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Sleep studies in asthmatic adults: Relationship of attacks to sleep stage and time of night
Sleep studies in asthmatic adults: Relationship of attacks to sleep stage and time of night Anthony Kales, M.D.,* Gildon N. Beall, M.D., George P. Bajor, M.D., Allan Jacobson, M.D., and Joyce D. Kales, M.D., Los Angeles, Galif. Twelve adult asthmatic patients were studied for 35 nights with EEG, electromyogram, and eye movements continuously reCOrded. A total of 93 asthmatic episodes were observed. Of these, 73 OCCurred out of nonrapid eye movement (NREM) sleep, 18 from rapid eye movement (REM) sleep, and 8 after lengthy awake periods. The attacks OGGWred throughout the night, with lowered incidence only in the first hour of sleep. Thus no clear-cut relationship was noted between asthmatic attacks and sleep stages and/or time of night. The sleep patterns of the young adult asthmatic patients were compared with normal young adults previously studied. The asthmatic young adults had considerably less total sleep time because of frequent awakenings after sleep onset and early final awakenings. The time of onset of sleep was similar in the two groups. The asthmatio young adults had significamtly less stage 4 sleep, while the percentage of REM sleep was similar to that of normal young addts. The sleep patterns of asthmatic patients taking adrenal corticosteroids were Compared with those who were not. No differences were noted in sleep latency, total sleep time, and number of REM periods nightly. There were only slight differences (nonsignificant) between the two groups in the percentages of time spent in the various sleep stages. The study did not support the hypothesis that asthmatic episodes were specifically related to REM sleep nor did it support other theories linking nocturnal asthmatic episodes with the noctwrnal ebb in adrenal secretion, with disturbing dreams, or with allergenic influences. It was GOnGhkded that noctu,rnal asthmatic attacks are multidetermined, with factors such as reowmbenoy, U-OH GOrtiGOSterOid levels, anxiety, dreaming, and depth of sleep playing roles varying from subject to subject. From the Departments of Psychiatry, Medicine and Anatomy, and Neuropsychiatric and Research Institutes, U.C.L.A. School of Medicine. Supported in part by’Nationa1 Institute of Mental Health Training Grants 5TI MH-6415 and NB-02808 of the Brain Research Institute, U.C.L.A., and National Institute of Allergy and Infectious Diseases Training Grant ZE-138 5TI AI 138-05. Also assisted by the U.C.L.A. Brain Information Service, a part of the National Information Network of the National Institute of Neurological Diseases and Blindness and supported under contract PH-43-66-59. Presented in part to the American Academy of Allergy, Feb., 1967, and the Association for the Psychophysiologic Study of Sleep, April, 1967. Received for publication Nov. 6, 1967. “Reprint requests to Department of Psychiatry, U.C.L.A. Medical Center, 760 Westwood Plaza, Los Angeles, Calif. 90024 (Dr. Kales).
Brain
164
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atients with asthma frequently have attacks of dyspnea at night and complain of their inability to sleep properly, To learn more about asthma and sleep we investigated the sleeping patterns of a number of asthmatic patients. Considerable knowledge regarding normal and altered sleep patterns has been provided recently by a series of observations beginning with Aserinsky and KleitmanW 2 discovery of clusters of conjugate, rapid eye movements (RKM’s) during sIeep. Further studies showed that these REM periods* are asso&ted with a low-voltage, fast electroencephalogram (EEG) and occur every 80 to 100 minutes throughout the night, 314 There are four to six periods a night, depending on the length of sleep, and 20 to 25 per cent of a normal young adult’s sleep time is spent in REM sleep.3T 5v6 In addition, in awakening studies, REM sleep is the sleep phase most regularly associated with dream recall.*, 7, g Associated with REM periods are a number of physiologic changes, including: increased act,ivity and irregularity of pulse rate, respiration, and blood pressurP~ ll; a decrease in the tonus of most head and neck muscles12~13; frequent complete or partial penile erectionl’v 15; an increase in plasma and urinary 17-hydroxyeorticoid concentration16, 17; and an increase in catecholamine meta.bo1ism.l” nement and Kleitman3 have defined the various EEG stages of sleep. Stage 1 consists of low-amplitude, high-frequency EEG activity without spindles. Stage 2 is characterized by low-amplitude, fast activity with “sleep spindles” of 14 to 16 cycles per second (c.P.s.). In sbage 3, high-amplitude, slow waves (1 to 3 c.p.s.) are present with some spindling superimposed, whereas in st)agct 4 at least half the record is dominated by these high-amplitude, slow wav(‘s. The preponderance of stages 3 and 4 sleep in a night is accumulated during the first severa hours of sleep, while the first REM period occurs 60 to 90 minutes after sleep onset. REM periods occur when a stage 1 BEG follows another sleep stage. Associated with the low-amplitude, fast stage 1 EEG activity are REM’s and ;t markedly decreased tonus of certain head and neck muscles. In contrast, when a stage 1 EEG is present as an individual falls asleep, REM’s do not. occur and the muscle tonus of the head and neck muscles is higher t,han during REM sleep. Stages 2, 3, and 4 and stage 1 without REM’s arc collectively referred t,o as nonrapid eye movement (NREM) sleep. Since the discovery of REM’s, various sleep disturbances and disease stilt)cw have been studied with all-night EEG recordings. Sleep walking,“‘, ‘“’ slecbIj talking,21 and bedwettingZ2 occur predominantly in NREM periods. In nar(aolrptic patients with eataplexy, the cataplectic attacks are associated with thch onset of REM sleep and the concomitant loss of muscle one.Zs. 24 Hypothyroitl”’ and depressed20-28 patients have markedly decreased levels of stage 1 slecy with increases in this sleep phase following treatment. In patients with duo(len;il ulcers, peak secretions of gast.ric acid were demonsstrated in REM slecp.29 while in three patients with coronary artery disease, electrocardiographic ( EK.(; ‘) changes with subsequent awakening and angina pect,oris occurred out of RF:N sleep.“O *The throughout
t,erms the
REM paper.
periods,
REM
sleep,
and
stage
REM
are
used
it~t~rcllangpahly
166
Kales et al.
