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A laboratory study of sleep in Asperger's syndrome
Page 1
SLEEP
N
EURO
R
EPORT
0959-4965
&
Lippincott Williams & Wilkins
Vol 11 No 1 17 January 2000
127
A laboratory study of sleep in Asperger's
syndrome
Roger Godbout,
1,3,CA
Cybe¡le Bergeron,
1
E¬lyse Limoges,
1
Emmanuel Stip
1,3
and Laurent Mottron
2,3
1
Centre de Recherche Fernand-Seguin, Hoˆpital Louis-Hippolyte Lafontaine, Montre¬al, Que¬bec H1N 3V2;
2
Clinique spe¬cialise¬e
de l'autisme, Hoˆpital Rivie¡re-des-Prairies, Montre¬al, Que¬bec;
3
De¬partement de Psychiatrie, Universite¬ de Montre¬al, Montre¬al,
Que¬bec, Canada
CA,1
Corresponding Author and Address
Received 28 September 1999; accepted 25 November 1999
Acknowledgements: This study was supported in part by the Fonds de la recherche en Sante¬ du Que¬bec.
Asperger's syndrome (AS) is a pervasive developmental dis-
order that may fall along the autistic spectrum. We compared
the sleep of eight patients with AS with that of participants
matched for age and gender. Patients with AS showed de-
creased sleep time in the Ærst two-thirds of the night, increased
number of shifts into REM sleep from a waking epoch, and all
but one patient showed signs of REM sleep disruption. EEG
sleep spindles were signiÆcantly decreased while K complexes
and REM sleep rapid eye movements were normal. Three
patients with AS, but none of the comparison participants,
showed a pathological index of periodic leg movements in
sleep. These observations show that sleep disorders are
associated with AS and suggest that defective sleep control
systems may be associated with the clinical picture of AS.
NeuroReport 11:127±130
&
2000 Lippincott Williams & Wilk-
ins.
Key words: Autism; Electroencephalography; Oculomotor; Pervasive developmental disorders; Sleep spindles; Thalamus
INTRODUCTION
Asperger's syndrome (AS) is a pervasive developmental
disorder whose continuity with high-functioning autism is
still a matter of debate [1]. DSM-IV diagnostic criteria
stipulate that individuals suspected of AS must show
altered social interactions, restricted interests and repetitive
and stereotyped behaviors as in autism but, contrary to the
latter, should not show any signiÆcant language abnormal-
ities and, more particularly, any delay in the acquisition of
language, psychomotor or cognitive skills [2]. There are
very few reports on the neuroanatomical or neurochemical
basis of AS so that researchers and clinicians have to rely
on studies of autism in order to further pathophysiological
hypotheses. Anatomical and brain imaging studies in
persons with autism have provided a list of candidate
structural markers for the syndrome, including temporal/
temporo-occipital systems, frontal lobes, hippocampus, and
the cerebellum. However, when neurological (epilepsy,
etc.) and medication status and IQ are controlled, results
are far from unequivocal (for a complete review, see [3]).
Neurochemical and neuropharmacological studies have
revealed some interesting results regarding serotonin.
Three studies that measured plasma 5-HT found higher
levels (hyperserotoninemia) in groups of children with
autism than in children without autism [4±6]. More pre-
cisely, about 50% of children with autism showed high
levels of plasma 5-HT, although this proved to be true only
for those children with high functioning autism, i.e.,
patients with an IQ of > 70 [7]. The presence of antibodies
directed against 5-HT receptors was also recently identiÆed
in the plasma of high functioning persons with autism but,
again, not in those persons with intellectual handicaps (IQ
, 70) [5]. These results show that 5-HT neurotransmission
is affected in high functioning autism, a Ænding that is
likely true for persons with AS as well, given the resem-
blance between the two syndromes. However, as the two
syndromes are independent clinical entities, it is also
possible that they diverge in physiological, behavioral, and
cognitive physiopathological measures.
The neuroanatomical and biochemical literature cited
above prompted us to explore whether these etiological
hypotheses could also point toward disorders of sleep or
nocturnal EEG abnormalities. 5-HT is a major element in
the modulation of the sleep±wake cycle and there is
evidence in the literature suggesting that serotonergic
neurotransmission abnormalities could be associated with
sleep disorders in AS and autism [8,9]. Although there are
no published reports dealing speciÆcally with the EEG
during sleep in persons with a clear diagnosis of autism,
daytime waking recordings have shown that a relationship
can be drawn between daytime waking EEG activity and
the clinical picture [10].
