Medical Hypotheses 97 (2016) 131–133
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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
Possible neuronal mechanisms of sleep disturbances in patients with
autism spectrum disorders and attention-deficit/hyperactivity disorder
Jun Kohyama
Tokyo Bay Urayasu Ichikawa Medical Center, Japan
a r t i c l e
i n f o
Article history:
Received 12 August 2016
Accepted 2 November 2016
a b s t r a c t
The most common form of sleep disturbance among both patients with autism spectrum disorders and
patients with attention-deficit/hyperactivity disorder is sleep-onset insomnia, but the neuronal mechanisms underlying it have yet to be elucidated and no specific treatment strategy has been proposed.
This means that many caregivers struggle to manage this problem on a daily basis. This paper presents
a hypothesis about the neuronal mechanisms underlying insomnia in patients with autism spectrum
disorders and attention-deficit/hyperactivity disorder based on recent clinical and basic research. It is
proposed that three neuronal mechanisms (increased orexinergic system activity, reduced
5-hydroxytryptamine and melatonergic system activity, rapid eye movement sleep reduction) are
involved in insomnia in both autism spectrum disorders and attention-deficit/hyperactivity disorder.
This suggests that antagonists against the orexin receptors may have beneficial effects on insomnia in
patients with autism spectrum disorders or attention-deficit/hyperactivity disorder. To the best of the
author’s knowledge there has been no research into the effects of this agent on insomnia in these patient
groups. Large, controlled trials should be carried out.
Ó 2016 Elsevier Ltd. All rights reserved.
Introduction
Children with neurodevelopmental disorders (NDDs) are known
to experience chronic sleep disturbances. The prevalence of sleep
disturbance in patients in autism spectrum disorders (ASD) and
attention-deficit/hyperactivity disorder (ADHD) has been highlighted [1,2] probably because these clinical entities are prevalent
in modern societies. These patient populations experience a wide
range of forms of sleep disturbance including insomnias, parasomnias, sleep-related breathing disorders, sleep-related movement
disorders [2] and circadian rhythm sleep-wake disorders [3], but
a review by Singh and Zimmerman [2] concluded that sleeponset insomnia is the most prevalent form of sleep disturbance
among both patients with ASD and patients with ADHD. Although
it has been suggested that the melatonergic system is involved in
sleep-onset insomnia in both clinical populations on the basis of
clinical observations of the efficacy of melatonin and its agonist
[4], no specific treatment strategy has been proposed. The neuronal
mechanisms underlying sleep-onset insomnia have yet to be
elucidated and many caregivers struggle to manage the problem
on a daily basis. This paper presents a hypothesis about the neuronal mechanisms underlying insomnia in patients with autism
E-mail address: j-kohyama@jadecom.or.jp
http://dx.doi.org/10.1016/j.mehy.2016.11.001
0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.
spectrum disorders and attention deficit hyperactivity disorder
based on recent clinical and basic research, and is expected to provide ideas on the effective therapy on insomnia in these disorders.
ASD and the medial prefrontal cortex (Fig. 1)
Children with ASD are known to have a problem with theory of
mind tasks [5]. The following example illustrates what having a
theory of mind means in practice: John eats half his chocolate
bar and put the rest in a basket on the kitchen table then goes outside to play. When John’s mother comes into the kitchen and finds
the chocolate in the basket she puts the chocolate in the fridge.
When John comes back into the kitchen where will he look for
his chocolate? The correct answer is obvious, and an individual
who is able to give the correct answer displays an understanding
of John’s mind and is therefore said to have a ‘theory of mind’. From
the age of about five years most typically developing children have
a theory of mind [6]. The medial prefrontal cortex (mPFC) [5,6] is
one of the brain regions thought to be involved in theory of mind,
alongside the dorsomedial prefrontal cortex and the temporoparietal junction in the superior temporal sulcus [5].
It was recently reported that ASD patients show reduced
functional connectivity between the posterior cingulate cortex
and mPFC [7]. Eilam-Stock et al. [8] recently found that
132
J. Kohyama / Medical Hypotheses 97 (2016) 131–133
Melatonine↓
Worsening of
the quality of
wakefulness
5-HT↓
䐠
VS↑
mPFC↓
ADHD
ASD
Amyg↓
䐡
Sleep loss
Control
Amyg↑
䐟
REMS↓
Orexine↑
Non-REMS ↓
Prolonged
wakefulness
Fig. 1. Schematic illustration of the neuronal mechanisms which may underlie insomnia in patients with ASD and ASDHD. Number represents three presumable neuronal
mechanisms involved in insomnia in both autism spectrum disorders and attention deficit hyperactivity disorder.
high-functioning adults with ASD had an increased volume of grey
matter in frontal brain regions, including the mPFC, superior and
inferior frontal gyri and middle temporal gyrus.
Intranasal administration of oxytocin to adult men with ASD
was reported to reduce core symptoms of autism as well as
improving mPFC functioning [9]. In rats the mPFC is a site where
exogenous oxytocin attenuates anxiety-related behaviour [10]
and a review of 31 studies examining the prevalence of anxiety disorders in children (those under 18 years old) with ASD concluded
that about 40% of children with ASD had been diagnosed at least
one comorbid anxiety disorder [11]. Together these findings suggest that anxiety in patients with ASD may be related to reduced
mPFC function.