J. Allergy Marcl1, 1968
The aims of this project were to observe the relationships between ast,hmatic attacks, sleep stages, and t,ime of night and to compare the sleep patterns of the asthmatic subjects with control subjects. METHODS
The 12 patients participating in this study were all volunteers who had been attending the medical outpatient department for treatment of their asthma. By asthma, we mean the presence of diffuse bronchial obstruction which can be relieved sponta,neously or with drugs. There were 6 men and 6 women, their ages ranging from 22 to 45 years. The patients selected were having nocturnal symptoms but were not so disabled that they were not sleeping or working. All the subjects were taking inhaled isoproterenol and oral ephedrine, aminophylline, and phenobarbital. Five of the 12 patients were receiving adrenal corticosteroid medication. Four were receiving 10 to 20 mg. of prednisone spread throughout the day, while the fifth patient was taking 40 mg. of prednisone every other morning. Two patients were studied nightly, each sleeping in a temperature-controlled and quiet room. Each patient was told that we were interested in studying theis sleep patterns. They were instructed not to nap in the daytime while the sleep studies were in progress and to omit their usual bedtime medication. Patients were usually ready for sleep between 9 :30 to 10 :00 P.M. They were not awakened in the morning, but the night’s sleep was terminated whenever the patient felt that he could not go back to sleep. Each patient was studied for two or three consecutive nights with EEG, electromyogram (EMG) , and eye movements being continuously monitored with monopolar and bipolar scalp and facial leads.“l There was a total of 35 subject-nights. For the purposes of this study, an “attack” of asthma was defined as a sensation of dyspnea sufficient to awaken the patient and motivate him to use the isoproterenol nebulizer. In the first part of the study, t,he subjects were instructed to signal the investigator by ringing the bell at their bedside if they awakened, were short of breath, and needed to use their inhaler. In the second part of t,he study, an electrical circuit was set up so that a light went off outside the subject’s room when he picked up the inhaler to use it. When the inhaler was returned to its container the light would go back on. Sleep measurements included such parameters as: total time spent in the laboratory, percentage of time asleep, number of awakenings and total time spent awake, and total and percentage of time spent in each sleep stage. Other measurements included time from lights out to sleep onset (sleep latency) and time from sleep onset to the first REM period. RESULTS Asthmatic
attacks
related
to time
of
night
and
sleep
stages
Since the subjects were ready for sleep and fell asleep at different times of the night, the incidents were plotted in relation to the time of sleep onset (Fig. I). The incidents were distributed fairly evenly throughout the night, with a lowered incidence only during the first hour or so of sleep. This fairly even
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IlO MINUTES
Sleep
patterns
of asthmatic
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1
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Fig.
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$0
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patients:
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lk0
240 FROM
asthmatic
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3bO SLEEP
.
Sk0
4;0
ONSET
incidents.
distribution of asthmatic episodes throughout the sleep periods was true whether or not the patient was taking adrenal corticosteroids. The incidents were also distributed fairly evenly throughout the sleep cycle, i.e., in ten minute segments marked off from the beginning and the end of t,he prior REM period. It is difficult to evaluate the time from the asthmatic episodes until the next REM period since the subjects were awake for lengthy and varying intervals. If just the tim from sleep onset following an attack to the next REM period is taken, then there were many instances of a short latency from sleep onset to the next RRXI period. Of the 93 asthmatic incidents, 73 occurred out of NREM sleep, 18 from RE?YI sleep, and 2 followed lengthy awake periods. Fig. 2 illustrates the relationship of sleep stages to the asthmatic incidents. It can be seen that the percentage of incidents arising from each sleep stage approximated the percentage of sleep t)ime spent in that period. In an occasional record it, appeared as if the patients may have had the onset of symptoms in stage 3 or 4 sleep; t’his was indicated by frequent body movements and respiration artifacts throughout the FE(: recording, with a subsequent shift to stage 2 sleep from which they finall) awoke and used their medication. In the first part of the study, when the patients signaled their attacks ant1 the investigators went into the room, 12 of 38 incidents (32 per cent) arose out of REM sleep. The proportion of incidents from REM sleep with this method was similar for the steroid and nonsteroid groups : 5 of 15 and ‘7 of 23, respectively. When the patients did not have to signal and were unaware of the electrical circuit, there were only 6 of 55 incidents ( 11 per cent) arising from REM sleep. This was also consistent between the two sets of subjects: 5 of gl VS. 1 of 13 incidents arose out of REM sleep in the steroid and nonsteroid groups, respectively.
168
Kales et al.
too
J. Allergy March, 1968 REM
i
STAGE I
STAGE 2
STAGE 3
1;
STAGE 4
Mean %‘slee,o lime -35nighls
’ ?
60-
5
40-
31ic Es4Asthma (“h OfEa
r-i LA
Fig.
incidents
c-3
-
2
Relationship
of sleep
stages
to asthmatic
incidents
on nights
1 and
2.
