Sleep Medicine 11 (2010) 628–636

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Sleep Medicine
journal homepage: www.elsevier.com/locate/sleep

Review Article

Cyclic alternating pattern: A window into pediatric sleep

Oliviero Bruni a,*, Luana Novelli a, Silvia Miano b, Liborio Parrino c, Mario Giovanni Terzano c, Raffaele Ferri d
a
Department of Developmental Neurology and Psychiatry, Centre for Pediatric Sleep Disorders, Sapienza University, Rome, Italy
b
Department of Pediatrics, Sleep Disease Centre, Sapienza University, S. Andrea Hospital, Rome, Italy
c
Sleep Disorders Center, Department of Neuroscience, University of Parma, Parma, Italy
d
Department of Neurology I.C., Sleep Research Centre, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Cyclic alternating pattern (CAP) has now been studied in different age groups of normal infants and chil-
Received 6 September 2009 dren, and it is clear that it shows dramatic changes with age. In this review we first focus on the impor-
Received in revised form 12 October 2009 tant age-related changes of CAP from birth to peripubertal age and, subsequently, we describe the
Accepted 16 October 2009
numerous studies on CAP in developmental clinical conditions such as pediatric sleep disordered breath-
Available online 27 April 2010
ing, disorders of arousal (sleep walking and sleep terror), pediatric narcolepsy, learning disabilities with
mental retardation (fragile-X syndrome, Down syndrome, autistic spectrum disorder, Prader-Willi syn-
Keywords:
drome) or without (dyslexia, Asperger syndrome, attention-deficit/hyperactivity disorder). CAP rate is
Cyclic alternating pattern
Spectral analysis
almost always decreased in these conditions with the exception of the disorders of arousal and some
Sleep disordered breathing cases of sleep apnea. Another constant result is the reduction of A1 subtypes, probably in relationship
Disorder of arousal with the degree of cognitive impairment. The analysis of CAP in pediatric sleep allows a better under-
Narcolepsy standing of the underlying neurophysiological mechanisms of sleep disturbance. CAP can be considered
Neuropsychological deficits as a window into pediatric sleep, allowing a new vision on how the sleeping brain is influenced by a spe-
Infants cific pathology or how sleep protecting mechanisms try to counteract internal or external disturbing
Children events.
Ó 2010 Elsevier B.V. All rights reserved.

1. The cyclic alternating pattern
The birth of the ‘‘cyclic alternating pattern” (CAP) is linked to
the manuscript published in Sleep in 1985 [1] that indicated CAP
as a physiological component of normal non-Rapid Eye Movement
(NREM) sleep, based on the observation that the electroencephalo-
graphic (EEG) patterns like K-complexes, phases d’activation transi-
toire, spindles, and delta bursts were not only stage markers but
also dynamic elements non-randomly distributed throughout the
sleep cycle. CAP represented a framework capable of including all
these single pieces in an organized context, allowing quantification
of the oscillating arousability during NREM sleep concept [2].
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AS, Asperger
syndrome; CA, conceptional age; CAP, cyclic alternating Pattern; DOA, disorders
of arousal; DS, Down syndrome; EEG, electroencephalogram; fraX, Fragile-X; GH,
growth hormone; HSD, hypersynchronous delta activity; HVS, high-voltage slow
activity; IGF-1, insulin growth factor-1; IQ, intelligence quotient; NCAP, non-CAP;
NREM, non-Rapid Eye Movement; PWS, Prader-Willi syndrome; S1, NREM sleep
stage 1; S2, NREM sleep stage 2; SDB, sleep disordered breathing; ST, sleep terror;
SW, sleepwalking; SWA, slow-wave EEG activity; SWS, slow-wave sleep; TA, tracé
alternant.
* Corresponding author. Address: Center for Pediatric Sleep Disorders, Depart-
ment of Developmental Neurology and Psychiatry, Sapienza University of Rome, Via
dei Sabelli 108, 00185 Rome, Italy. Tel.: +39 06 44712257; fax: +39 06 4957857.
E-mail address: oliviero.bruni@uniroma1.it (O. Bruni).
CAP is an endogenous rhythm present in NREM sleep character-
ized by a periodic EEG activity with sequences of transient electro-
cortical activations (phase A of the cycle) that are distinct from
background EEG activity (phase B of the cycle). These sequences
are repeated several times during the night and organized in a cyc-
lic pattern interrupted by the presence of a stable sleep without
oscillations, called non-CAP (NCAP), longer than 60 s. Sequences
of CAP are evenly distributed in NREM sleep, and the percentage
of CAP time to NREM sleep time (CAP rate) is considered to be a
physiologic marker of NREM sleep instability.
At a given age, CAP rate in normal sleepers tends to remain sta-
ble, but in a given subject it can be enhanced when sleep is dis-
turbed by internal or external factors, and therefore an increase
of CAP rate in general reflects a poor sleep quality. But it should
be interpreted in relation to the different A subtypes that construct
it.
CAP A phases have been subdivided into different subtypes: A1,
A2 and A3, based on their frequency content [3,4], with subtype A1
composed predominantly by slow waves (EEG synchrony), subtype
A3 with prevalence of fast EEG activities (EEG desynchrony), and
subtype A2 presenting a combination of both (Fig. 1). The rules
for scoring the different CAP subtypes, based on their EEG ampli-
tude, duration, interval, and frequency content are detailed in an
Atlas published in 2001 [3].

