Improvement of clinical features in children with autism spectrum

disorder after improvement of sleep pattern

Jimenez-Xolalpa R.a,b, Arana Lechuga Y.a,b, Teran-Perez G.b, Sanchez-

Escandon O.b,c, Mercadillo-Caballero R.b,d,e and Velazquez-Moctezuma J.a,b,e*

a
Sleep Disorders Center, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City,
Mexico; bNeuroscience and Sleep Disorders Center, Mexico City, Mexico; cNeurological
Center, ABC Hospital, Santa Fe, Mexico City, Mexico; dConsejo Nacional de Ciencia y
Tecnología, Mexico City, Mexico; eNeuroscience Area, Department of Reproductive
Biology, Universidad Autónoma Metropolitana, Mexico City, Mexico.

*Corresponding Author: JVM

Email: jvelazquezmoctezuma@gmail.com
Orcid: https://orcid.org/0000-0003-2165-2174.
Neuroscience Area and Sleep Disorders Center
Department of Reproductive Biology
Universidad Autonoma Metropolitana-Iztapalapa
San Rafael Atlixco 186. Col. Leyes de Reforma
Alcaldía Iztapalapa. CP 09340
Mexico City, Mexico
 ABSTRACT

Objectives: To analyze the effects of improvements in sleep patterns on the clinical

characteristics of children diagnosed with autism spectrum disorder. Method: The
children were polysomnographically studied overnight, and their parents were trained
to maintain sleep diaries. Subsequently, the children received behavioral cognitive
therapy for 3 weeks. Melatonin was administered every day in the evening. Sleep
diaries were analyzed after the training period, and the parents were interviewed.
Results: The results showed significant improvements in several characteristics of
sleep patterns, mainly sleep latency and duration. Furthermore, the clinical features
of ASD also showed significant improvements, with behavioral assessments
indicating better social abilities. Conclusions: Our results support the idea that
addressing sleep patterns as an early intervention for ASD has beneficial effects on
the clinical picture of ASD.

Introduction

According to the American Psychiatric Association (1), autism spectrum disorder

(ASD) is a common failure in neurodevelopment in children. Its worldwide prevalence
ranges from 0.7 to 1% (2). Clinically, it is characterized by deficits in adaptive skills,
language development, and social communication. In addition, patients and their parents
frequently complain of sleep disturbances (3), including insomnia and circadian rhythm
disorders (4).

However, sleep disorders are notable and have not been sufficiently studied, despite
the fact that they can seriously affect not only patients, but also their parents or primary
caregivers. Between 40% and 86% of ASD patients have sleep disorders that persist in
childhood and adolescence; these include resistance to bedtime, circadian rhythm
alterations, insomnia, and decreased sleep efficiency (4; 5).
 It is well known that sleep is crucial for the proper development of an organism,
particularly the nervous system, and consequent behaviors, including cognitive skills (6).
Sleep during early childhood ranges from 14 to 20 hours and is divided into multiple
episodes throughout the day (7). This pattern evolves as an individual grows and is closely
related to brain function, memory consolidation, and cognitive performance (8). In
addition, sleep has been proposed to be indispensable for neuronal connectivity, allowing
changes in electrical brain activity, sleep spindles, and slow waves that occur during
different sleep stages, which are essential for normal cognitive development (9). Therefore,
sleep disorders in children with ASD are a central issue in their clinical treatment. Some
studies have shown that low IQs and cognitive impairment in patients with ASD correlate
with a decrease in the quantity and quality of sleep (10).

Another cause of sleep disorders may be low melatonin levels, which are commonly
observed in children with ASD (11). Pediatric prolonged-release melatonin is a new
formulation for the treatment of sleep disorders in children presenting with
neurodevelopmental disorders and difficulties in swallowing solids. A study conducted in
children with ASD showed that the use of pediatric prolonged-release melatonin improves
sleep latency, sleep maintenance, and total sleep time (12). Another study reported that one-
year of prolonged-release melatonin use in children with ASD and sleep disorders
improved sleep quality and decreased awakenings. This treatment not only benefited the
patients but also improved the sleep quality of their primary caregivers (13).

In this study, we aimed to determine the incidence of sleep disorders in children

diagnosed with ASD. In addition, we evaluated the effects of a cognitive-behavioral
intervention based on sleep medicine and the use of melatonin on sleep patterns and clinical
behavior. We expected that such interventions would improve sleep and reduce the severity
of behavioral symptoms.

