Future Research Directions in Sleep and ADHD

Abstract

Objective: To explore relationships between basic and translational science research regarding sleep and ADHD in children. Method: A multidisciplinary group of experts in pediatric sleep medicine and ADHD convened in November 2010 to summarize the current literature, delineate knowledge gaps, and formulate recommendations regarding future research directions and priorities. Results: Six major research areas of interest were identified: (a) brain centers regulating sleep, arousal, and attention; (b) neurotransmitter systems involved in both sleep and attention regulation; (c) alterations of neural systems regulating sleep in ADHD; (d) phenotypic similarities between behavioral, mood, and cognitive manifestations of insufficient/disrupted sleep and ADHD; (e) hypoarousal and sleepiness in ADHD; and (f) external sleep–wake signals that affect sleep regulation in ADHD. Conclusion: An enhanced understanding of the complex mechanisms regulating sleep promotion, wakefulness, and attention may contribute to new insights regarding the core impairments in ADHD and lead to the development of new therapies.

Keywords

ADHD sleep circadian rhythms

Introduction

ADHD, one of the most prevalent mental health disorders in childhood, is characterized by the core symptoms of chronic and significant inattention and/or impulsivity/hyperactivity. ADHD is estimated to occur in 3% to 7.5% of school-age children, and its clinical manifestations frequently continue into adolescence and adulthood (Barkley, Fischer, Smallish, & Fletcher, 2002; Fischer, Barkley, Smallish, & Fletcher, 2005). If untreated, individuals with ADHD struggle with impairments across many crucial domains of functioning, including academic, occupational, and social realms (Centers for Disease Control and Prevention [CDC], 2001).

There is considerable overlap between the core features of ADHD and neurobehavioral and neurocognitive manifestations of sleep disorders such as obstructive sleep apnea and restless legs syndrome (Chervin et al., 2002a, 2002b; Cortese et al., 2005; Huang et al., 2007; Picchietti et al., 2007). Moreover, clinical observation suggests that comorbid sleep problems, including prolonged sleep onset latency, are highly prevalent in children with ADHD and may confound both the diagnosis and clinical management of the disorder (Gruber et al., 2009; Owens et al., 2009; Sung, Hiscock, Sciberras, & Efron, 2008). In addition, there may be intrinsic deficits in sleep–wake regulation in at least some children with ADHD; for example, preliminary data from objective studies using the Multiple Sleep Latency Test (MSLT) show that children with ADHD exhibited more daytime sleepiness than typically developing controls (Golan, Shahar, Ravid, & Pillar, 2004; Lecendreux, Konofal, Bouvard, Falissard, & Mouren-Simeoni, 2000).

Thus, the relationship between sleep and ADHD is a highly complex one that is both important from a clinical perspective as it relates to the diagnosis and management of ADHD and from the standpoint of potentially elucidating basic mechanisms regulating attention, vigilance, arousal, and alertness, which are key aspects of the deficits associated with ADHD. Although a number of excellent recent reviews (Cohen-Zion & Ancoli-Israel, 2004; Cortese, Faraone, Konofal, & Lecendreux, 2009; Cortese, Konofal, Yateman, Mouren, & Lecendreux, 2006; Gruber, 2009; Lecendreux & Cortese, 2007; O’Brien et al., 2003; Sadeh, Pergamin, & Bar-Haim, 2006; Spruyt & Gozal, 2011) have focused on sleep characteristics (i.e., sleep architecture and sleep parameters such as sleep onset latency and sleep duration) and sleep disorders in children with ADHD in clinical settings, relatively little has been published in nonbasic science journals summarizing what is known about the underlying neurobiological mechanisms linking sleep and ADHD (“bench”) and their potential relevance to clinical practice (“bedside”).

To begin to address this translational knowledge gap, an international multidisciplinary working group of leading experts in the fields of pediatric sleep medicine and ADHD convened at Brown University in Providence, Rhode Island, in November 2010 at a conference supported by an unrestricted educational grant from Shire Pharmaceuticals. In the present article, we summarize the key information discussed in this meeting to (a) briefly review the relevant current basic science research on the neurobiology of sleep and ADHD, highlighting findings that are most likely to extend our understanding of the relationships among sleep, attention, and arousal, and which are most translatable to clinical practice; (b) identify knowledge gaps in basic and translational science research regarding sleep and ADHD; and (c) craft a set of open research questions important for future studies. A fourth goal, to identify key methodological issues, is the subject of a separate report.

Review of Relevant Current Basic Science Research on the Neurobiology of Sleep

It is first critical to highlight current understanding of the mechanisms involved in the regulation, and in the neurobiology of sleep and circadian rhythms to fully appreciate the intricate relationships among the various constructs linking sleep, wakefulness, attention, and arousal, and to identify knowledge gaps associated with the research pertaining to sleep and ADHD.