1. Sleep measurements of all asthmatic patients
Table
70 Stage
time
of
total
sleep
time
Night 1
19.5
77.1
13.2*
13.8
61.1
9.5
2.4
2
15.5
84.2
20.6’
6.8
60.1
10.9
1.6
*Probability:
Sleep
patterns
p<
of
0.05.
all
asthmatic
subjects
On both nights of study, the patients spent considerable time awake; this was less pronounced on the second night (Table I). There was little change in the sleep latency, while there was less awake time following sleep onset on the second night. There was a significant increase in the percentage of time spent in REM sleep on the second night, while the percentage stage l-NREM time decreased. A decrease in REM sleep accompanied by a greater time spent awake has been previously noted in normal subjects and is considered an adaptation or “first-night” effects2 Sleep
patterns
of asthmatic
young
adults
and
normal
young
adults
Sleep patterns of normal subjects vary considerably with age; particularly there is a decrease in stage 4 sleep in the elderly.33a 34 We were unable to compare the sleep measurements of all our asthmatic group with normal subjects of the same age. Thus we compared the sleep patterns of 6 of our asthma.tic young adults with those of 10 normal young adult subjects previously studied in this laboratory.35 The second night of each study was used (Table II) so as to allow for
Volume Number
41 3
II. Comparison
Table
of
sleep patte,rns* on night 2 Sleep
X0.
Asthmatic tients Asthmatic adults Normal adults
subjects
latency
12
15.5
6
14.3
393 -r- 13f.
87.9 ? 2.2g
10
20.8
155c
95.5 k 1.16
payoung 89
4
young
*All measurements except number of REM’s minutes. tOf total time from sleep onset to final awakening. JProbability : p < 0.001. $Probability: p < 0.01.
REM
100
STAGE I
STAGE
‘it
c>ent
and
per
2
STAG E3
103 time
deep
STAGE
4 cxpreswtl
i II
4
80 r-Y L --I $
60
lu g x
m
Sleep
Asthmatic (mean
of 12 c SE)
40
NIGHT
Fig.
Normal young adults (mean ofIO+SE)
1
2
1
2
3 patterns
of asthmatic
patients.
adjustment to the laboratory. The mean sleep time was significantly less in the asthmatic young adults. This was due to frequent awakenings following slccip onset and early final awakenings rather than to an increase in sleep latcnc*y. The mean number of REM periods was similar in bot,h groups, and while thr time from sleep onset to the first REM period was shortcr in the asthmatie subjects, t,his was not statistically significant. Fig. 3 illustrates the percentage of each sleep stage for both groups oi subjects. It shows that there was little difference in the percentage of REM sleep and stage 3 sleep. A marked decreasc in stage 4 sleep was noted for III~J asthmatic young adults (p < 0.02) ; this decrease was made up for .by an increase primarily in stage 2 sleep and to a, lesser extent in stage I-NREM. Since t,he total sleep time was considerably dccrcasccl in t)hc asthmatic young :~(lllit.s,
170
.J. Allergy >Iarcll, 196X
Kales et al.
111.Sleep patterns of asthnmtic putients:” corticosteroids (night 2)
Efl’ects
Table
No. subjects
Steroids No steroids
5 7
Skep Z&XC7J
15 16
% Time
SlCCpi7lg
time
uskept
363 + 18 379 ? 23
“All measurements except number of REM’s and tOf total time from sleep onset to final awakening. $Not significant: p > 0.05.
of adrenal
83.5 f 3.4 85.1 + 4.4 per
cent
time
Time
to
first REM
No. REX’s
76 ? 14$ 133 !I 43i
4 4
asleep
expressed
in minutes.
the changes between sleep stages in both groups was even greater if one considers the absolute time spent in these stages rather than percentage time. Effects
of adrenal
corticosteroids
Table III compares various sleep measurements in the asthmatic subjects on the basis of whether they were taking steroid medication. No significant differences were observed in total sleep time, sleep latency, per cent of time asleep, time from sleep onset to the first REM period, and number of REM periods per night. Although there was a large difference in the time from sleep onset to the first REM period between the two groups, this was not statistically significant since one subject accounted for much of this difference. The steroidtreated patients had slightly less stage 3 and 4 sleep and a slightly greater amount of REM and stage 2 sleep. None of these differences was statistically significant. Some decrease in stage 3 and 4 sleep would be expected in the steroid patients since they were older and sicker. COMMENT
The frequency of asthmatic symptoms at night was once thought to be related to a decrease in vital capacity in the recumbent position, but lung volume measurements of asthmatic patients did not support this idea.3G Other theories proposed to account for nocturnal asthmatic attacks included retained secretions, disturbing dreams, and the presence of allergenic materials (such as feathers) in the bedroom. A correlation of lowered urinary 17-hydroxycorticost,eroids (17-OHCS) excretion and asthmatic attacks has also been described.37 In this study little evidence for any of these theories was obtained. The laboratory was relatively free of allergenic and irritating environmental materials. The attacks occurred throughout the nocturnal hours and not at the time the 17-OHCS excretion would be expected to be at an ebb. However, this factor is complicated in the asthmatic subjects since most of them had considerable awake time during the night, and it has been shown that middle of the night awakenings are associated with marked rises in the urinary 17-OHCS concentrations. Another factor which may be contaminating any attempt to relate the incidents to corticoid levels is the fact that a number of subjects were on exogenous steroid medication. Finally, it is also possible that the physiologic early morning increase in 17-OHCS concentration was not great enough to exert a pharmacologic effect and prevent the asthmatic attacks.