1389-9457/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2009.10.003
 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636
Fig. 1. Example of CAP (top panel), with its different A phase subtypes, and NCAP periods (bottom panel).
The hierarchical activation from the slower EEG patterns (mod-
erate autonomic activation without sleep disruption) to the faster
EEG patterns (robust vegetative activation associated with visible
sleep fragmentation) can have different meanings: A1 subtypes
are involved in the build-up and maintenance of deep NREM sleep
and can have a protective role for sleep continuity; CAP A1 sub-
types reflect sleep defense ensuring the maintenance or even the
deepening of sleep; instead of having an arousing effect we can
interpret CAP A1 subtypes as ‘‘antiarousals” [5]. On the other hand,
A2 and A3 can be involved in the preparation of REM-on activity
and have the function of maintaining the subject arousability [3].
Accordingly, A1 subtypes dominate the first part of the NREM
sleep cycle when they accompany the progressive transition from
light sleep to deep sleep and, therefore, appear to be involved in
the process of build-up and maintenance of EEG synchronization.
By contrast, A2 and A3 subtypes prevail physiologically during
the final part of the NREM sleep cycle, when they disrupt EEG syn-
chronization and prepare the appropriate desynchronized back-
ground for the onset of REM sleep. Moreover, the ‘‘stable” NCAP
NREM sleep prevails during stage 2 after each REM sleep period
(Fig. 2).
A1 subtypes show a power spectrum characterized by a pre-
dominant peak in the frequency range of 0.25–2.5 Hz [6–9]; these
629
frequencies are likely to be generated at the frontal and prefrontal
areas of the brain; the scalp topographic mapping and localization
of their eventual scalp generators by means of the Low Resolution
Topographical Analysis (LORETA) method [10,11] confirms this
idea [7]. On the contrary, the high-frequency components charac-
terizing CAP A2 and A3 phases have been shown to involve both
midline and hemispheric areas within the parietal and occipital
areas [7].
It has been established that approximately 90% of the microa-
rousals and bursting EEG patterns during NREM are separated by
an interval <60 s, and over 70% are separated by an interval be-
tween 20 and 40 s; therefore, they are organized in repetitive se-
quences based on an approximately 0.033 Hz periodicity [12]. In
humans, a spontaneous ultra-slow rhythm of 0.05–0.025 Hz has
also been described during deep NREM sleep [13,14].
From the EEG point of view, arousals are identified by a fre-
quency shift towards rapid rhythms, but slow high-voltage EEG
activities (A1 subtypes), typical markers of deep NREM sleep, do
not fit the ASDA definition of arousal and could represent a physi-
ological activation with or without very mild sleep disruption. On
the other hand, the A2 and A3 subtypes of CAP correlate closely
with ASDA arousals; this means that when CAP is measured in
NREM sleep we are also collecting all the information supplied
630 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636

Fig. 2. Distribution of CAP and NCAP periods in the sleep structure (small vertical lines overimposed to the hypnogram indicate the occurrence of each CAP A subtype event).