Sleep Regulation: The Two-Process Model

The regulation of sleep on a functional level involves the “two-process system,” the simultaneous operation of two highly coupled processes that govern sleep and wakefulness (Borbély, 1982; Czeisler et al., 1986; Moore, 1999; Figure 1). The homeostatic process (“Process S”) primarily regulates the length and depth of sleep and may be related to the accumulation of the neurotransmitter adenosine and other sleep-promoting chemicals (“somnogens”) such as cytokines during prolonged periods of wakefulness. Sleep pressure accumulates as the length of wake time increases and dissipates during a sleep episode; this homeostatic sleep drive is also highly dependent on the quality and quantity of prior sleep and is also affected by such factors as individual differences in sleep needs and developmental level. This “sleep pressure” appears to build more quickly in infants and young children, thus limiting the duration of sustained wakefulness during the day and necessitating periods of daytime sleep (i.e., naps) to restore alertness. The amount, timing, and density of slow-wave sleep (delta or “deep” sleep) activity serve as markers of the homeostatic sleep drive. Homeostatic dysregulation can result in chronic insufficient sleep and/or nonrestorative sleep, which can in turn lead to “sleep debt” and significant neurobehavioral impairments.

Figure 1.

The two-process model of sleep regulation.

Interacting with this “sleep homeostat” is the endogenous circadian rhythm (“Process C”) that influences the internal organization of sleep and timing and duration of daily sleep–wake cycles, and governs predictable patterns of maximum sleepiness (“circadian troughs”) and maximum alertness (“circadian nadirs”) throughout the 24-hr day (Allada, White, So, Hall, & Rosbash, 1998; Ebadi et al., 1986). There are two clock-dependent periods of maximum sleepiness, one in the late afternoon (3:00-5:00 p.m.) and one toward the end of the night (3:00-5:00 a.m.), and two periods of maximum alertness, one in midmorning and one in the evening, just prior to sleep onset (the so-called “second wind” or “forbidden zone” phenomenon). The master circadian “clock” that controls sleep–wake patterns is located in the suprachiasmatic nucleus (SCN) in the ventral hypothalamus; other “circadian clocks” govern the timing of virtually every physiologic system in the body (e.g., cardiovascular reactivity, hormone levels, renal and pulmonary functions).

Because the human circadian clock is actually slightly longer than 24 hr, intrinsic circadian rhythms must be synchronized or “entrained” to the 24-hr-day cycle by environmental cues called “zeitgebers.” The most powerful of these zeitgebers is the light–dark cycle; light signals are transmitted to the SCN via the circadian photoreceptor system within the retina (functionally and anatomically separate from the visual system), which switch the body’s production of the hormone melatonin off (light) or on (dark) by the pineal gland. Circadian rhythms are also synchronized by other external time cues such as timing of meals and alarm clocks.

The homeostatic and circadian processes are independent, interrelated, and important in determining both relative levels of alertness and sleepiness throughout the day and sleep quality, quantity, and timing.

Brain Systems Regulating Sleep, Arousal, and Attention

There are three basic states of neural activity in humans that are interrelated but distinct in terms of their generating systems, regulation, behavioral features, and role in maintenance of bodily physiologic and brain cognitive functions: wake, rapid eye movement (REM) sleep, and nonrapid eye movement (NREM) sleep. A few salient features pertaining to the anatomical and functional aspects of the wake-promoting arousal systems and wake-suppressing or sleep-generating neuronal mechanisms responsible for these three states underlie the interplay between sleep, arousal, and attention. As illustrated in Figure 2, the reticular activating system in the brain stem and hypothalamus is a key component of the ascending arousal system, which promotes both behavioral and electroencephalographic (EEG) aspects of wakefulness in the locus ceruleus (norepinephrine [NE]), in the substantia nigra and ventral tegmentum (dopamine), and dorsal raphe nucleus (serotonin). Neurons in the reticular formation send excitatory projections to the thalamus and hypothalamus, which in turn contributes to global cortical activation in wakefulness; conversely, there is a rapid decline in neuronal activity in all the involved arousal systems just prior to or at sleep onset.

Figure 2.

Sleep–wake regulation.

Many of the neurotransmitter systems involved in wake promotion (Table 1) and their location in the midbrain and pons are familiar to ADHD researchers and clinicians, particularly as they relate to the pharmacologic mechanism of psychostimulants and other psychotropic medications. In addition, while the locus coeruleus (LC) has a potentially important role in collection and processing salient sensory information and in experience-dependent alterations in neural function and behavior inputs, the integrity of the LC-noradrenergic system is also necessary for the initiation and maintenance of the waking state.

Table 1.

Wake- and Sleep-Promoting Neurotransmitters.

	Sleep-promoting neurotransmitters
Wake-promoting neurotransmitters	NREM	REM
Glutamate	GABA	Acetylcholine
Acetylcholine	Galanin	Glutamate
Dopamine	Adenosine	GABA
Norepinephrine	Melatonin	Glycine (muscle atonia)
Serotonin
Histamine
Orexin/hypocretin

Note: NREM = nonrapid eye movement; REM = rapid eye movement; GABA = gamma-amino-butyric acid.