The results do not indicate a specific relationship between asthmatic attacks, sleep stages, and/or time of night. As mentioned, the episodes occurred in all stages of sleep throughout the night and were fairly equally distributed between the two halves of the night. Since dreamin, LPis most frequently associated wit 11 REM sleep, our findings are contrary to the thesis that disturbing dreams a w primarily responsible for precipitating asthmatic symptoms. WC have concluded that asthmatic attacks occur in all stages of sleep with no clear-cut correlation with any part of the sleep cycle, although there may he considerable variability from subject to subject. It may be that instructing or questioning subjects, as we did early in the study, heightens their level (~1: anxiety and/or degree of consciousness, favoring attacks out of RElM sleep. Other factors such as recumbency, U-OH corticosteroid levels, dreaming, and depth of sleep may play varying roles from subject to subject and night to night in precipitating asthmatic attacks. Thus, nocturnal asthmat,ic attacks Knit> be multidet,ermined-just, as they are in the daytime. The finding of greatly increased awake time in the asthmatic patient was 01 considerable interest. This confirms the reports of many patients that inabilitr\ to rest and sleep is one of their greatest handicaps. It is presumed that subjects on steroids are more severely afflicted, and thus it is not surprising that the\ show a greater number of incident,s. The more rapid onset of the first REAI period in steroid-treated patients may be due to the considerable awake timca and concomitant relative REM deprivation.““, :jn Xven though the perccnt,ag(s of time spent in REM sleep by asthmatic young adults was no different from normal young adults, the absolute REM time was decreased since the total slrcip time was decreased. This deprivation effect, if long-term, could result in a dccreased latency for the first REM period. It is not surprising that such a pattern might occur in the patients taking steroids since thcp hare hat1 mow difficulty over a longer period of time. The marked decrease in stage 4 sleep in the asthmatir subjects was of’ illterest. It is possible that the multiple awakenings, with or without asthmatit attacks, may not permit the subject to gradually descend into stage 4 sleep. 01’ it may be that as a subject goes into stage 3 or 4 sleep there is associatcaci respiratory difficulty. Decreased levels of stage 4 sleep have been reportctl in normal elderly subjectP9 35 and hypothyroidz” and depressed patients.2”-2s ‘1’1~ elderly, hypothyroid, depressed, and asthmatic patients, as well as patients with many disorders, complain that they feel they have not slept very well. In addition to the total sleep time, it appeals that the kind of sleep they obtain ma) be a crucial factor in how they feel they have slept. Stage 4 sleep is a deep st,agf> of sleep as far as auditory awakening thresholds.‘n, 41 A lowered level of this sleep phase may have a greater effect on how an individual feels he has slept than if stage REM sleep is altered. In conclusion, the asthmatic incidents occurred throughout t,he night antI were not localized to any particular phase of the sleep cycle, The asthmatic young adults had less stage 4 sleep than normal young adults. In addition, the? did not sleep as long nor did they sleep as well, since they spent (aonsidcrabl!. more time awake.
172
Kales et al.
J. Allergy March, 1968
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164
P
atients with asthma frequently have attacks of dyspnea at night and complain of their inability to sleep properly, To learn more about asthma and sleep we investigated the sleeping patterns of a number of asthmatic patients. Considerable knowledge regarding normal and altered sleep patterns has been provided recently by a series of observations beginning with Aserinsky and KleitmanW 2 discovery of clusters of conjugate, rapid eye movements (RKM’s) during sIeep. Further studies showed that these REM periods* are asso&ted with a low-voltage, fast electroencephalogram (EEG) and occur every 80 to 100 minutes throughout the night, 314 There are four to six periods a night, depending on the length of sleep, and 20 to 25 per cent of a normal young adult’s sleep time is spent in REM sleep.3T 5v6 In addition, in awakening studies, REM sleep is the sleep phase most regularly associated with dream recall.*, 7, g Associated with REM periods are a number of physiologic changes, including: increased act,ivity and irregularity of pulse rate, respiration, and blood pressurP~ ll; a decrease in the tonus of most head and neck muscles12~13; frequent complete or partial penile erectionl’v 15; an increase in plasma and urinary 17-hydroxyeorticoid concentration16, 17; and an increase in catecholamine meta.bo1ism.l” nement and Kleitman3 have defined the various EEG stages of sleep. Stage 1 consists of low-amplitude, high-frequency EEG activity without spindles. Stage 2 is characterized by low-amplitude, fast activity with “sleep spindles” of 14 to 16 cycles per second (c.P.s.). In sbage 3, high-amplitude, slow waves (1 to 3 c.p.s.) are present with some spindling superimposed, whereas in st)agct 4 at least half the record is dominated by these high-amplitude, slow wav(‘s. The preponderance of stages 3 and 4 sleep in a night is accumulated during the first severa hours of sleep, while the first REM period occurs 60 to 90 minutes after sleep onset. REM periods occur when a stage 1 BEG follows another sleep stage. Associated with the low-amplitude, fast stage 1 EEG activity are REM’s and ;t markedly decreased tonus of certain head and neck muscles. In contrast, when a stage 1 EEG is present as an individual falls asleep, REM’s do not. occur and the muscle tonus of the head and neck muscles is higher t,han during REM sleep. Stages 2, 3, and 4 and stage 1 without REM’s arc collectively referred t,o as nonrapid eye movement (NREM) sleep. Since the discovery of REM’s, various sleep disturbances and disease stilt)cw have been studied with all-night EEG recordings. Sleep walking,“‘, ‘“’ slecbIj talking,21 and bedwettingZ2 occur predominantly in NREM periods. In nar(aolrptic patients with eataplexy, the cataplectic attacks are associated with thch onset of REM sleep and the concomitant loss of muscle one.Zs. 24 Hypothyroitl”’ and depressed20-28 patients have markedly decreased levels of stage 1 slecy with increases in this sleep phase following treatment. In patients with duo(len;il ulcers, peak secretions of gast.ric acid were demonsstrated in REM slecp.29 while in three patients with coronary artery disease, electrocardiographic ( EK.(; ‘) changes with subsequent awakening and angina pect,oris occurred out of RF:N sleep.“O *The throughout
t,erms the
REM paper.
periods,
REM
sleep,
and
stage
REM
are
used
it~t~rcllangpahly
166
Kales et al.