by the analysis of conventional arousals. Therefore, CAP scoring
covers the measurement of ASDA arousal in NREM sleep (subtypes
A2 and A3), encompasses the process of sleep maintenance (sub-
types A1), and provides information on the time structure of these
events [4].
CAP analysis allows a better understanding of sleep modifica-
tions induced by sleep disturbances and underlying neurophysio-
logical mechanisms. CAP provides integrative information to that
supplied by the simple counting of arousals because CAP is not a
simple measure of sleep fragmentation; instead, it quantifies the
amount of unstable, nonconsolidated sleep and casts light on the
adaptive properties of the sleeping brain. In this perspective, CAP
can be considered as a window into pediatric sleep, allowing a
new vision on how the sleeping brain is influenced by a specific
pathology or how sleep protecting mechanisms try to counteract
internal or external disturbing events.
2. Ontogeny of CAP
In 1998, Parrino et al. [15] reported normative data of CAP from
adolescence to elderly and showed a U-shaped curve of CAP rate,
hypothesizing that in younger children CAP rate should be higher,
decreasing progressively from 100% in the so-called ‘‘tracé alter-
nant” (TA) of newborns to adulthood. We subsequently published
data, however, reporting an increase of CAP rate from school-age
to adolescence [16]. Soon after, we analyzed CAP in preschool chil-
dren and found an even lower CAP rate [17]. Consequently, the
curve of CAP rate was found to be progressively increasing from
preschool-age to adolescence and then U-shaped with a minimum
in young adults and increasing again in late adulthood and in the
elderly (Fig. 3).
Finally, CAP has now been studied in different age groups of
normal infants and children and even if relatively low numbers
of normal subjects were included in the various studies, it is clear
that CAP shows dramatic changes with age.
2.1. Newborns
Age is the most important factor influencing EEG patterns and
contributes to the occurrence and features of arousals. It was ini-
tially hypothesized that TA might represent a precursor of CAP in
newborns. The term TA was used to describe the periodic change
in amplitude and frequency content of QS recorded in premature
and at-term babies after 37 weeks conceptional age (CA) [12,13].
TA usually disappears between 3 and 4 weeks after birth; the dis-
appearance of TA and the appearance of sleep spindles led to the
constitution of the NREM sleep stage 2, reflecting the maturation
of the thalamocortical pathways and rostro-caudal pons-thalamus
connections [18,19].
CAP cannot be scored in a recording if it is not possible to rec-
ognize K-complexes, delta bursts, and/or spindles. Spindles are
usually first present by 46–48 weeks CA, whereas K-complexes