Since the speciÆc diagnostic criteria for AS were not
published until very recently, only one case-study of sleep
Page 2
and EEG in AS is available in the scientiÆc literature [11].
Clinical observations suggest, however, that persons with
AS may present the same sleep disorders as persons with
autism, namely, difÆculties in initiating and maintaining
sleep, as well as disordered REM sleep [9,12±16] and
nocturnal EEG abnormalities (see [11]). In the present
study we investigated sleep organization and EEG phasic
activity in eight patients diagnosed with AS.
MATERIALS AND METHODS
Subjects: Patients with AS were recruited through a
specialized clinic in autism. Upon approval from the Ethics
Committee, the Ærst 10 patients formally diagnosed with
AS and having a full-scale IQ . 80 were asked if they
would agree to be recorded at the sleep laboratory. Of
these 10, eight patients with AS accepted (seven male, one
female; 22.6 13.6 years, range 7±53 years). Patients were
diagnosed by explicit checking of DSM-IV criteria for AS
[2], as well as with the administration of the Autism
Diagnostic Interview by a trained clinician (LM) [17].
Inclusion criteria were a score above the cut-off point in
the three relevant areas (social, communication, and re-
stricted interest and repetitive behaviors) and an absence
of delay for language and of language abnormalities
typical of autism (echolia, stereotyped behavior, pronoun
reversal) in past or current behaviors. The patient de-
scribed in the published case-study [11] is part of the
present sample.
Eight right-handed participants (seven male, one female;
24.3 18.7 years old, range 7±61 years) formed the group
of age- and gender-matched comparison participants. Ex-
clusion criteria for comparison participants were a past or
current history of psychiatric, neurological or other medical
or sleep disorders. Comparison participants were also
excluded if any of their Ærst-degree relatives had a history
of primary sleep disorder or major psychiatric illness.
All participants were asked to refrain from taking any
CNS-active medication for at least 14 days prior to the
recording. None of the participants but two had been
exposed to antidepressants or neuroleptics in the 12
months preceeding the recording and none had been
taking benzodiazepines for the last 3 months. The two
treated patients were unable to comply with the medica-
tion withdrawal requirements for therapeutic reasons. One
patient (No. 3) continued taking 40 mg of the 5-HT re-
uptake blocker Øuoxetine each morning, and the other (No.
7) continued taking 3.5 mg haloperidol and 20 mg triØuo-
perazine daily.
Sleep was recorded for two consecutive nights and
scored according to standard methods using 20 s epochs
[18]. Sleep onset was deÆned as the Ærst occurrence of
either 10 consecutive minutes of stage 1 or one epoch of
stage 2, 3, 4 or REM sleep. Total sleep time was deÆned as
the total amount of minutes spent in any of the sleep stages
during the sleep period (i.e. from sleep onset to Ænal
awakening). Total sleep time was broken down into thirds
of the sleep period. Anterior tibialis EMG (two nights) and
respiration Øow (one night) were also recorded. Periodic
leg movements in sleep (PLMS) were scored according to
standard criteria [19].
Three sleep phasic activities were scored. Stage 2 sleep
spindles were visually identiÆed on the C
3
lead according
to the following criteria: bursts of EEG activity at 12±15 Hz
and lasting 0.5±2.0 s; no amplitude criteria were applied.
Stage 2 K complexes were also visually identiÆed on the C
3
lead according to the following criteria: a negative-going
biphasic wave with a sharp onset and smoother offset,
lasting 0.5±1.5 s and with an amplitude > 75 ÏV. REM
density was deÆned as the number of 2 s REM sleep
epochs containing at least one REM. Sleep spindle and K
complex, and REM density indices were calculated by
dividing the total number of events by the time (in hours)
spent in stage 2 and REM sleep, respectively.
Statistical analysis: All variables except stage shifts
(waking to REM sleep, stage 1 to REM sleep, and stage 2 to
REM sleep) and indices of phasic events (sleep spindles, K
complexes, and REMs) were compared with the Kolmogor-
ov±Smirnov two-sample test using an alpha of 0.10 [20].