J. Allergy Marcl1, 1968
The aims of this project were to observe the relationships between ast,hmatic attacks, sleep stages, and t,ime of night and to compare the sleep patterns of the asthmatic subjects with control subjects. METHODS
The 12 patients participating in this study were all volunteers who had been attending the medical outpatient department for treatment of their asthma. By asthma, we mean the presence of diffuse bronchial obstruction which can be relieved sponta,neously or with drugs. There were 6 men and 6 women, their ages ranging from 22 to 45 years. The patients selected were having nocturnal symptoms but were not so disabled that they were not sleeping or working. All the subjects were taking inhaled isoproterenol and oral ephedrine, aminophylline, and phenobarbital. Five of the 12 patients were receiving adrenal corticosteroid medication. Four were receiving 10 to 20 mg. of prednisone spread throughout the day, while the fifth patient was taking 40 mg. of prednisone every other morning. Two patients were studied nightly, each sleeping in a temperature-controlled and quiet room. Each patient was told that we were interested in studying theis sleep patterns. They were instructed not to nap in the daytime while the sleep studies were in progress and to omit their usual bedtime medication. Patients were usually ready for sleep between 9 :30 to 10 :00 P.M. They were not awakened in the morning, but the night’s sleep was terminated whenever the patient felt that he could not go back to sleep. Each patient was studied for two or three consecutive nights with EEG, electromyogram (EMG) , and eye movements being continuously monitored with monopolar and bipolar scalp and facial leads.“l There was a total of 35 subject-nights. For the purposes of this study, an “attack” of asthma was defined as a sensation of dyspnea sufficient to awaken the patient and motivate him to use the isoproterenol nebulizer. In the first part of the study, t,he subjects were instructed to signal the investigator by ringing the bell at their bedside if they awakened, were short of breath, and needed to use their inhaler. In the second part of t,he study, an electrical circuit was set up so that a light went off outside the subject’s room when he picked up the inhaler to use it. When the inhaler was returned to its container the light would go back on. Sleep measurements included such parameters as: total time spent in the laboratory, percentage of time asleep, number of awakenings and total time spent awake, and total and percentage of time spent in each sleep stage. Other measurements included time from lights out to sleep onset (sleep latency) and time from sleep onset to the first REM period. RESULTS Asthmatic
attacks
related
to time
of
night
and
sleep
stages
Since the subjects were ready for sleep and fell asleep at different times of the night, the incidents were plotted in relation to the time of sleep onset (Fig. I). The incidents were distributed fairly evenly throughout the night, with a lowered incidence only during the first hour or so of sleep. This fairly even
Volume Number
41 3
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IlO MINUTES
Sleep
patterns
of asthmatic
.
. .
1
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:
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Fig.
. .
.
$0
.
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. .
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.
patients:
.
.
lk0
240 FROM
asthmatic
.
3bO SLEEP
.
Sk0
4;0
ONSET
incidents.
distribution of asthmatic episodes throughout the sleep periods was true whether or not the patient was taking adrenal corticosteroids. The incidents were also distributed fairly evenly throughout the sleep cycle, i.e., in ten minute segments marked off from the beginning and the end of t,he prior REM period. It is difficult to evaluate the time from the asthmatic episodes until the next REM period since the subjects were awake for lengthy and varying intervals. If just the tim from sleep onset following an attack to the next REM period is taken, then there were many instances of a short latency from sleep onset to the next RRXI period. Of the 93 asthmatic incidents, 73 occurred out of NREM sleep, 18 from RE?YI sleep, and 2 followed lengthy awake periods. Fig. 2 illustrates the relationship of sleep stages to the asthmatic incidents. It can be seen that the percentage of incidents arising from each sleep stage approximated the percentage of sleep t)ime spent in that period. In an occasional record it, appeared as if the patients may have had the onset of symptoms in stage 3 or 4 sleep; t’his was indicated by frequent body movements and respiration artifacts throughout the FE(: recording, with a subsequent shift to stage 2 sleep from which they finall) awoke and used their medication. In the first part of the study, when the patients signaled their attacks ant1 the investigators went into the room, 12 of 38 incidents (32 per cent) arose out of REM sleep. The proportion of incidents from REM sleep with this method was similar for the steroid and nonsteroid groups : 5 of 15 and ‘7 of 23, respectively. When the patients did not have to signal and were unaware of the electrical circuit, there were only 6 of 55 incidents ( 11 per cent) arising from REM sleep. This was also consistent between the two sets of subjects: 5 of gl VS. 1 of 13 incidents arose out of REM sleep in the steroid and nonsteroid groups, respectively.
168
Kales et al.
too
J. Allergy March, 1968 REM
i
STAGE I
STAGE 2
STAGE 3
1;
STAGE 4
Mean %‘slee,o lime -35nighls
’ ?
60-
5
40-
31ic Es4Asthma (“h OfEa
r-i LA
Fig.
incidents
c-3
-
2
Relationship
of sleep
stages
to asthmatic
incidents
on nights
1 and
2.