Fig. 3. Age-related distribution of CAP rate. Legenda: HVS: infants with High-Voltage Slow pattern; SW_Spindle: infants with Slow-wave pattern and Spindle. The
percentages expressed by A2 and A3 subtypes are aggregated (data pooled from Refs. [15–17,21,27]).
 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636
first appear 5 months post-term and slow-wave activity of slow-
wave sleep (SWS) is first seen as early as 2–3 months post-term
and is usually present 4–4.5 months post-term [19]. Because these
EEG patterns are not well developed at the time of TA, we can ex-
clude TA as the precursor of CAP, since the ‘‘bricks” that constitute
the basic structure of CAP are not present. An advanced nonlinear
analysis of this type of pattern confirmed its differences with CAP
at the level of the EEG signal structure [20]. The progressive matu-
ration of thalamocortical networks might lead to the gradual
appearance of an oscillating pattern of slow EEG activities (differ-
ent from that of TA) which would represent the first prototype of
CAP appearing at 46 to 55 weeks CA. This idea is based on the re-
sults of a recent study on CAP in the first months of life that iden-
tified three distinct age-dependent basal sleep patterns [21]:
1. TA mixed with high-voltage slow activity (HVS) and mixed fre-
quency activity (mean CA 43.9 ± 1.3 weeks).
2. HVS and rudimentary spindles (mean CA 49.4 ± 3.1).
3. SWS and spindles, scored as NREM sleep (mean CA 50.4 ±
2.9 weeks).
CAP analysis showed that CAP rate was 6.83 ± 3.58 in infants
belonging to Group 2 and increased to 12.9 ± 2.21 in Group 3.
The percentage of A1, A2 and A3 showed insignificant variations
with age, but an increase of A1 index (i.e., the number of A1 sub-
types/h of NREM sleep) was observed in Group 3. The duration of
CAP events was similar in all age groups considered [21].
There is a gap in normative studies on CAP since no data are
available for the age range between 5 months and 2 years.
2.2. Preschool children
During the 3- to 6-year age period, several modifications of
sleep structure take place, which mainly include the redistribution
of NREM sleep and the change in proportion of NREM stages
[22,23]. In younger children, the most common pattern of EEG fre-
quency changes associated with an arousal is a shift to a more
rhythmic pattern, primarily in the theta range or, with maturation,
also in the alpha range [19]. Taking this into account, CAP scoring
criteria were modified considering EEG rhythms in the theta range
as the equivalent of alpha in adults, characterizing A2 and A3 CAP
subtypes (associated or not with different degrees of electromyo-
graphic activities) [17].
Preschool-aged children [17] showed a CAP rate value lower
than that reported in all the other age groups studied earlier; how-
ever, we still observed the same trend of a progressive increase of
CAP rate with the deepness of sleep, with highest values during
SWS, as reported in school-aged children and adolescents [15,16].
In comparison with school-aged children, preschool subjects
showed a lower percentage of A1 and a corresponding increase
in percentage of A2; this finding might represent an indirect mar-
ker of an eventually higher sleep instability or of maturational pro-
cesses of sleep development during the preschool period.
The time structure of CAP can be studied by plotting the statis-
tical distribution of intervals between the onset of consecutive A
phases [24]. The analysis of the A1 interval distribution in this
age group showed a clear-cut periodicity, with a peak for intervals
of about 25 s for the A1 subtypes, while no clear peak for the A2–
A3 phases was evident [17].
2.3. School children
In children between 6 and 10 years of age, sleep structure has
nearly reached adult characteristics and there appears to be a rel-
ative stability of patterns [19,25]. In these subjects, CAP rate was
found to show a progressive increase with the deepness of sleep,
631
with high values during SWS [16]. CAP time showed its longest
duration during NREM sleep stage 2 (S2), followed by SWS and
sleep stage 1 (S1). No differences across NREM sleep stages were
found for CAP cycle and phase B mean duration; on the contrary,
phase A showed longer duration during SWS than in S1 and S2.
Phases A1 were the most numerous (84.45%) followed by A3
(9.14%) and by A2 (6.44%). The distribution of phase A subtypes
across NREM stages showed significant differences for the A1 sub-
types that occurred more frequently during SWS than in S2 and S1
(and during S2 than in S1). Subtypes A3 were more frequent during
S1 than SWS while no differences were found for subtype A2. The
analysis of A1 interval distribution showed a log-normal-like dis-
tribution with a peak around 25 s for the A1 phases and no clear
peak for A2–A3 phases [16]; these distributions were similar to
those of preschool-age children.
The increased CAP rate during SWS and higher percentage of A1
subtypes in school-aged children led us to rethink the significance
of CAP rate considering different age groups: in younger children
CAP is mainly constituted by A1 phases and by A2 and A3 in el-
derly. The increase in A1 percentage does not mean that sleep is
disrupted but that the homeostatic mechanism requires a higher
number of oscillations in order to maintain the restorative function
of sleep [5].
2.4. Peripubertal children
It is well known that, in addition to changes in sleep schedule,
sleep duration, and daytime sleepiness, sleep EEG undergoes dra-
matic developmental changes during the passage from preadoles-
cence to adolescence, mostly represented by a decline in NREM
EEG theta and delta activity [26]. Obviously, this also affects sleep
microstructure with dramatic changes involving CAP parameters
too.
Lopes et al. [27] evaluated CAP in a group of peripubertal chil-
dren (age 8–12 years; Tanner stages 2 and 3) revealing a CAP rate
of 62.1%; CAP A1 phases were the most numerous (85.5%), whereas
A2 phases were 9.1% and A3 phases were 5%. In this study, CAP rate
appeared to be higher than the values previously reported and this
might be related to the older age, the higher Tanner stage, or the
cultural and ethnic differences of the subjects studied.
If we pool together the results obtained in different age groups,
we can observe that the percentage of A1 subtypes shows first an
increase from preschool- to school-age and then a progressive de-
crease from school-age children to young adults (Fig. 4). On the
contrary, A2 and A3 subtypes show a progressive increase with
age from school-age to elderly following the same trends of arous-
als [28].
The ratio between A1 and A2/A3 is higher in school-age chil-
dren, supporting the notion that sleep of school-age children can
be considered the ‘‘gold standard” for sleep quality [29] because
of its length, continuity and restorative features. On the other
hand, the increase of the percentage of A2 in preschoolers might
represent the higher sleep instability of this age period.
The main CAP parameters from the normative studies reported
above are summarized in Table 1. Periodicity and time interval dis-
tribution of CAP A1 subtypes are similar to those of school-age
children and adults, indicating that the periodicity of CAP compo-
nents can be considered very stable during development [15–
17,21].
3. EEG spectral analysis studies
Computerized analysis of CAP by means of EEG spectral analysis
in adults showed that CAP subtypes are characterized by different
632 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636

Fig. 4. Age-related distribution of CAP A phase subtypes. Legenda: HVS: infants with High-Voltage Slow pattern; SW_Spindle: infants with Slow-wave pattern and Spindle.
The percentages expressed by A2 and A3 subtypes are aggregated (data pooled from Refs. [15–17,21,27]).