The Kolmogorov±Smirnov is a non-parametric test that
assesses the hypothesis that two samples were drawn from
different populations. It is sensitive to differences in the
general shapes of distributions in the two samples such as
dispersion, skewness, etc. Pilot work indicated that this
was the case with the present two samples. Since the
number of shifts between sleep stages and phasic activity
were similarly distributed within both samples, the Mann-
Whitney U-test was used, with an alpha of 0.05 [20].
Ethics: All participants gave informed consent to take
part in the study. The experimental protocol was approved
by the Ethics Committee of the Centre de recherche
Fernand-Seguin, Hoˆpital Louis-Hippolyte Lafontaine,
where the study was performed.
RESULTS
Table 1 shows that, as a group, patients with AS had less
sleep in the Ærst two-thirds of the night than did compari-
son participants. Those with AS also made more entries
into REM sleep from a waking epoch while comparison
participants made more entries into REM sleep from a
stage 2 epoch. Other macrostructural REM sleep par-
ameters were normal in the group of patients with AS.
Analysis of phasic EEG events revealed a signiÆcantly
lower density of sleep spindles in patients with AS. This
difference was also observed in the Ærst and the last third
of the night. The difference in the second third suggested a
trend approaching statistical signiÆcance (see Fig. 1). K
complexes in stage 2 were far more prevalent in patients
with AS, although this difference did not reach statistical
signiÆcance, perhaps due to a high variability among the
comparison participants that was noted for this measure.
Similar rapid eye movements in REM sleep were observed
between the two groups. As a group, patients with AS
showed a pathological index of PLMS (12.3 7.1) while
comparison participants did not. Sleep apnea syndrome
was absent from all participants.
Individual data of the patients with AS are presented in
Table 2. All patients but one (No. 5) displayed at least one
of the following disruptions of REM sleep: a short REM
sleep latency (patients 1, 7, 8), a long REM sleep latency
(patients 2, 3, 6), or dissociated REM sleep (patients 2, 3, 4,
7). REM sleep dissociation took the form either of increased
EMG levels during otherwise typical REM sleep (scored as
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Page 3
stage 1) or of rapid eye movements during otherwise
typical stage 2 sleep (scored as stage 2). Moreover, three
patients (1, 4, 6) presented a pathological PLMS index.
Patients 3 and 7 were taking CNS-active medications at
the time of recording. Their individual polysomnographic
results, however, are well within the range of the other
patients (see Table 2).
DISCUSSION
Apart from a case-study [11], this report is the Ærst to
objectively document sleep organization in AS. As a group,
the patients with AS had difÆculty initiating and maintain-
Table 1. Sleep organization in patients with Asperger's syndrome and
control subjects
Asperger's
syndrome
Controls
p
Total sleep time (min)
390.2 7.2
401.4 8.4
ns
Sleep time 1/3 (min)
127.8 4.7
135.9 4.0
Sleep time 2/3 (min)
132.5 1.3
137.7 1.3
Sleep time 3/3 (min)
129.8 1.6
127.7 6.2
ns
Sleep latency (min)
25.5 9.1
14.2 3.0
ns
SWS latency (min)
20.3 12.1
21.7 4.9
ns
REM sleep latency (min)
110.8 26.8
93.5 12.1 ns
Sleep efÆciency (%)
93.6 1.7
93.8 1.6
ns
REM sleep efÆciency (%)
89.0 3.3
85.7 3.1
ns
Stage shifts
Waking to REM sleep (no.)
4.1 1.3
1.3 0.4
Stage 1 to REM sleep (no.)
4.5 0.7
7.5 2.3
ns
Stage 2 to REM sleep (no.)
2.6 6.8
5.4 0.9
Stage 1 (%)
20.4 6.8
10.5 1.9
ns
Stage 2 (%)
43.7 6.6
56.9 3.2
ns
Stage 3 (%)
9.6 1.9
10.5 3.5
ns
Stage 4 (%)
7.0 3.4
7.6 1.9
ns
REM sleep (%)
19.3 2.1
18.6 1.5
ns
Sleep spindle index (no./h stage 2)
141.8 39.6 282.4 44.4
K complex index (no./h stage 2)
109.1 16.0
65.0 20.0 ns
REM index (no./h REM sleep)
288.1 55.5 305.8 40.6 ns
Statistically signiÆcant differences; see Materials and Methods for tests and alpha
levels used.