These findings also suggest that reduced mPFC activity may be
involved in the development of ASD. It should be noted that mPFC
stimulation alters the dynamics of 5-hydroxytryptamine (5-HT)
activity in the dorsal raphe nucleus [12].
ADHD and the ventral striatum
It has been shown that ADHD patients show increased
responses to receipt of reward in the ventral striatum (VS), the
orbitofrontal cortex and the occipital cortex relative to control participants [13]. Interestingly, the VS is known to reveal exaggerated
recruitment when required to suppress responses to alluring cues
in persons aged forties who were judged as low delayers when
they were undertaken marshmallow test at 4 years old [14]. The
marshmallow test was developed by Mischel and colleagues [15]
in the 1960s to assess the 4-year-old children’s ability to delay
gratification. In the test the child is given a choice between receiving a small reward (one marshmallow) immediately or waiting up
to 15 min to receive a larger reward (two marshmallows) [16]. It
has been shown that the test predicts social, cognitive and mental
health outcomes later in life [17], including educational achievement, self-worth, ability to cope with stress and risky drug use
[15]. Although not all children who showed little ability to delay
gratification at 4 years old (low delayers) were subsequently diagnosed with ADHD patients both low delayers on the marshmallow
test at 4 years of age ADHD patients might share a tendency to difficulty in being patient. Mischel described the ventral and dorsal
striatum as the ‘hot’ and ‘cold’ systems respectively [15]. It should
be noted that activity in the VS (hot system) correlates with shortterm reward predictions, whereas activity in the dorsal striatum
(cold system) correlates with long-term reward predictions [18].
Taken these together these results suggest that VS activation is
involved in the development of ADHD. It should be noted that
5-HT levels influence the pattern of correlations between
dorsal and ventral striatal activity and prediction of rewards. It
has been reported that low 5-HT levels increase the preference
for small, immediate rewards and the rate of discounting of
delayed rewards [19]. Low 5-HT levels (achieved by dietary tryptophan depletion) were also found to increase the correlation
between VS activity and short-term reward seeking [18] whereas
high levels of 5-HT (achieved by dietary tryptophan loading)
increased the correlation between dorsal striatal activity and
long-term reward seeking [18].
Medial PFC and VS are linked to the reward system via the
amygdala
The interaction between the mPFC and the amygdala is known
to play a crucial role in emotion regulation [20]. According to Etkin
et al. [21] mPFC is involved in down-regulation of the amygdala,
which has a dense projection to the VS [22]. The amygdala has
been implicated in reward processing [23] and fear-related learning [24]. Park et al. [25] argued that reduced amygdalar activity
might be a key factor in the development of ASD and hence a target
for therapy for the disease. Interestingly both morphological and
functional abnormalities of the amygdala have also been reported
recently in ADHD patients [26].
J. Kohyama / Medical Hypotheses 97 (2016) 131–133
Reward system and orexinergic system
The amygdala is known to be one of the main sources of input
to orexin neurons and this connection is assumed to play a significant role in the regulation of sleep and wakefulness [27]. In addition, the amygdala receives inputs from orexinergic neurons [28].
The reward and orexinergic systems are closely interconnected.
One might therefore argue that in both ASD and ADHD, dysfunction of the amygdala results in hyperactivity of the orexinergic
system and hence prolongation of wakefulness i.e. insomnia. Interestingly, prolonged wakefulness (sleep deprivation) has been
shown to reduce mPFC activity and disinhibit the functional activity of the amygdala [29] in control subjects. In ASD patients, however, the reduction in mPFC activity which follows sleep
deprivation may elicit a paradoxical amygdalar response. Moreover, in control subjects total sleep deprivation increased the VS
activity elicited by winning monetary rewards [30]. Insomnia in
ADHD patients may be initiated by VS activation which produces
amygdala deactivation, causing further activation of the orexinergic system which produces prolonged wakefulness.
Possible neuronal mechanisms underlying sleep disturbances
in ASD and ADHD (Fig. 1)
It is assumed that in both ASD and ADHD insomnia is induced
by orexinergic hyperactivity resulting from reduction of amygdalar
activity. This suggests that antagonists of the orexin receptors [31]
might have beneficial effects on insomnia in these patients; however to the author’s knowledge there has been no research on
the effects of such agents on insomnia in patients with ASD or
ADHD. Large controlled studies should be carried out.
VS activity is influenced by the 5-HT system whilst mPFC activity influences 5-HT activity. The 5-HT system may influence the
melatonergic system, which contributes to regulation of the
sleep-wake cycle, but the 5-HT activity may also be influenced
by the quality of awake, which is worsened by sleep loss [32]. It
is therefore possible that sleep disturbances in patients with ASD
and ADHD are also affected by 5-HT.
Finally, amygdalar activity is known to be closely related to
rapid eye movements during rapid eye movement sleep (REMS)
[33]. Inhibition of the amygdala may lead to a reduction in the
duration of REMS, which could also result in a decrease in nonREMS [34]. A reduction in the duration of both REMS and nonREMS would amount to sleep loss.
Conclusion
Three neuronal mechanisms (increased orexinergic system
activity, reduced 5-HT and melatonergic system activity, REMS
reduction) are presumed to be involved in insomnia in both ASD
and ADHD.
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