Materials and methods

Children (age: 2–10 years old) diagnosed with ASD were recruited from the Children’s
Psychiatric Hospital “Juan N. Navarro” and the Mental Health Center in Mexico City.
From an initial cohort of 55 children, only 49 met the inclusion criteria. The parents were
fully informed about the protocol and the need for their participation. Subsequently, the
parents signed an informed consent form. Participants with another neurological or
psychiatric disorder, as well as those who did not attend two consecutive appointments or
did not follow the treatment protocol, were excluded. The study protocol was designed
according to the guidelines of the Helsinki Declaration (14). The Ethics Committee of the
Psychiatric Hospital and Universidad Autónoma Metropolitana approved the study
protocol.

As a first step, the children were taken to the sleep disorders center, where they
underwent an overnight polysomnographic study. The electrodes were placed according to
the standard procedures of the American Academy of Sleep Medicine (15). After the
polysomnographic study, the parents were trained on how to maintain a sleep diary.
Subsequently, behavioral evaluation was carried out by applying two specialized
instruments, the Criteria Diagnostic Interview for Autism Spectrum Disorder (CRIDI-ASD)
and Autism Diagnostic Interview-Revised (ADI-R), which were applied before and after
treatment.

The CRIDI-ASD is a brief semi-structured interview based on the Diagnostic and

Statistical Manual, Fifth Edition (DSM-V) criteria for the diagnosis of ASD. This
instrument has been validated in Spanish for Latino and Mexican populations (16). It
includes items for factors such as intellectual disability, language level, and age of onset.
The interview allows the clinician to identify different autism phenotypes, and its brief
duration allows for the presence of the child. It consists of 20 core items organized into two
dimensions of the DSM-V criteria: A. Deficits in communication and social interaction, B.
Restricted and stereotyped patterns of behavior and interests, and unusual sensory
reactivity. Items were scored according to the following codes: 0 = normal behavior, 1 =
probably autistic behavior, 2 = autistic behavior, and 8 = not applicable. The interview
provides raw scores to assess severity and recoded scores to establish cutoff points, which
are in turn used for diagnosis.
 The ADI-R is a semi-structured interview conducted by an experienced health
professional with the assistance of parents or caregivers who are familiar with the
developmental and behavioral history of patients. The Spanish version has been validated
in the Mexican population. The scale is applied by an experienced health professional. It is
used only in children whose mental development is more than two years. The interview
assesses three functional domains: language/communication; reciprocal social interactions;
and restricted, repetitive, and stereotyped behaviors and interests (17).

After the initial assessment, the children received a daily dose of prolonged-release
oral melatonin (5–10 mg) throughout the study. The dose was administered following a
dose-response curve starting with the minimum dose. Trained professionals applied
behavioral cognitive therapy (BCT). BCT was performed one hour a week for 8 weeks,
always with the help of the parents. It involved eight sessions. In summary, the procedure
was as follows: Session 1: Sleep hygiene. Avoid caffeine, bright screens, or play games at
least one hour before bedtime. Make the room comfortable, and ensure that there are no
toys near the bed. Session 2: Consolidation of a routine and behavioral strategy for parents.
Session 3: Behavioral strategies, mainly starting with time limits. Session 4: Independent
sleep, with parents outside the bedroom. Session 5. Relaxation strategies, circadian training,
morning routine, light management, and consolidation of sleep hygiene. Session 6.
Cognitive therapy to understand the relationship between thoughts and feelings. Feeling
recording. Session 7. Management of anxiety, fears, worries, nocturnal concerns, and
nightmares. Consolidation of relaxation strategies. Session 8. Closing. Consolidation of
achievements and definition of a long-term schedule. After full BCT sessions, CRIDI and
ADI-R instruments were applied again.

Statistical analysis

All variables were analyzed using SPSS 20.0 software (IBM Corp., Armonk, NY, USA).
Descriptive statistics are presented as percentages for categorical variables and means with
standard deviations (SD) for numerical data. Polysomnography parameters were described
as means and SD, while sleep efficiency and sleep stages were reported as percentages.
Analysis by age range was performed for the total sleep time and total time in bed. The
sleep diary, CRIDI, and ADI-R scores were compared before and after treatment to
determine their effects. The Shapiro–Wilk test was used to verify the normality of each
variable. Given that non-normal distributions were identified (p < 0.01), the range test and
Wilcoxon signed-rank test were used for comparison. A 95% confidence interval and a p
value of < 0.05 determined significance.

Results

Table 1 presents the demographic characteristics of the participants. As previously

reported, male children were diagnosed with ASD more frequently, and most of them were
diagnosed around the age of 3 years. Approximately 80% of the participants were
diagnosed with moderate ASD.