Furthermore, noradrenergic systems and the LC are associated with circadian regulation of sleep and with attention. The SCN provide temporal organization to the sleep–wake cycle through arousal mechanisms that oppose the homeostatic drive for sleep, whereas the dorsomedial hypothalamic (DMH) nucleus modulates the circadian rhythm of sleep and waking via projections to the LC. The SCN–DMH–LC signaling pathway influences the activity of the LC and thereby regulates a variety of central nervous system (CNS) functions related to noradrenergic innervations (Warnecke, Oster, Revelli, Alvarez-Bolado, & Eichele, 2005), including alertness, vigilance, attention, learning, and memory. LC-noradrenergic neurons mediate the activation of the noradrenergic rapidly adapting thalamocortical arousal system by inhibiting the sleep-active ventrolateral preoptic nucleus (VLPO) of the hypothalamus (Aston-Jones, 2005; Lu, Jhou, & Saper, 2006; Robbins & Everitt, 1995; Saper, Chou, & Scammell, 2001; Steriade, 2003; Stratford & Wirtshafter, 1990). The SCN indirectly projects to the VLPO (Deurveilher & Semba, 2005) together with wake-active dopaminergic (DA) neurons in the ventral periaqueductal gray matter (vPAG), these circuits functionally link the homeostatic and circadian systems on one hand and the behavioral arousal and vigilance systems on the other.

Distinct but interrelated REM and NREM sleep-generating systems in the hypothalamus and midbrain are both wake inhibitory and sleep activating, and interact in an elaborate feedback loop. Key sleep-promoting neurotransmitters (Table 1) include gamma-amino-butyric acid (GABA; NREM) and acetylcholine (Ach; REM). Dysfunction in these interrelated systems is thought to contribute to oscillations between sleep and wake states observed in such clinical phenomena as sleepwalking (NREM sleep and wake) and narcolepsy (REM sleep and wake) and could be potentially related to sleepiness observed in children with ADHD.

In conclusion, available data indicate that underlying neurochemical and anatomical modulation of sleep, arousal, and attention overlap. Given the complexity of these relationships and the importance of these systems to the understanding of both ADHD and sleep, it is vital that we apply our understanding of these mechanisms to identify their contributions to the pathophysiology and symptoms manifested by individuals with ADHD.

Function of Sleep and the Impact of Sleep Loss

Another basic principle of sleep and chronobiology relates to the consequences of the failure to meet basic sleep needs, termed insufficient sleep or sleep loss. Sufficient sleep is a biological imperative that appears necessary for sustaining life, as well as for optimal physiologic, cognitive, and behavioral functioning. Sleep loss also has a direct impact on cognitive and behavioral functions that are impaired in individuals with ADHD. Sleep appears to be involved in many key brain functions, such as the consolidation of memory, as well as in neuronal plasticity, or the brain’s ability to respond and adapt to environmental influences.

Animal (Wilson & McNaughton, 1994) and human (Maquet et al., 2000) studies indicate that newly acquired memories are replayed and further processed during sleep, contributing to the brain plasticity underlying long-term memory formation (Ribeiro & Nicolelis, 2004). Specific brain activity patterns (Schabus et al., 2004) foster the transition of unstable memory into a form of recall that is more durable. A two-step model of memory consolidation suggests that an initial information transfer from the hippocampal–amygdala (for declarative memory) or thalamocortical circuits (for procedural memory) to neocortical sites occurs during slow-wave sleep, followed by later integration of this information (during REM sleep) into existing memory networks in the neocortex. This results in the strengthening of cortical connections and reorganization of neuronal representations associated with qualitative changes in memory status (Diekelmann & Born, 2010).

At the cellular level, animal models have demonstrated that experimentally induced sleep loss (and its corollary, prolonged wakefulness) affects a host of other basic brain processes that would be expected to have a profound impact on learning and cognitive function (i.e., gene activation/expression, neurogenesis, protection/repair from injury and stress exposure; Leibowitz, Lopes, Anderson, & Kushida, 2006).

Functional neuroimaging studies have shown that activity in the cerebrum (which mediates alertness, attention, and higher order cognitive processes) changes in response to sleep deprivation and that these changes are associated with differences in cognitive performance (Diekelmann & Born, 2010; Drummond et al., 2000; Drummond, Gillin, & Brown, 2001; Wu et al., 1991). Decreased regional glucose activity following sleep deprivation has been observed in the thalamus (Drummond et al., 2000; Drummond et al., 2001; Wu et al., 1991) as well as in the temporal (Wu et al., 1991), prefrontal, and parietal cortices (Drummond et al., 2001). Sleep-deprived individuals showed vast deactivations in the prefrontal and posterior parietal cortices and the heteromodal association areas as well as the Brodmann’s areas in the prefrontal (Fischer et al., 2005) and posterior parietal (Mesulam, 1990, 1995) cortices, which are involved in higher order analysis and integration of sensory-motor information and cognition (Mesulam, 1990).