Table 1 SWS, reflecting the difficulty of scoring CAP visually in some

Age-related changes of the main CAP parameters during development. epochs of SWS.
1– Preschool- School- Peripubertal Adolescence
4 Months age [16] age [15] [27] [14]
4. CAP analysis in pediatric sleep disordered breathing
[20]
Cap rate% 12.9 25.93 33.43 62.1 43.4
A disruption of NREM sleep expressed by CAP alterations has
A1% 85.2 63.2 84.45 85.5 –
A2% 10.3 21.5 6.44 9.1 –
been hypothesized to exist in children with sleep disordered
A3% 4.4 15.3 9.14 3.2 – breathing (SDB) [34–38]. The studies on CAP in SDB children
A1 index 19.8 24.8 39.54 – 45 showed partially contradictory results: in one study [36], children
A2 index 2.8 6.5 2.66 – 12.4 with OSAS (aged 5–8 years) had a decreased CAP rate (mainly dur-
A3 index 0.5 4.0 3.30 – 5.7
ing SWS) of A1 percentage and of A1 index compared to normal
controls, together with a longer interval between consecutive A
phases (longer duration of phase B) and a decrease in entropy cal-
spectra, and the same subtypes show a different power spectrum if culated by the Markovian analysis. Lopes et al. [37] found, in
they occur during sleep stage 2 or SWS [9]. school-age children with primary snoring, a slight increase of
EEG frequencies are overall slower in children and gradually get CAP rate, of A2% and A3% and a slight decrease of A1% compared
faster until they reach adult values, while the amplitude of wave- to control subjects. The apparently conflicting results might be re-
forms at all frequencies increases gradually, reaching a peak in the lated to the milder SDB of snoring children and to the older age of
school-age period and then declines. These developmental changes children in the Lopes study. The same authors [37] also found a po-
occur also in several polysomnographic measures, particularly dur- sitive correlation between the increase of CAP rate and behavioral
ing transition from preschool- to early school-age [30], with a complaints (school difficulties, hyperactivity, inattention, aggres-
change in proportion of NREM stage, related to the gradual disap- siveness, and irritability).
pearance of napping [22]. Also during the transition from preado- An increased CAP rate was also reported in school-age children
lescence to adolescence, this process determines a dramatic change with sleepwalking associated with upper airway resistance syn-
in power density involving all frequency bands between 0.3 and drome or OSAS [35]. The same increase of CAP rate, mainly during
30 Hz but most evident in the theta and delta bands [26]. SWS, associated with an increase of A2 index, was found in a group
In our study [31], the analysis of the relative power density in of children with mild OSAS aged 4–8 years compared to normal
three age groups (preschool, school, adults) revealed that in sleep controls [38]. Interestingly, in the latter study, CAP analysis was re-
stage 2 and in SWS, CAP A1, A2 and A3 subtypes had a significantly peated in the same patients after one year of orthodontic treat-
higher power in all frequency ranges in preschool children than in ment: children with OSAS showed a compensatory increase of
adults, while school children differed mainly for the lower frequen- CAP rate and A1 index during SWS compared to controls associated
cies (<7 Hz) [31]. This finding might be associated with the age-re- with a significant improvement of sleep respiratory parameters. An
lated delta amplitude decline in the 0–3 Hz frequency band increase of CAP rate during SWS was also found after nasal contin-
reported by Feinberg et al. [32] and Coble et al. [33] in children uous positive airway pressure therapy in a 5-year-old obese child
of the same ages. Also NCAP EEG spectra were completely different with severe OSAS, associated with an increase of both A1 index
in the three age groups; this shows that NREM sleep undergoes during SWS and A1% compared to the baseline recording [39]. Con-
profound modification in its structure during development. versely, a lower CAP rate associated with a lower A1 index during
Nevertheless, the pattern of the relative spectral differences be- SWS and lower total A2 and arousal index was found in a group of
tween CAP and NCAP periods in stage 2 was similar in the three age school-age children with OSAS and EEG abnormalities compared to
groups, indicating that the structural component of CAP is very sta- those without EEG abnormalities. The EEG abnormalities were not
ble over time and is not greatly influenced by age. associated with seizures and mostly occurred over the central,
Furthermore, EEG spectra showed that the B phase of CAP does temporal and occipital brain regions [40].
not seem to be a simple return to the ongoing baseline activity but Although the age ranges and the degree of the OSAS severity
is characterized by a small and significant increase in power in the were different in the various studies, apart from the discrepancy
delta-theta frequencies and a decrease in power in the sigma fre- of the values of the CAP rate, some constant results in all studies
quency range. The difference is more marked in stage 2 than in can be noticed, represented by a decrease of A1 subtypes (mainly
 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636
during SWS) with a corresponding increase of A2 and A3 and a long-
er duration of B phases. These findings might represent the main ef-
fect of SDB on sleep microstructure, leading to an increase in SWS
instability, which may even be a trigger for other sleep events such
as parasomnias or seizures. In fact, the treatment of OSAS typically
leads to an increase in A1 percentage and to a normalization of
sleep structure with a decrease of SWS instability, presumably
mediated by a normalization of the duration of phase B [38].
Nevertheless, the relatively low number of subjects and the het-
erogeneity of the groups investigated (different ages, different
severity of sleep breathing disorders) do not allow a clear compar-
ison of these studies, and new investigations with a larger group of
children and with a long outcome period are required.
Few data are available about the correlation between CAP anal-
ysis and neurocognitive function. Recently, O.B. and Ferri [41]
hypothesized an intriguing pathogenetic model for pediatric OSAS
linking inflammatory, endocrinological and neurophysiological
factors: since a consistent relationship between SWS and increased