--------- INSERT TABLE 1 -----------

Polysomnography

It is well known that the sensorial characteristics of children with ASD make body contact
difficult. The placement of the electrodes was easier when they were attached to a puppet in
front of the child. Table 2 summarizes the results of the sleep recordings. No differences
were detected among the children of different ages. Both sleep latency and sleep efficiency
were abnormal. The mean latency was 85 min, and sleep efficiency was 76. Based on the
sleep recordings, 33% of the participants met the criteria for the diagnosis of periodic limb
movements. In addition, 67% of the children also met the criteria for insomnia. Figure 1
shows individual values related to sleep efficiency and Figure 2 individual values related to
sleep latency. As reported in previous studies, most samples fail to reach normal values
based on their age.

----------INSERT TABLE 2----------

----------INSERT FIGURE 1----------

Sleep diaries

Analysis of sleep diaries allowed us to analyze the subjective sleep changes recorded by
parents. The main features displaying impairments since the beginning were sleep latency,
awakening, and total sleep duration. Parents reported weekly improvements in sleep in
almost all children. The final assessment showed a significant difference in sleep latency (a
decrease to 41 min); awakenings decreased to one by night, and sleep duration increased to
a mean of 9.44 hours. Figure 2 shows the results for latency and sleep duration.

---------INSERT FIGURE 2----------

CRIDI:

When comparing the results before and after BCT, some parameters such as direct gaze,
social smile, and stereotyped behaviors showed a significant improvement. Table 3 presents
significant changes after the Wilcoxon test. Despite some improvements, some behaviors,
such as friendship, sharing, and social gesticulation, did not reach statistical significance.

----------INSERT TABLE 3--------

ADI-R

Regarding the ADI-R instrument, behavioral features showed significant improvement.

Table 4 shows the results obtained after the Wilcoxon test, comparing before and after the
BCT. In summary, children seem to be more capable of socializing. Direct gaze and smile,
attention and closeness to other children, quality of social approaches, and emotional
sharing are some of the expressions that indicate significant progress toward normal social
interactions.
 ----------INSERT TABLE 4---------

Discussion

The present study deepens our knowledge of sleep patterns in children diagnosed with
ASD. Some studies have reported polysomnographic results in these patients, but given the
difficulties in touching and handling children for recording, the samples included only a
few individuals (18). Guidelines and strategies have been published for the proper
management of these patients in some scenarios, such as dental treatment (19). To our
knowledge, this is the first study to analyze the polysomnographic results in 49 patients.

The decrease in stage 2 sleep in our study supports the notion of aberrant synaptic pruning.
This atypical pruning in patients with ASD represents a steep curve of brain development.
(9). The decrease in the percentage of sleep in stage 2 is consistent with the findings of
Tessier et al. (20), who observed fewer sleep spindles and fewer K complexes in children
with ASD than in healthy controls. Lehoux et al. (21) analyzed 13 children with autism and
13 controls using polysomnographic recordings. They reported a lower amount of N3,
which is similar to the values observed in the present study. In the same study, they
reported an average total sleep time of 9.4  0.8 hours. However, in our study, sleep
duration values at different ages were significantly lower than those reported by Lehoux et
al. (21). The average total sleep time was 6  2.4 hours for 2-year-olds, 6.4  2 hours for
3–5-year-olds; and 6.9  2 hours for 6–10-year-olds. In our sample, only one child had an
average total sleep time of more than 9 hours.

Sleep restriction during childhood has neurodevelopmental consequences (22). Thus, sleep
deficits in children with ASD could worsen their cognitive and behavioral impairments
(23). Furthermore, solid evidence indicates that sleep plays a major role in neurogenesis
and the establishment of neuronal networks that determine behavioral evolution during
childhood (24; 25). The harmful effects of sleep restriction on hippocampal neurogenesis
could explain the memory deficits in children with ASD (25; 26).
Previous studies have reported low melatonin levels in children with ASD. The results of
the present study strongly suggest an improvement in circadian rhythms, which not only
facilitates the consolidation of a long period of nocturnal sleep but also normalizes the
appearance of several behaviors during the daytime. In addition, this study corroborates the
finding that children with ASD suffer from chronic sleep restriction. The amount of
nighttime sleep is significantly low; therefore, the crucial role that sleep plays in
neurological development is not fully understood. Moreover, sleep restriction induces
short-term behavioral changes that closely resemble those seen in children with ASD, such
as inattention, memory, and irritability (27).

Acknowledgements: This work was submitted in partial fulfillment of the requirements for
the PhD degree of RJX at the Doctorate in Biological and Health Sciences (Universidad
Autónoma Metropolitana). Financial support was obtained from Conacyt.

Disclosure statement: The authors report there are no competing interests to declare.

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