1. Sleep measurements of all asthmatic patients
Table
70 Stage
time
of
total
sleep
time
Night 1
19.5
77.1
13.2*
13.8
61.1
9.5
2.4
2
15.5
84.2
20.6’
6.8
60.1
10.9
1.6
*Probability:
Sleep
patterns
p<
of
0.05.
all
asthmatic
subjects
On both nights of study, the patients spent considerable time awake; this was less pronounced on the second night (Table I). There was little change in the sleep latency, while there was less awake time following sleep onset on the second night. There was a significant increase in the percentage of time spent in REM sleep on the second night, while the percentage stage l-NREM time decreased. A decrease in REM sleep accompanied by a greater time spent awake has been previously noted in normal subjects and is considered an adaptation or “first-night” effects2 Sleep
patterns
of asthmatic
young
adults
and
normal
young
adults
Sleep patterns of normal subjects vary considerably with age; particularly there is a decrease in stage 4 sleep in the elderly.33a 34 We were unable to compare the sleep measurements of all our asthmatic group with normal subjects of the same age. Thus we compared the sleep patterns of 6 of our asthma.tic young adults with those of 10 normal young adult subjects previously studied in this laboratory.35 The second night of each study was used (Table II) so as to allow for
Volume Number
41 3
II. Comparison
Table
of
sleep patte,rns* on night 2 Sleep
X0.
Asthmatic tients Asthmatic adults Normal adults
subjects
latency
12
15.5
6
14.3
393 -r- 13f.
87.9 ? 2.2g
10
20.8
155c
95.5 k 1.16
payoung 89
4
young
*All measurements except number of REM’s minutes. tOf total time from sleep onset to final awakening. JProbability : p < 0.001. $Probability: p < 0.01.
REM
100
STAGE I
STAGE
‘it
c>ent
and
per
2
STAG E3
103 time
deep
STAGE
4 cxpreswtl
i II
4
80 r-Y L --I $
60
lu g x
m
Sleep
Asthmatic (mean
of 12 c SE)
40
NIGHT
Fig.
Normal young adults (mean ofIO+SE)
1
2
1
2
3 patterns
of asthmatic
patients.
adjustment to the laboratory. The mean sleep time was significantly less in the asthmatic young adults. This was due to frequent awakenings following slccip onset and early final awakenings rather than to an increase in sleep latcnc*y. The mean number of REM periods was similar in bot,h groups, and while thr time from sleep onset to the first REM period was shortcr in the asthmatie subjects, t,his was not statistically significant. Fig. 3 illustrates the percentage of each sleep stage for both groups oi subjects. It shows that there was little difference in the percentage of REM sleep and stage 3 sleep. A marked decreasc in stage 4 sleep was noted for III~J asthmatic young adults (p < 0.02) ; this decrease was made up for .by an increase primarily in stage 2 sleep and to a, lesser extent in stage I-NREM. Since t,he total sleep time was considerably dccrcasccl in t)hc asthmatic young :~(lllit.s,
170
.J. Allergy >Iarcll, 196X
Kales et al.
111.Sleep patterns of asthnmtic putients:” corticosteroids (night 2)
Efl’ects
Table
No. subjects
Steroids No steroids
5 7
Skep Z&XC7J
15 16
% Time
SlCCpi7lg
time
uskept
363 + 18 379 ? 23
“All measurements except number of REM’s and tOf total time from sleep onset to final awakening. $Not significant: p > 0.05.
of adrenal
83.5 f 3.4 85.1 + 4.4 per
cent
time
Time
to
first REM
No. REX’s
76 ? 14$ 133 !I 43i
4 4
asleep
expressed
in minutes.
the changes between sleep stages in both groups was even greater if one considers the absolute time spent in these stages rather than percentage time. Effects
of adrenal
corticosteroids
Table III compares various sleep measurements in the asthmatic subjects on the basis of whether they were taking steroid medication. No significant differences were observed in total sleep time, sleep latency, per cent of time asleep, time from sleep onset to the first REM period, and number of REM periods per night. Although there was a large difference in the time from sleep onset to the first REM period between the two groups, this was not statistically significant since one subject accounted for much of this difference. The steroidtreated patients had slightly less stage 3 and 4 sleep and a slightly greater amount of REM and stage 2 sleep. None of these differences was statistically significant. Some decrease in stage 3 and 4 sleep would be expected in the steroid patients since they were older and sicker. COMMENT
The frequency of asthmatic symptoms at night was once thought to be related to a decrease in vital capacity in the recumbent position, but lung volume measurements of asthmatic patients did not support this idea.3G Other theories proposed to account for nocturnal asthmatic attacks included retained secretions, disturbing dreams, and the presence of allergenic materials (such as feathers) in the bedroom. A correlation of lowered urinary 17-hydroxycorticost,eroids (17-OHCS) excretion and asthmatic attacks has also been described.37 In this study little evidence for any of these theories was obtained. The laboratory was relatively free of allergenic and irritating environmental materials. The attacks occurred throughout the nocturnal hours and not at the time the 17-OHCS excretion would be expected to be at an ebb. However, this factor is complicated in the asthmatic subjects since most of them had considerable awake time during the night, and it has been shown that middle of the night awakenings are associated with marked rises in the urinary 17-OHCS concentrations. Another factor which may be contaminating any attempt to relate the incidents to corticoid levels is the fact that a number of subjects were on exogenous steroid medication. Finally, it is also possible that the physiologic early morning increase in 17-OHCS concentration was not great enough to exert a pharmacologic effect and prevent the asthmatic attacks.