growth hormone (GH) secretion has been reported and the insulin
growth factor-1 (IGF-1) test is an indirect measure of the average
amount of GH levels, OSAS children who develop neurocognitive
deficits may have low levels of IGF-1, as recently reported [42], ele-
vated high-sensitivity C-reactive protein levels [43], high preva-
lence of the e4 apolipoprotein E allele [44] and a low amount of
transient EEG slow oscillations (A1 phases) during sleep.
5. CAP in the disorders of arousal
The disorders of arousal (DOA) are the most common parasom-
nias in children, and are subdivided into three main forms: confu-
sional arousals, sleepwalking (SW) and sleep terrors (ST).
The typical feature of sleep architecture in DOA is represented
by a high degree of arousal from SWS and by a peculiar EEG pattern
defined as hypersynchronous delta activity (HSD) [35,45–49], de-
scribed as continuous high-voltage (>150 lV) delta waves occur-
ring during SWS or immediately prior to an episode [47] and
considered to be part of the CAP A1 subtype and possibly A2
[50]. HSD is not specific for the diagnosis of NREM parasomnias
in adults and even less in children, since the definition of HSD is
suitable only for adults and does not seem to be adequate for the
description of children’s slow-wave activity (SWA) with or without
parasomnia [49].
Chronic sleepwalkers have instability of NREM sleep detectable
by CAP analysis, even on nights without sleepwalking episodes and
probably related to the presence of associated sleep disorders such
as upper airway resistance syndrome or other sleep disorders
(periodic limb movement disorder) that are known to be associ-
ated with chronic sleepwalking [35,51]. Moreover, CAP rate corre-
lates with the presence of sleep respiratory disturbances [52].
The studies on CAP in subjects with SW or ST showed conflict-
ing results: Zucconi et al. [48] found an increase of A1% and of CAP
rate and a decrease in phase B duration. Guilleminault et al. [35,52]
also found an increase in CAP rate but also in A2 and A3 index,
while A1 index was decreased; more recently we [53] reported
an increase of CAP rate and of A1 index in SWS (but decreased in
stage 1 and stage 2 NREM) and a decrease of phase B (in SWS)
and CAP cycle duration. This shorter duration of CAP cycle and
phase B determined an abnormally fast oscillatory pattern of the
amplitude of EEG slow components in SWS that was previously
named HSD, SWS arousals or CAP A1 in different studies [35,45–
49]. Guilleminault [50], when commenting on the paper by Pilon
et al. [47], highlighted the importance of CAP phase B, reporting
that abnormality in sleepwalking is not the HSD per se, but the
reappearance of the background-like activity (phase B) that inter-
rupts the persistence of the slow delta and determines the bursting
633
pattern of delta during SWS; he also questioned why the delta
burst (CAP A1) is abruptly interrupted [52].
It might be possible to hypothesize that in parasomnias the
numerous recurrent arousals from SWS create a SWA deficit within
sleep, leading to a continued SWA reappearance, due to an ultra-
short intra-sleep recovery process. The coexistence of pressure
for delta sleep and a high level of arousal intrusion in SWS might
contribute to trigger SWS parasomnias, confirming the hypothesis
of Broughton [54] that arousal disorders are precipitating factors
for some sleep disturbances related to delta sleep, such as SW
and ST. Also Espa et al. [45] concluded in adults that high SWS frag-
mentation might be responsible for the occurrence of SW or ST epi-
sodes. This ‘‘abnormally faster oscillatory pattern in SWS” might be
responsible for the occurrence of parasomnia episodes and might
be considered as a neurophysiological marker of DOA [53].
6. CAP in children with narcolepsy
The alterations of CAP recently found in narcoleptic adult pa-
tients [55,56] seem to suggest the presence of an impaired modu-
lation of the fluctuations of the arousal level during their NREM
sleep, possibly because of the persistence of neurophysiological
mechanisms typical of REM sleep. The sleep microstructure
changes observed in adulthood are already present and detectable
in childhood and might have a role in the already known impaired
prefrontal functioning of these subjects [57].
CAP rate was found to be decreased in narcoleptic children in all
NREM sleep stages and A1 and A2 indexes were also significantly
lower than in normal controls; the relative percentages of the dif-
ferent subtypes were somewhat similar but A3 subtypes were
more prevalent in narcoleptic children [57]. The most important
finding was a reduced amount of CAP in narcoleptic children and
adolescents, even more evident than that already reported in
adults [55,56].
The NREM sleep alterations of narcoleptic children are very
similar to those found in children affected by attention-deficit/
hyperactivity disorder [58], suggesting a similar condition of hyp-
oarousability in the two groups. These similarities are also evident
from a clinical point of view because in young narcoleptic children,
restlessness and motor hyperactivity can sometimes overcome the
drowsiness and lead to behavioral problems; further, adults who
have been diagnosed with narcolepsy frequently report a history
of attention deficit disorder and hyperactivity superimposed to
their sleepiness [59].
7. CAP in neuropsychological disabilities
Recently, some reports have highlighted the relationships be-
tween CAP and cognitive [60,61] and memory performances [62].
Specifically, CAP slow components (A1) are modified by a learning
task during the day preceding sleep [61] and are positively related
with intelligence quotient (IQ) [60] and superior memory [62],
supporting the idea that these components might play a role in
sleep-related cognitive processes. These pioneering studies have
led to a growing interest in the role of NREM sleep in children with
mental retardation or other cognitive disorders. The analysis of
CAP might disclose new important findings in the sleep structure
of children with mental retardation and might characterize sleep
microstructural patterns of different phenotypes of intellectual
disability.
7.1. CAP in neuropsychological disabilities with mental retardation
The studies on CAP in children with mental retardation are
scarce and involved the two most common causes of inherited
634 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636