On a functional level, partial sleep loss (sleep restriction) on a chronic basis accumulates over time as a “sleep debt,” eventually producing deficits equivalent to those seen under conditions of total sleep deprivation. If the sleep debt becomes large enough and is not voluntarily paid back (by obtaining adequate recovery sleep), the body may respond by overriding voluntary control of wakefulness, resulting in periods of decreased alertness, dozing off, and napping, that is, excessive daytime sleepiness. In addition, the sleep-deprived individual may experience very brief (several seconds) repeated daytime “microsleeps” of which he or she may be completely unaware but which nonetheless may result in significant lapses in attention and vigilance.

Multiple studies have shown that sleep loss impairs performance on measures of executive functions. Completion of complex tasks requiring abstract thinking, creativity, integration, and planning are fundamentally influenced by sleep deprivation (Dahl, 1996). Sleep loss also affects supervisory control (Nilsson et al., 2005), problem solving, divergent thinking capacity, and working memory (Horne, 1988; Linde & Bergstrom, 1992).

Sleep deprivation also has effects on brain circuits underlying generation and regulation of emotions. Sleep-deprived adult volunteers viewing emotional images have been shown to have increased activation in the amygdala on functional neuroimaging, which was accompanied by evidence of a weaker connection between the amygdala and prefrontal cortex (PFC), that is, heightened emotional response but less emotional control (van Helm, 2010). Sleep loss may also results in more negative perception of neutral stimuli. Moreover, sleep deprivation and/or poor sleep quality also appear to disrupt the ability to accurately identify emotional expressions in others (Dahl & Lewin, 2002; Soffer-Dudek, Sadeh, Dahl, & Rosenblat-Stein, 2011).

Neurocognitive functions that involve brain structures such as the striatum and basal ganglia, particularly those such as risk avoidance and responsiveness to rewards that involve an affective component, may also be affected by sleep deprivation. For example, studies in adults suggest that insufficient sleep is linked to changes in reward-related decision making, so that sleep-deprived individuals take greater risks and are less concerned about potential negative consequences of their behavior (Dijk, 2011). There is also some evidence to suggest that the circadian system, under the influence of the light–dark cycle, may also modulate reward activation (Forbes et al., 2012).

From a developmental perspective, it is significant that sleep is the primary activity of the developing brain, particularly in the first few years of life during which over half of the 24-hr day is spent asleep. Thus, it is not surprising that recent studies indicate that adequate amounts of both REM and NREM sleep stages, especially during critical developmental periods, are necessary for optimal learning. Both insufficient quantity and poor quality of sleep in children and adolescents result in excessive daytime sleepiness and decreased daytime alertness levels. The presence of poor sleep quality/short sleep duration in young children has been shown to predict later behavior/emotional problems, and poor performance on neurobehavioral tasks; for example, increased levels of sleep fragmentation in second, fourth, and sixth graders were associated with lower performance on neurobehavioral tests, particularly more complex tasks (Sadeh, Gruber, & Raviv, 2002). Studies of experimental sleep manipulation in school-age children and adolescents have demonstrated that children restricted to 5 hr of sleep for one night showed performance deficits in complex cognitive tasks, including verbal creativity and abstract thinking (Randazzo, Muehlbach, Schweitzer, & Walsh, 1998) and in sustained attention (Gruber et al., 2011) while extending sleep above baseline amounts by approximately 30 min on average for three nights of resulted in significant improvement on vigilance and memory in fourth and sixth graders (Sadeh, Gruber, & Raviv, 2003). Finally, the effects of sleep loss extend beyond the impact of sleep loss on basic processes associated with cognition and learning to studies that have examined the connection between sleep and academic performance. Short sleep duration (Buckhalt, El-Sheikh, Keller, & Kelly, 2009; El-Sheikh, Buckhal, Cummings, & Keller, 2007; Meijer, 2008; Wolfson, Spaulding, Dandrow, & Baroni, 2007) and poor sleep quality (El-Sheikh et al., 2007; Meijer, Habekothe, & Van Den Wittenboer, 2000) have both been shown to be related to poorer academic performance, either when purely subjective measures, like self-reports (BaHammam, Al-Faris, Shaikh, & Saeed, 2006; Horn & Dollinger, 1989; Meijer, 2008), or objective measures of sleep, like actigraphy and academic performance, were employed (Buckhalt et al., 2009; El-Sheikh et al., 2007; Keller, El-Sheikh, & Buckhalt, 2008). In addition, sleep deprivation has been shown to be associated with behavioral problems often encountered within school settings, as well as with school absence and tardiness, which may further reduce the ability of a child or adolescent to perform well at school (Pagel, Forister, & Kwiatkowki, 2007).

In summary, the impact of sleep on brain circuits that underlie executive functions, emotional regulation, learning, and memory has been demonstrated in numerous studies (Drummond et al., 1999; Harrison & Horne, 1998, 2000; Horne, 1988; Mesulam, 1990). These findings suggest that sleep disruption impairs key processes that are impaired in individuals with ADHD.