*
*
1/3
2/3
3/3
Third of night
0
40
80
120
160
200
240
Counts/hour of sleep (means
s.e.m.)
Asperger's
Controls
SLEEP SPINDLES
Fig. 1. Evolution of sleep spindles through the night in Asperger's
syndrome and comparison participants. Stars indicate a statistically signiÆ-
cant difference between the two groups.
Table
2.
Sleep
organization
ineight
patie
nts
with
Asp
erger's
syndrome
ID(sex)
Age
Sleep late
ncy
(min)
Late
ncy
SWS (min)
Latency REM (min)
Tota
lsleep
time (min)
Sleep efÆcency
a
No. awakening
s
No.
REM
peri
ods
Mean
REM
cycle
length
(min)
REM efÆc
iency
b
Stage
1
(%)
Stage
2
(%)
SWS (%)
REM (%)
PLMS
index
1(M)
53
85.7
103.3
48.0
372.0
88.7
61
5
81.9
90.9
63.4
11.1
0.4
25.1
47.3
2(M)
20
26.7
16.3
139.3
403.8
97.1
19
3
108.9
85.8
8.4
61.9
8.2
21.5
0
3(M)
15
10.3
5.7
134.7
399.7
96.1
30
4
100.1
92.6
8.2
47.5
21.3
23.1
2.4
4(M)
7
6.3
1.7
80.7
401.7
96.9
20
4
99.8
96.1
18.2
21.0
42.2
18.6
35.3
5(M)
25
14.3
18.0
87.0
365.0
89.3
45
4
97.2
91.4
19.1
57.4
5.1
18.4
0
6(M)
22
30
0.3
277.7
361.7
86.0
32
2
175.5
67.6
24.2
46.9
13.3
6.5
13.6
7(M)
16
11.3
7.7
48.7
410.3
97.6
20
5
72.3
97.4
7.6
49.6
18.3
24.6
0
8(F)
22
19.0
9.7
70.7
407.3
96.9
23
5
83.8
90.9
11.1
53.4
18.1
17.2
0
Mean
22.5
25.5
20.3
110.8
390.2
93.6
31.3
4
102.4
89.1
20.0
43.6
15.9
19.4
12.3
s.e.m.
4.8
9.1
12.1
26.8
7.2
1.7
5.3
0.4
11.3
3.3
6.6
6.3
4.9
2.1
7.1
a
sleep
efÆcicency
ñ[(total
sleep
time/total
sleep
time
›waking
time
after
sleep
onset)
3100]
b
REM
efÆciency
ñ[(min
REM
sleep
inREM
periods/total
REM
period
time)
3100]
SLEEP IN ASPERGER'S SYNDROME
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Page 4
ing sleep, as evidenced by the low amount of sleeping time
in the Ærst two-thirds of the night. Sleep latency, sleep
efÆciency and the proportion of stage 1 were, however,
within the normal range. More striking than this limited
sleep disruption, two interesting characteristics were ob-
served in the present group of patients with AS: low
incidence of sleep spindles and abnormalities of REM
sleep.
Sleep spindles are thought to represent a sleep protective
mechanism by which access of inputs to the brain (and
their processing) are diminished through a deactivation of
the thalamo-cortical loops [21]. Recent results have sug-
gested that EEG sleep spindle density signiÆcantly corre-
lates with selective attention in young, healthy human
participants [22]. This is congruent with present results
since persons with high functioning autism (and patients
with AS) have selective attention atypicalities, namely
difÆculty switching attentional focus, enhanced visual
search, and locally-oriented perceptual processing [23].
Decreased EEG sleep spindles could therefore reØect an
abnormality in the capacity of the thalamo-cortical loop to
contribute to the Æltering of inputs, including of the
perceptual type [21].
The REM sleep abnormalities found in seven of the eight
patients may also be related to daytime cognitive difÆcult-
ies in AS. It has been long known that REM sleep is related
to daytime cognitive functioning [24]. The relationship
between this sleep stage and daytime cognitive functioning
in AS deserves further investigation.
