWS and, increased in the course of the sleep cycles. Furthermore in RN after PSD, a decrease of the SSI during the first NREM sleep cycle was found in control subjects. These results are in accordance with studies showing that both the power density in the sigma band and the spindle density are reduced after sleep deprivation

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(Dijk et al., 1987a,b, 1991a,b, 1993). These data suggest the existence of an inverse relationship between SWA and spindles. This relationship is enhanced when sleep pressure is high and diminished when sleep pressure is low (Aeschbach et al., 1994, 1996; Werth et al., 1996). This reciprocal relationship between the SSI and sleep stages on the one hand and between the lower part of delta band on the other is not observed in SMI prior to and after PSD. It might be hypothesised that in such patients an alteration of the homeostatic process (due to an hyperexcitation of the CNS?) is responsible for an insufficient sleep pressure and hence inability to maintain sleep for an extended period. Otherwise, both spindles and slow waves are dependent on the hyperpolarization of thalamocortical neurones (Steriade et al., 1993). SMI may be hypothesised to be due in part to an insufficient functioning of the thalamocortical axis during sleep. It seems that this specific spindle reduction is not definitive because hypnogenic agents generally enhance spindle activity and decrease SWA, and can, for a short time, restore good sleep in insomniacs. However, these pharmacological modifications are observed to continue, while beneficial effects on sleep disappear. Hypnotic agents cannot restore the sleep pressure which occurs during the day, and the effects of behavioural therapy on sleep microstructure being as yet unknown, further studies are needed.

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