The results do not indicate a specific relationship between asthmatic attacks, sleep stages, and/or time of night. As mentioned, the episodes occurred in all stages of sleep throughout the night and were fairly equally distributed between the two halves of the night. Since dreamin, LPis most frequently associated wit 11 REM sleep, our findings are contrary to the thesis that disturbing dreams a w primarily responsible for precipitating asthmatic symptoms. WC have concluded that asthmatic attacks occur in all stages of sleep with no clear-cut correlation with any part of the sleep cycle, although there may he considerable variability from subject to subject. It may be that instructing or questioning subjects, as we did early in the study, heightens their level (~1: anxiety and/or degree of consciousness, favoring attacks out of RElM sleep. Other factors such as recumbency, U-OH corticosteroid levels, dreaming, and depth of sleep may play varying roles from subject to subject and night to night in precipitating asthmatic attacks. Thus, nocturnal asthmat,ic attacks Knit> be multidet,ermined-just, as they are in the daytime. The finding of greatly increased awake time in the asthmatic patient was 01 considerable interest. This confirms the reports of many patients that inabilitr\ to rest and sleep is one of their greatest handicaps. It is presumed that subjects on steroids are more severely afflicted, and thus it is not surprising that the\ show a greater number of incident,s. The more rapid onset of the first REAI period in steroid-treated patients may be due to the considerable awake timca and concomitant relative REM deprivation.““, :jn Xven though the perccnt,ag(s of time spent in REM sleep by asthmatic young adults was no different from normal young adults, the absolute REM time was decreased since the total slrcip time was decreased. This deprivation effect, if long-term, could result in a dccreased latency for the first REM period. It is not surprising that such a pattern might occur in the patients taking steroids since thcp hare hat1 mow difficulty over a longer period of time. The marked decrease in stage 4 sleep in the asthmatir subjects was of’ illterest. It is possible that the multiple awakenings, with or without asthmatit attacks, may not permit the subject to gradually descend into stage 4 sleep. 01’ it may be that as a subject goes into stage 3 or 4 sleep there is associatcaci respiratory difficulty. Decreased levels of stage 4 sleep have been reportctl in normal elderly subjectP9 35 and hypothyroidz” and depressed patients.2”-2s ‘1’1~ elderly, hypothyroid, depressed, and asthmatic patients, as well as patients with many disorders, complain that they feel they have not slept very well. In addition to the total sleep time, it appeals that the kind of sleep they obtain ma) be a crucial factor in how they feel they have slept. Stage 4 sleep is a deep st,agf> of sleep as far as auditory awakening thresholds.‘n, 41 A lowered level of this sleep phase may have a greater effect on how an individual feels he has slept than if stage REM sleep is altered. In conclusion, the asthmatic incidents occurred throughout t,he night antI were not localized to any particular phase of the sleep cycle, The asthmatic young adults had less stage 4 sleep than normal young adults. In addition, the? did not sleep as long nor did they sleep as well, since they spent (aonsidcrabl!. more time awake.
172
Kales et al.
J. Allergy March, 1968
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2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
Aserinsky, E., and Kleitman, N.: Regularly Occurring Periods of Eye Motility and Concomitant Phenomena During Sleep, Science 118: 273, 1953. Aserinsky, E., and Kleitman, Two Types of Ocular Motility Occurring in Sleep, N.: J. Aunl. Phvsiol. 8: 1. 1955. Dem’eit, WY C., and-kleitman, N.: Cyclic Variations in EEG During Sleep and Their Relations to Eve Movements. Bodv Motilitv. and Dreaming, -, Electroencephalography & Clin. Neurouhvsiol. 9: 673. i957. ” “’ Dement, W. &,*and Kleitman, -N.: The Relation of Eye Movements During Sleep to Dream Activity: An Objective Method for the Study of Dreaming, J. Exper. Psychol. 5s: 339. 1957. Roffwaig, H. P., Dement, W. C., and Fisher, C.: Preliminary Observations on the Sleep-Dream Patterns in Neonates, Infants, Children, and Adults, in E. Harms, editor: Problems of Sleep and Dreams in Children, Oxford, 1963, Pergamon Press, Inc., p. 147. Williams, R. L., Agnew, H. W., and Webb, W. B.: Sleep Patterns in Young Adults: An EEG Study, Electroencephalography & Clin. Neurophysiol. 17: 376, 1964. Foulkes, D. : Dream Reports From Different Stages of Sleep, J. Abnorm. & Social Psvehol. 65: 14.1962. Kales, A., Hoedemaker, F. S., Jacobson, A., Kales, J. D., Paulson, M. J., and Wilson, T. : Mentation During I Sleep:_ REM and NREM Recall Reports, Percept. Mot. Skills 24: 555, 1967. Rechtschaffen, A., Verdone, P., and Wheaton, Joy: Reports of Mental Activity During Sleep, Canad. Psychiat. A. J. 8: 409,1963. Jouvet, M., Michel, F., and Mounier, D.: Analyse Electroencephalographique Comparee Du Sommeil Physiologique Ches le Chat et Chez l’Homme, Rev. Neurol. 