Contrary to two previous studies which quantiÆed
oculomotor activity during REM sleep in patients with
autism and reported either increased [12] or decreased [15]
REM density, we did not Ænd differences between patients
with AS and comparison participants in terms of their
REM density. While it is possible that patients with AS and
those with autism may differ on oculomotor activity meas-
ures, the divergent Ændings are more likely explained by
the present use of stringent diagnostic criteria, including
IQ.Finally, patients with AS, as a group, displayed a
pathological index of PLMS; three patients contributed to
this effect, including a 7-year-old child. It is still to be
determined whether AS presents a particular susceptibility
to this dopamine-dependent sleep disorder [19] and/or if it
has a particular impact on daytime functioning in these
patients. It is noteworthy however that PLMS has been
frequently observed in Gilles de la Tourette Syndrome [25],
a neuro-developmental disorder that shows co-morbidity
with AS.
CONCLUSION
Sleep in AS presents with a variety of disturbances: sleep
time in early night was low, sleep spindles were decreased,
REM sleep was disrupted and PLMS was prevalent. Some
of these features have also been reported in autism and
most of them can be related to hyperserotoninemia [11].
The relevance of this instability of the sleep process to the
clinical picture in AS needs to be systematically investi-
gated.
REFERENCES
1. Volkmar FR, Klin A and Pauls D. J Autism Dev Disord 28, 4,57±463
(1998).
2. American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV), 4th edn. Washington (DC): American
Psychiatric Association, 1994.
3. Minshew N. Neurological aspects of autism. In: Cohen D and Volkmar
F, eds. Handbook of Autism and Pervasive Developmental Disorders. New
York: Wiley, 1996: 344±369.
4. Laszlo A, Horvath E, Eck E et al. Clin Chim Acta 229, 205±207 (1994).
5. Singh VK, Singh EA and Warren RP. Biol Psychiatry 41, 753±755 (1997).
6. Yuwiler A, Shih JC, Chen CH et al. Autism Dev Disord 22, 33±45 (1992).
7. He¬rault J, Petit E, Martineau J et al. Psychiatry Res 65, 33±43 (1996).
8. Posey DJ, Litwiller M, Koburn A et al. J Am Acad Child Adol Psychiatry
38, 111±112 (1999).
9. Segawa M and Nomura Y. Brain Dev 14 Suppl, S46±S54 (1992).
10. Dawson G, Klinger LG, Panagiotides H et al. J Abnorm Child Psychol 23,
569±583 (1995).
11. Godbout R, Bergeron C, Stip E et al. Dreaming 8, 75±88 (1998).
12. Elia M, Ferri R, Musumeci SA et al. Brain Dysfunction 4, 348±354 (1991).
13. Ornitz EM, Ritvo ER, Brown MB et al. Electroencephalogr Clin Neurophy-
siol 26,167±175 (1969).
14. Richdale AL. Dev Med Child Neurol 41, 60±66 (1999).
15. Tanguay PE, Ornitz EM, Forsythe AB et al. J Autism Childh Schizophr 6,
275±288 (1976).
16. Stores, G and Wiggs L. Autism 2, 157±169 (1998).
17. Le Couteur A, Rutter M, Lord C et al. J Autism Dev Dis 19, 363±387
(1989).
18. Rechtschaffen A and Kales A. A Manual of Standardized Terminology,
Techniques and Scoring System for Sleep Stages of Human Subjects. Los
Angeles: BIS/BRI, University of California at Los Angeles, 1968.
19. Montplaisir J, Godbout R, Pelletier G et al. Restless legs syndrome and
periodic limb movements during sleep. In: Kryger MH, Roth T and
Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia:
Saunders, 1993: 589±597.
20. Statsoft, Inc. (1998) Statistics for Windows (Computer program manual).
Tulsa (OK). http://www.statsoft.com
21. Steriade M, McCormick DA and Sejnowski TJ. Science 262, 679±685
(1993).
22. Forest G, Godbout R, Riopel L et al. Soc Neurosci Abstr 23, 1848 (1997).
23. Plaisted K, O'Riordan M and Baron-Cohen S. J Child Psychol Psychiatry
39, 765±775 (1998).
24. Smith C. Behav Brain Res 78, 49±56 (1996).
25. Voderholzer U, Muller N, Haag C et al. J Neurol 244, 521±526 (1997).
N
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R
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