How Sleep and Chronobiology Relate to ADHD Research

Much of what is currently known about the complex interface between the neuroanatomy and neurophysiology of sleep and wakefulness and ADHD derives from animal models and thus is still largely theoretical in its applicability to the human brain and behavior. Nevertheless, it remains important for researchers in both sleep and ADHD research fields to have an appreciation of these fundamental concepts and to further examine them in children with ADHD to help elucidate neural mechanisms responsible for the clinical manifestations of both sleep and ADHD. In the following section, we apply the information acquired in these fields of research to outline general mechanisms and propose a number of related and concordant hypotheses pertaining to the interplay between sleep and ADHD. Key-related research questions generated from these hypotheses are then proposed.

Mechanisms Underlying the Interplay Between the Regulation of Sleep and Wakefulness, and Attention and Arousal

Hypothesis 1.1: Alterations in neural circuitry involved in both sleep–wake regulation and control of attention underlie dysfunction in both sleep and attention in children with ADHD.

The cortical and brain stem regions that are most involved in the regulation of arousal and attention and the most sensitive to sleep deprivation are also among the major sites implicated in the pathophysiology of ADHD. These include abnormalities in their frontal, dorsolateral prefrontal, ventrolateral prefrontal, and dorsal anterior cingulate cortices, along with the striatum (caudate and putamen) and lateral temporal and parietal regions (Bush, Valera, & Seidman, 2005; Seidman, Valera, & Makris, 2005; Swanson et al., 1998). In addition, altered circuitry and reduced connectivity in key circuits pertaining to sleep-dependent learning, including disruption of limbic-prefrontal circuits and changes in connections between prefrontal regions (especially the ventral medial PFC) and the hippocampus and amygdala have been demonstrated in ADHD (Konrad & Eickhoff, 2010; Sheridan, Hinshaw, & D’Esposito, 2010; Wang et al., 2009; Zang et al., 2007). Furthermore, in addition to a decrease in the global efficiency of brain networks, an abnormal nodal performance in all the prefrontal, temporal, occipital, and subcortical regions of thalamocortical fibers have been found in children with ADHD (Wang et al., 2009; see Konrad & Eickhoff, 2010, for a review). These structural and functional abnormalities in brain connectivity have a negative impact on the connection between the PFC and subcortical regions that is essential for memory consolidation. It is not known whether this underlie the deficits observed in children with ADHD.

Hypothesis 1.2: Alterations in neurotransmitter systems involved in control of both sleep and attention underlie dysfunction in both sleep and attention in children with ADHD.

As noted above, there is overlap in the neurotransmitter systems involved in the regulation of sleep and attention. Recent animal, pharmacological, neuroimaging, and genetic investigations fully support the idea that many of the core deficits of ADHD are due to dysregulation of NE and DA (Konrad & Eickhoff, 2010; Pagel et al., 2007; Wang et al., 2009; Zang et al., 2007). For example, proposed genetic targets implicated in ADHD include a number of dopamine receptors (DRD4 gene on Chromosome 11, dopamine active transporter [DAT] on Chromosome 5, and other DA sites such as dopamine D5 receptor [DRD5] and dopamine beta-hydroxylase [DBH]), as well as serotonergic receptors (5-HTT, HTR1B) and others (SNAP-25 [synaptosomal-associated protein]). Catecholamine systems have also been implicated in the regulation of sleep and arousal (for a review, see Boutrel & Koob, 2004).

Hypothesis 1.3: Wakefulness is altered in children with ADHD.

A number of mechanisms postulated to underlie some of the core deficits in ADHD involve the concept of “hypoarousal” in these individuals. A small number of studies have utilized a validated measure of physiologic sleep propensity, the MSLT, to objectively assess levels of sleepiness/alertness in children with ADHD. The MSLT consists of a series of five daytime 20-min standardized “nap opportunities” separated by 2-hr intervals, and is considered the “gold standard” in quantifying sleepiness. The results of these studies have suggested that children with ADHD, who have no evidence of an underlying primary sleep disorder (e.g., obstructive sleep apnea), are objectively “sleepier” (i.e., they are more likely to fall asleep, to fall asleep very quickly and on a greater percentage of naps on the MSLT) compared with typically developing controls (Golan et al., 2004; Lecendreux et al., 2000; Prihodova et al., 2010). Although there are a number of potential explanations for this observed phenomenon, including those involving dysfunction in catecholamine transmission in the CNS, the relationship between ADHD and wake dysregulation resulting from alterations in the hypocretin/orexin neurotransmitter system may also be of interest. Animal studies suggest that hypocretin/orexin neurons located in perifornical and DMH nuclei increase arousal, whereas those located in the lateral hypothalamus are primarily implicated in reward processing, appetite, and other reward-seeking behaviors. Thus, it is hypothesized that hypocretin/orexin neurons located in perifornical and DMH areas are hypoactivated, whereas those located in the lateral hypothalamus are overactivated in patients with ADHD (Cortese, Konofal, & Lecendreux, 2008).