mental retardation: Fragile-X (fraX) and Down syndrome (DS). The SWS and A1 index in SWS was found. With respect to children with
analysis of CAP [63] in these two groups of children showed a low- autism, subjects with AS showed increased CAP rate in SWS and A1
er percentage of A1 and a higher percentage of A2 and A3 in both percentage.
patient groups, compared to normal controls. FraX subjects Another common neuropsychological problem in children is the
showed the most disrupted sleep microstructure: total CAP rate attention-deficit/hyperactivity disorder (ADHD). The analysis of
and CAP rate in S2 NREM were lower than those of DS patients CAP [58] showed that the number of CAP sequences and CAP rate
and controls and CAP rate in SWS was lower than in normal con- are reduced in children with ADHD, mostly because of the low
trols. The A1 index in S2 and SWS was significantly lower in fraX CAP rate during NREM sleep stage 2; this reduction is mediated
syndrome than in DS and controls. The differences in sleep micro- by a selective decrease in the overall number of A1 subtypes. Inter-
structure found between fraX syndrome and DS might be in some estingly, CAP changes in ADHD seem to be similar to what we have
way related to their different degree of mental retardation. found in narcoleptic patients [57] and the CAP similarities between
Similar results were found in children with autistic spectrum these two conditions further reinforce the hypothesis of a deficit of
disorder [64] and mental retardation: a decrease of CAP rate (sim- the arousal-level fluctuations and of a ‘‘primary disorder of vigi-
ilar to that of DS and fraX children) more evident during SWS and lance” in ADHD [72,73].
mainly due to a reduction of A1 CAP subtypes.
Recently we also analyzed CAP in Prader-Willi syndrome (PWS),
another genetic syndrome commonly associated with mental 8. Conclusions
retardation [65,66]. CAP analysis [67] revealed a global reduction
of CAP rate in all sleep stages (not only in SWS) and of all A sub- Table 2 summarizes the main CAP parameters derived from the
types, suggesting the presence of a decreased NREM sleep instabil- available studies on different childhood pathologies. CAP rate is al-
ity. Moreover, we found few, but relevant, differences in CAP most always decreased; DOA are the only conditions in which CAP
parameters in PWS children on GH therapy (GH + PWS) vs. PWS rate is increased, together with some cases of sleep apnea: in DOA,
children without GH therapy (GH  PWS): GH + PWS patients the increase is related to the presence of a congenital high degree
showed higher CAP rate in SWS and higher A1 index in SWS which of arousal from SWS associated with the HSD pattern, while in
might reflect an increase of EEG slow oscillations in SWS, possibly sleep apnea the respiratory events are likely to determine the in-
favored by GH therapy. This finding is supported by the evidence of crease in CAP rate. Another constant result is the reduction of per-
a linear relationship between the amount of SWS and of concomi- centage of A1 subtypes and of A1 index, probably in connection
tant GH secretion [68]. Therefore, we can hypothesize that GH with the degree of cognitive impairment. Also in disorders charac-
treatment in PWS patients determined an increase of A1 CAP sub- terized by hypoarousability (narcolepsy, ADHD and PWS) there is a
types in SWS. global decrease of NREM instability, represented by a reduction of
Summarizing the results of these investigations on CAP in dif- CAP rate and of A indexes.
ferent developmental disorders [63,64,67], we might hypothesize
that NREM sleep microstructure alterations, associated with the
reduction in REM sleep percentage, are distinctive features of intel- Table 2
lectual disability. Changes of the main CAP parameters (vs. age-matched normal controls) in the
different pathologies studied.
7.2. CAP in neuropsychological disabilities without mental retardation CAP A1% A2% A3% A1 A2 A3
rate% index Index Index
CAP has also been studied in developmental disabilities and Autism = ; " " ; = "
other neuropsychological disorders without mental retardation. Down syndrome = ; " " = – –
Dyslexia is the most frequent learning disability in childhood and FraX syndrome ; ; " " ; – –
is characterized by a difficulty with accurate and/or fluent word Prader-Willi ; " ; ; ; ; ;
syndrome
recognition and by poor spelling and decoding abilities unrelated
Dyslexia = = " = = " =
to a dysfunction of the factors (intelligence, motivation, exposure Asperger ; " ; = ; ; ;
to reasonable reading instruction) that are necessary to turn print syndrome
into meaning [69]. In order to overcome reading difficulties, dys- OSAS ; ; = = ; = =
lexic subjects need to overactivate thalamocortical and hippocam- ADHD ; = = = ; = =
Sleep terror " = = = " = =
pal circuitry and to transfer information between cortical posterior Narcolepsy ; = = ; ; ; =
and anterior areas. CAP analysis [70] revealed a higher total CAP
rate and A1 index in stage N3 in dyslexic children vs. controls that See Refs. [35–38,40,52,53,55,57,58,60,63,64,67,70].

