Why do autistic children have trouble entering deep sleep states ?

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Children with autism have more significant sleep difficulties caused by shallower brain waves than typically developing children, according to researchers at Ben-Gurion University of the Negev (BGU). The study was reported in Sleep, the premier journal in the field..

“For the first time, we found that children with more serious sleep issues showed brain activity that indicated more shallow and superficial sleep,” says BGU Prof. Ilan Dinstein,” head of the National Autism Research Center of Israel and a member of BGU’s Department of Psychology.

“We also found a clear relationship between the severity of sleep disturbances as reported by the parents and the reduction in sleep depth.

It appears that children with autism, and especially those whose parents reported serious sleep issues, do not tire themselves out enough during the day, do not develop enough pressure to sleep and do not sleep as deeply.”

Previous studies have shown that 40% to 80% of children on the autism spectrum have some form of sleep disturbances – trouble falling asleep, frequently awakening during the night and rising early – which create severe challenges for the children and their families.

Determining the causes that create these sleep disturbances is a first critical step in finding out how to mitigate them.

The research team, led by Prof. Dinstein, examined the brain activity of 29 children with autism and 23 children without.

Their brain activity was recorded as they slept during an entire night in the Sleep Lab at Soroka University Medical Center, managed by Prof. Ariel Tarasiuk.

Previous studies have shown that 40% to 80% of children on the autism spectrum have some form of sleep disturbances – trouble falling asleep, frequently awakening during the night and rising early – which create severe challenges for the children and their families.

Normal sleep starts with periods of deep sleep that are characterized by high amplitude slow brain waves. However, the recordings revealed that the brain waves of children with autism are, on average, 25% weaker (shallower) than those of typically developing children, indicating that they have trouble entering deep sleep — the most critical aspect of achieving a restful and rejuvenating sleep experience.

Now that the team has identified the potential physiology underlying these sleep difficulties, BGU researchers are planning follow-up studies to determine how to generate deeper sleep and larger brain waves.

This could include increasing daytime physical activity, behavioral therapies and pharmacological alternatives, such as medical cannabis.

Funding: The research was supported by the Simmons Foundation Autism Research Initiative.


Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder whose core features have been defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (1).

It is characterized as persistent difficulties in social interaction and communication, presence of stereotypic behaviors, restricted interests, and atypical sensory reactivity. ASD, in fact, encompasses a set of clinical phenotypes that includes previously described autistic disorder (AD) and Asperger syndrome (AS), from severe to mild variants as endpoints of a continuum upon a spectrum model approach (23).

Intellectual disability is observed in more than half of ASD cases (45) and ASD autistic symptoms also affect social language skills and emotion regulation. In addition, ASD symptoms are often related to coexisting mental disorders and to other developmental disorders (6).

Within the last decades, the diagnosis rate of autism has increased dramatically, and it has been reported that cases of ASD have a rate of 0.6–0.8% in preschool children, 1.0% in school children and young adults, and around 1.0% in adults (78).

In the last few years, an increased interest has been developed for mild forms of ASD, which often remain undiagnosed or misdiagnosed until adulthood. Although ASD is defined as a developmental disorder because symptoms appear within the first 2 years of life, it is generally considered a lifelong disorder with negative consequences on scholastic, working, social, and economic performances and quality of life.

Some studies have shown that mild forms of autism are related to high rates of psychiatric comorbidity in adulthood such as anxiety, mood disorders, psychosis, stress-related disorders, and suicidal behaviors (910).

In this framework, understanding the mechanisms involved in the development of ASD should be a priority for identifying early markers that could help improve early diagnosis with a significant impact on lifelong prognosis (3).

The mechanisms underlying the development of ASD may be the result of the interaction between multiple gene arrangement and the environment that may lead to the alteration of brain structures and functions (1112).

This interaction may determine epigenetic alterations disrupting the regulation of gene expression with a negative impact on biological pathways relevant for brain development (13). Abnormalities during brain development in autistic subjects go beyond the “social brain” encompassing sensory processing and attentional control.

In fact, current evidence strongly supports a model of brain-wide abnormalities during the early development of autistic children (12). Indeed, it remains an open question if a single mechanism or several independent factors can lead to the emergence of autism.

In the last few years, a new hypothesis has emerged, suggesting the role of circadian system desynchronization in the development of ASD (1114). Human physiological and biochemical processes as well as behavioral patterns have a circadian rhythmicity orchestrated by the master biological clock of the hypothalamus: the suprachiasmatic nuclei (SCN).