Key Research Questions

Research Question 1: How might an enhanced understanding of the interrelationships among systems help elucidate neural mechanisms linking attention, sleep–wake regulation, and behavior?

Research Question 2: What is the role of neurotransmitters identified in the regulation of REM and NREM sleep and wakefulness such as orexin/hypocretin in ADHD? A related questions is in regard to the possible clinical and neurobiological links between ADHD and narcolepsy (e.g., cosegregation in families, brain dysfunctions, similarities in phenomenology, neuropsychology).

Research Question 3: Related to the above, how might an increased understanding of the role of noncatecholamine neurotransmitters in sleep and ADHD lead to development of alternative categories of pharmacologic options? For example, histamine is involved in the control of arousal and cognitive functions; therefore, H receptor antagonists may be potentially useful for the treatment of ADHD and sleep disorders.

Research Question 4: Are there are previously unidentified differences in sleep architecture in children with ADHD that might be detectable with more sophisticated analysis of polysomnographic parameters such as cyclic alternating patterns (CAPs)? (Bruni et al., 2010; Miano et al., 2006; Parrino, Ferri, Bruni, & Terzano, 2012).

Research Question 5: Might these eventually lead to the development of novel therapeutic approaches? For example, recent studies in children with autism have found differences in several REM sleep characteristics compared with typically developing children (Buckley et al., 2010). This has led to speculation not only that alternations in REM sleep are a marker for neurodevelopmental delay in general but that pharmacologic interventions targeted toward increasing REM sleep (e.g., donepezil) may be beneficial in improving both sleep and daytime function, assuming that REM alterations play a causal role in daytime behavioral impairments in children with ADHD.

Clinical Similarities Between the Cognitive, Behavioral, and Mood Impairments Associated With ADHD and Those Induced by Sleep Loss

Hypothesis 2.1: Phenotypic similarities between neurocognitive manifestations of sleep loss and ADHD can be used as a tool to elucidate bidirectional relationships between sleep and ADHD symptoms.

Sleepiness and its neurocognitive effects, grounded in sleep initiating mechanisms in hypothalamic, midbrain, and brain stem nuclei, result in wake state instability, manifesting as increased moment-to-moment variability in attention and waking cognitive functions requiring executive processes. Furthermore, as noted above, even short-term sleep deprivation produces global decreases in brain activity, especially in those regions that are selectively affected in ADHD (i.e., the PFC) and is associated with distributed changes in frontal/parietal control regions, secondary sensory processing areas, and thalamic areas (thalamic hyperactivation). It is therefore hypothesized that sleepiness could be related to the neurobehavioral deficits that are associated with ADHD.

There are a number of potential neurocognitive outcome measures of interest that could further delineate impact of insufficient sleep on the key domains of dysfunction in children with ADHD. However, there is no consensus on the specific domains to be tested, or the sleep tests that should be used. In addition to the need for a set of standardized outcome measures optimally relevant to the study of sleep restriction and daytime functioning in children with ADHD, it is important to determine the optimal setting and procedures for obtaining these measures; for example, little is known about impact of circadian timing on performance in children with ADHD.

Hypothesis 2.2: Phenotypic similarities between mood dysregulation resulting from sleep loss and affective manifestations of ADHD can be used as a tool to elucidate bidirectional relationships between sleep and ADHD symptoms.

In addition to the overlap in cognitive and attentional deficits, the impact of sleep loss on emotional regulation described above mirrors the mood dysregulation frequently seen in children with ADHD. It has been found that children with ADHD have reduced capacity to appreciate and integrate salient social cues. In regard to the latter, there is intriguing evidence that stimulants may restore some aspects of these subtle affective misperceptions in the face of sleep loss (Huck, McBride, Kendall, Grugle, & Killgore, 2008). Similarly, the reduced response to external rewards, increased risk-taking behavior, and misperception of potential risks seen under conditions of experimental sleep restriction are well recognized as often occurring in children with ADHD.

Hypothesis 2.3: Phenotypic similarities between behavioral manifestations of sleep loss and ADHD can be used as a tool to elucidate bidirectional relationships between sleep and ADHD symptoms.

In addition to studies demonstrating increased sleepiness on objective measures of sleep propensity (Golan et al., 2004; Lecendreux et al., 2000), subjective parental reports suggest that behavioral manifestations of daytime sleepiness are also more common in children with ADHD (Owens et al., 2009). These manifestations include not only behaviors “classically” considered to be indicative of increased sleepiness (difficulty getting out of bed in the morning, dozing off during sedentary activities) but also “externalizing” behaviors commonly attributed by caregivers to dysregulation related to being “overtired” (motoric hyperactivity, poor impulse control, oppositional and disruptive behavior). However, although it has been theorized that “paradoxical” hyperactivity is a behavioral strategy to preserve wakefulness in the face of an increased sleep drive (Weinberg & Brumback, 1990), it is unclear whether “hyperactivity” truly represents a behavioral response to perceived sleepiness in children in general and if so, whether this phenomenon is materially different in quality or degree in children with ADHD compared with controls.