103: 189, 1960. Snyder, F., Hobson, J. A., Morrison, D. F., and Goldfrank, F.: Changes in Respiration, Heart Rate, and Systolic Blood Pressure in Relation to Electroeneephalographic Patterns of Human Sleep, J. Appl. Physiol. 19: 417,1964. Berger, R. J.: Tonus of Extrinsic Laryngeal Muscles During Sleep and Dreaming, Science 134: 840. 1961. Jacobson, A., Kales, A., Lehman?, D., and Hoedemaker, F. 5.: Muscle Tonus in Human Subjects During Sleep and Dreamrng, Exper. Neurol. 10: 418, 1964. of Penile Erection Synchronous With Fisher, C., Gross, J., and Zuch, J.: A Cycle Dreaming (REM) Sleep, Arch. Gen. Psychiat. 12: 29, 1965. of Exciting Presleep Events on Dream Reporting and Penile Karacan, I.: The Effect Erections During Sleep, Doctor of Medical Science Thesis, May, 1965, unpublished, Downstate Medical Center Library, New York University, Brooklyn. Weitzman, E., Schaumburg, H., and Fishbein, W.: Plasma 17-Hydroxycorticosteroid Levels During Sleep in Man, J. Clin. Endocrinol. 26: 121, 1966. Mandell, M. P., et al.: Activation of the Pituitary-Adrenal Axis During Rapid Eye Movement Sleep in Man, Life SC. 5: 583,1966. Mandell, A. J., et al.: Urinary Excretion of 3-Methoxy-4-Hydroxymandelie Acid During Dreaming Sleep in Man, Life SC. 5: 169, 1966. Jacobson, A., Kales, A., Lehmann, D., and Zweizig, J. R.: Somnambulism: All-Night Eleotroencephalographic Studies, Science 148: 975, 1965. Kales, A., Jacobson, A., Paulson, M. J., Kales, J. D., and Walter, R. D.: Somnambulism: Psychophysiological Correlates. I. All-Nrght EEG Studies, Arch. Gen. Psychiat. 14: 586, 1966. Rechtschaffen, A., Goodenough, D. R., and Shapiro, A.: Patterns of Sleep Talking, Arch. Gen. Psychiat. 7: 418, 1962. Gastaut, H., and Broughton, R.: A Clinical and Polygraphic Study of Episodic Phenomena During Sleep, in Wortis, J., editor: Recent Advances in Biological Psychiatry, New York, 1964, Plenum Press, Inc., Vol. 7, pp. 197-221. Dement, W. C., Rechtschaffen, A., and Gulevich, G.: The Nature of the Narcoleptic Sleep Attack, Neurology 16: 18, 1966. Hishikawa, Y., and Kaneko, Z.: Electroencephalographic Study on Narcolepsy, Electroencephalography & Clin. Neurophysiol. 18: 249, 1965. Kales, A., et al.: Changing Sleep Patterns in Hypothyroidism, presented to PsychoDhvsiolonie Studv of Sleeo. Los Anaeles. Anril. 1967. G&sham, S. C., “Agnew, H. W., anYd Williams; R. L.: The Sleep of Depressed Patients, Arch. Gen. Psyohiat. 13: 505, 1965. Hawkins, D., and Mendels, J.: Sleep Disturbance in Depressive Syndromes, Am. J. Psvchiat. 123: 682. 1966. Z&g, W. W. K., Wilson, W. P., and Dodson, W. D.: Effect of Depressive Disorders on Sleep EEG Responses, Arch. Gen. Psychiat. 10: 439, 1964. Armstrong, R. OH., et al.: Dreams and Gastric Secretions in Duodenal Ulcer Patients, New Physician 14: 241, 1965.
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Nowlip, $.;;;.eration
Sleep studies i4b asthmatic J.
B., of
Troyer, Nocturnal
W.
cf., Collins, W. Angina Pectoris
S., Silverman, With Dreammg,
G.,
and Ann.
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C. R-: The 63: 1040,
31. Jacobson, A., Kales, A., Zweisig, J. R., and Kales, J,: Special EEG Technique and EMG Techniques for Sleep Research, Am. J. Electroencephalography 5: 5, 1965. 32. Agnew, H. W., Jr., Webb, W. B., and Williams, R. L.: The First Night Effect: An EEG Study, Psychophysiology 2: 263, 1966. 33. Kales, A., Wilson, T., Paulson, M. ,J., Kales, .J. D., ant1 Walter, R. D.: All-Night Sleep Effects of Aging, J. Am. Geriatrics Sot:. Measurements in Normal Elderly Subjects: 15: 405, 1967. Sleep Patterns in Late Middle Age 34. Agnew, H. W., Webb, W. B., and Williams, R. I,.: Males: An EEG Study, Electroencephalography & Clin. Neurophyaiol. 23: 168, 1967. 35. Kales, A., Jacobson, A., Kales, J. D., Kun, T., and Weissbuch, R.: All-Night EkX: Sleep Measurements in Young Adults, Psychonom. SC. 7: 67, 1967. 36. Michelson, A. L., and Lowell, F. C.: Some Effects of Change in Position on Pulmonar,~ Function in Bronchial Asthma, Am. J. Med. 24: 225, 195s. 37. Reinberg, A., Ghata, J., and Sidi, E.: Nocturnal asthma Attacks: Their Relationships to the Circadian Adrenal Cycle, J. ALLERGY 34: 323, 1963. 38. Dement, W.: The Effect of Dream Deprivation, Science 131: 1705, 1960. 39. Kales, A., Hoedemaker, F. S., Jacobson, A., and Lichtenstein, E. L.: Dream Depriva tion: An Experimental Reappraisal, Nature 204: 1337,1964. 40. Rechtschaffen, A., Hauri, P., and Zeitlin, M.: Auditory Awakening Thresholds in Rk:;\l and NREM Sleep, Percept. Mot. Skills 22: 927, 1966. 41. Goodenough, D. R., Lewis, H. B., Shapiro, H., Jaret, L., and Sleser, 1.: Dream Reporting FoBowrng Abrupt and Gradual Awakenings From Different Stages of Sleep, J. Personality & Sot. Psychol. 2: 170, 1965.