The expression of many genes changes rhythmically over 24 h and the specific circadian genes are responsible for the main SCN clock-working machinery as well as that of subsidiary clocks at the peripheral level [among them: circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like protein 1 (BMAL1), cryptochromes CRY1-2, and band period homolog (PER)] [(1516); for an overview see Ref. (17)]. The suprachiasmatic nuclei is daily synchronized by environmental signals such as light, food intake, activities, or social cues and exposure to stress/trauma (1820), and while driving, secretion of the melatonin hormone regulates peripheral clock within feed-forward mechanism. Rhythmic clock gene expression regulates multiple monoaminergic brain regions that control mood and motivational behaviors, stress and inflammatory systems, reward circuits, arousal, and sleep by interacting with the homeostatic regulation of sleep and wake [for an overview, see Refs. (1721)].

The circadian system is critical for the synchronization with the environment and allows a correct functioning of various internal physiological processes essential for the optimization of responses to environmental fluctuations and for the strengthening of homeostatic control mechanisms (21).

Abnormalities in the maturation of the circadian system principally lead to alterations in the sleep–wake pattern (22), which may interest around 50–80% of subjects with ADs (23). Wimpory and colleagues (24) have hypothesized that timing and social timing deficits were relevant in subjects with AD symptoms and were related to pathological variations in the structure/function of clock/clock-related genes: the authors hypothesized a key role for circadian sleep dysregulation in autistic symptoms.

This hypothesis has been confirmed by later studies, which have shown circadian-relevant gene abnormalities in ADs (2526). Mutations in Clock, Bmal1, Cry1, and Cry2 genes determine an alteration in the circadian system regulation as well as in sleep fragmentation (2728). Sleep is increasingly recognized as a key process in neurodevelopment and in brain optimization processes [for an overview, see Ref. (29)].

Both humans and animals’ data have shown that sleep is essential for maturation of fundamental brain functions, and epidemiological findings increasingly indicate that children with early sleep disturbances suffer from later cognitive, attentional, and psychiatric problems.

Indeed, from birth throughout infancy and early childhood, sleep patterns undergo dramatic changes that include the gradual consolidation of sleep and waking cycles, the intensification of deep NREM sleep slow-wave activity (EEG power in the 1–4.5 Hz frequency range), and a progressive decrease of REM sleep proportion.

It has been suggested that REM sleep is an inducer of brain development and of early myelination in the sensory processing areas in the fetus and the newborns and that it follows the maturational trajectory of the brain (2934).

Animal studies have shown that REM sleep has multifaceted functions in brain development, including learning and memory consolidation by selectively eliminating and maintaining newly formed synapses (35).

On the other hand, slow-wave sleep and sleep spindles (10–14 Hz) seem to be even involved in synaptic remodeling, being important for synaptic strength and synchronized neuronal firing, and it has been shown that while following the trajectory of brain maturation, they may orchestrate synaptic plasticity and pruning during brain development (303640).

Particularly, Ringli and Huber hypothesized that slow-wave sleep may contribute to cortical maturation by playing a role in the balance of brain synaptic strengthening/formation weakening/elimination that is tilted during development (39). Sleep promotes myelination and oligodendrocyte precursor cell proliferation (41), enhances transcription of genes involved in synthesis and maintenance of membranes and myelin too (42), and modulates the neuronal membrane homeostasis (43).

Since adequate sleep has been proposed to be fundamental for brain development (313539), sleep has received considerable research attention, as it appears to be important in the study of neurodevelopmental psychopathology (31394446). Hence, if sleep is fundamental for brain development, we may hypothesize that sleep disturbances, via alterations in brain development, may contribute to autistic symptoms. This idea has been previously developed for other psychiatric disorders.

In fact, extensive data have shown that poor sleep during childhood and adolescence is related to alterations in brain development (39444753) to problems in cognitive, attentional, emotional, and behavioral areas, including risk-taking and aggression; and to psychiatric conditions such as attention deficit hyperactivity disorder and mood disorders (54).

Indeed, we may also hypothesize that alteration in brain development related to ASD may contribute to sleep disturbances within a self-reinforcing loop.

Conclusion

Overall, results from this systematic review highlight the idea that sleep and circadian sleep disturbances are frequent in subjects with autistic symptoms who have shown polymorphisms in clock gene expression and in genes involved in melatonin production.

The impairment of circadian sleep regulation may increase the individual’s vulnerability to develop symptoms of ASD by impairing the sleep regulation in toto, which instead plays a key role in normal brain development.

Even though controversies and “research gaps” are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing loop.

An early identification and assessment of circadian sleep dysrhythmicity could be useful for improving treatment strategies in both children and adults with ASD.


Source:
Ben-Gurion University of the Negev

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