Among the behavioral dysfunctions associated with ADHD, recent research points to previously overlooked dysregulated eating behaviors in a subset of individuals with ADHD (Cortese, Bernardina, & Mouren, 2007). Interestingly, a recent 14-day model of instrumental sleep fragmentation in mice (Baud, Magistretti, & Petit, 2012) demonstrated that sleep fragmentation increases food intake. Thus, research from animal models on sleep fragmentation has the potential to inform the knowledge on the pathophysiology of abnormal eating behaviors in ADHD. In a related vein, recent research shows a significant association between ADHD and obesity. Animal models show that dysregulated circadian rhythm may lead to metabolic dysfunctions (Arble, Ramsey, Bass, & Turek, 2010; Cortese, Vincenzi, 2012).

Key Research Questions

Research Question 1: Are children with ADHD more vulnerable to the effects of sleep loss on the cognitive, emotional, and behavioral systems? Alternatively, does extending sleep improve these functions in children with ADHD?

Research Question 2: What is the relative impact of superimposed “naturalistic” sleep curtailment (i.e., levels of sleep loss commonly experienced by middle school and high school students) on the cognitive, emotional, and behavioral symptoms of children with ADHD compared with typically developing children?

Research Question 3: What are the ideal outcome measures for studies that examine the impact of sleep on daytime functioning (cognition, mood, and behavior) of children with ADHD? In particular, future studies should compare objective office-based neuropsychological evaluation, naturalistic observational information, and parent/teacher reporting to better select standardized outcome measures.

Research Question 4: Given the similarities in clinical presentation, is it possible to differentiate attention, mood, and behavior deficits associated with ADHD from those which are attributable to diminished sleep quality and/or quantity? In other words, are there identifiable, reliable, and distinct patterns of neurocognitive and neurobehavioral impairments that would help to distinguish children with ADHD from children with “ADHD symptoms” related to a primary sleep disorder or sleep deficit?

Research Question 5: To what extent do possible abnormalities of neural networks involved in circadian disorders aggravate metabolic dysfunctions associated with obesity in individuals with ADHD? Related to this, does sleep fragmentation contribute to abnormal eating behaviors and obesity associated with ADHD?

Research Question 6: What is the nature of the increased daytime sleepiness observed in children with ADHD in terms of specific behaviors, degree and timing, and do these differ from those observed in children without ADHD? Are these behaviors a manifestation of a general state of hypoarousal in these children, a result of insufficient or poor quality sleep, or some combination?

Research Question 7: Are there specific phenotypes of ADHD that may be delineated in which manifestations of daytime sleepiness are more or less prominent, and would their identification assist us in making therapeutic choices such as stimulant versus nonstimulant medications as “first-line” treatment?

The Interplay Between Homeostatic and Circadian Dysregulation and Genetic and Environmental Factors in Children With ADHD

Hypothesis 3.1: Children with ADHD differ from typically developing children in their vulnerability to alterations in homeostatic and circadian mechanisms regulating sleep.

As previously noted, alterations in both circadian and homeostatic processes have been identified in children with ADHD. Adults with ADHD have been shown to have behavioral, endocrine, and molecular level alterations in circadian rhythms (Baird, Coogan, Siddiqui, Donev, & Thome, 2011). A number of studies have implicated the circadian sleep regulation abnormalities in the genesis of delayed sleep onset, in particular, in children with ADHD, having demonstrated alterations (delay) in the normal nocturnal pattern of melatonin secretion in these children compared with controls (Van der Heijden, Smits, Van Someren, & Gunning, 2005; Van der Heijden, Smits, Van Someren, Ridderinkhof, & Gunning, 2007). Specifically, these studies have suggested that children with ADHD may have a delayed endogenous circadian pacemaker, as measured by delays in sleep onset, dim light melatonin onset, and waking time; this may be pertinent to the clinical observation that children with ADHD appear to have an increased vulnerability to developing delays in sleep onset.

In addition, a largely unexplored implication of this circadian abnormality could be that the presleep circadian-mediated surge in alertness known as the “forbidden zone” is exaggerated in children with ADHD, resulting in increased difficulty settling for sleep and perhaps accounting for the common caregiver description that their child with ADHD “fights sleep.” This has therapeutic implications not only for the use of melatonin in these children, which has been shown in a number of studies to be effective in reducing sleep onset latency in ADHD (Bendz & Scates, 2010; Hoebert, Van der Heijden, van Geijlswijk, & Smits, 2009), but also potentially for melatonin receptor agonists, which may act by dampening the circadian-mediated presleep onset alertness surge (Zlotos, 2012). It has also been postulated that the observed phenomenon of increased motor activity at the time of sleep onset with resultant increased sleep latency associated with psychostimulant use may be due to disruption of circadian amplitude/phase delay rather than a direct stimulant effect (Ironside, Davidson, & Corkum, 2010).