could be related to the compensatory overactivation of the ancil-

lary frontal areas that represent the generators of the sleep EEG
Table 3
low-frequency band (0.25–2.5 Hz) of CAP A1 phases [71]. Also, dys-
Suggested topics for future research.
lexic children showed a significant positive correlation between A1
index in NREM sleep stage 3 and verbal and full-scale IQ, while CAP
rate in NREM sleep stage 3 was positively correlated with verbal
IQ. The same positive correlation between IQ and slow CAP compo-
nent was found previously in children and adolescents with Asper-
ger syndrome (AS) [60].
AS is a high-functioning autism characterized by normal intelli-
gence, social deficits, rigid ritualistic behaviors, interests or activi-
ties, and communication problems, but without clinically
significant cognitive or language delay. Compared to normal con-
trols and autism, AS subjects [60] revealed an increased percentage
of A1 and a decreased percentage of A2 subtypes; moreover, a sig-
nificant positive correlation of IQ with total CAP rate, CAP rate in
1. Normative studies in children in the age range between 5 months and
3 years.
2. Studies on larger samples of normal children
3. Studies on homogenous groups of specific sleep disorders, such as
obstructive sleep apnea syndrome or upper airway resistance syndrome
4. Longitudinal studies of CAP changes during development
5. CAP in children with insomnia
6. Close examination of the relationships between CAP and cognitive
functioning in children (normal controls and with learning impairment)
7. CAP night-to-night variability?
8. First-night effect on CAP?
9. Effect of sleep deprivation on CAP in children
10. CAP in children with hormonal dysfunction (i.e., GH deficit)
11. CAP in children with different forms of epilepsy
 O. Bruni et al. / Sleep Medicine 11 (2010) 628–636 635

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