Alternatively, the role of homeostatic dysregulation as a contributor both to the increase in sleep propensity noted above in children with ADHD and to their difficulty in “turning off” cognitive and emotional activity at bedtime has been largely unexplored. Animal models, for example, have examined the effect of the sleep-promoting neuromodulator adenosine, which accumulates as a biological marker of sleep homeostat. Although adenosine is known to exert influence on DA transmission on the action of stimulant drugs such as methylphenidate in animal models (Mioranzza et al., 2010), adenosine’s potential role in sleep problems in ADHD has not been well studied. Moreover, the role of central adenosine receptors is now viewed as much broader than just controlling D(2) receptor function and there is speculation that adenosine may act as “messenger” between glutamate and dopamine, two of the key players in mood processing as well as sleep regulation (Ciruela et al., 2011). It is hypothesized that this may have implications for ADHD treatment. For example, findings show that the discriminative learning impairments can be attenuated by the blockade of either A1 or A2A adenosine receptors, suggesting that adenosinergic antagonists should be examined as potential drugs for the treatment of ADHD (Cunha, Ferré, Vaugeois, & Chen, 2008). Finally, there is also increasing interest on emotional dysregulation associated with ADHD (Biederman et al., 2012; Peyre, Speranza, Cortese, Wohl, & Purper-Ouakil, 2012). McClung (2011) showed that circadian alterations contribute to mood dysregulation. Thus, the identification and treatment of alterations in circadian rhythm might be pivotal for the management of mood lability on ADHD.

Hypothesis 3.2: There is genetically determined vulnerability to sleep dysregulation in at least a subgroup of children with ADHD.

Identified genetic markers have been linked not only to an increased risk for specific sleep disorders such as narcolepsy (Viorritto, Kureshi, & Owens, 2011), restless legs syndrome (Xiong, 2011), and obstructive sleep apnea (Khalyfa et al., 2009; Khalyfa, Serpero, Kheirandish-Gozal, Capdevila, & Gozal, 2011) but also to differential vulnerability to the effects of sleep loss in adults (Verma & Verma, 2010). Similarly, there is evidence to support a genetic predisposition to individual differences in circadian preference (“morningness” vs. “eveningness”; Barclay et al., 2011); for example, polymorphisms in genes coding for melatonin-synthesizing enzymes or receptors or in “clock genes” in children with ADHD may account for observed deficits in circadian periodicity. Although studies thus far have failed to find an association between PER3 clock genes polymorphisms and sleep initiation insomnia in ADHD, we know very little in general about these genetic markers in children, and there may be important relationships that contribute to the pathophysiology of ADHD.

Hypothesis 3.3: Children with ADHD are differentially responsive to external sleep–wake signals, which in turn affect their sleep regulation.

Although they do not in and of themselves “cause” increased sleep propensity, environmental, physiologic, and psychological factors such as noise and temperature level, hunger and satiety, and motivation and engagement with the environment may facilitate or interfere with sleep onset. For example, descent into sleep requires disengagement of cortical functioning from the environment, which may be particularly challenging for children with ADHD. Sleep propensity is also affected by physiologic, behavioral, and environmental sleep facilitators and inhibitors (i.e., hunger, motivation, noise, temperature) to which children with ADHD may be differentially sensitive. Children with ADHD may also have increased levels of sensitivity to (or perceive as relatively more reinforcing) external factors that inhibit sleep such as competing priorities for sleep (TV, social interactions, etc.) or wakefulness-promoting substances such as caffeine. The common co-occurrence of sensory integration deficits in children with ADHD may also serve to heighten their vulnerability to sleep interference by sensory (i.e., auditory, tactile) stimulation in the bedtime environment. Conversely, they may have a higher level of resistance to environmental factors that tend to facilitate sleep (i.e., caregiver prompts, bedtime routines).

Hypothesis 3.4: Children with ADHD are exposed to inconsistent external sleep–wake signals, which in turn affect their sleep regulation.

Caregiver-driven unhealthy sleep practices and lack of routines, especially at bedtime, both have been shown to be more common in children with ADHD and to have a significant negative impact on sleep initiation (Weiss, Wasdell, Bomben, Rea, & Freeman, 2006). Similarly, the circadian sleep–wake cycle is also dependent on synchronization or “entrainment” of the system by cues in the environment, the most important of which are light and darkness, but also include regular timing of activities such as meals and physical activity. Thus, the relative absence of daily routine in many families of children with ADHD may serve to “weaken” circadian regulation. Alternatively, similar to the phenomenon described in adolescents (Crowley, Acebo, & Carskadon, 2007), at least some children with ADHD might have increased sensitivity to evening light exposure, with a consequent delay in melatonin release. When coupled with more exposure to computer and television screens around bedtime, this may further delay sleep.

Key Research Questions

Research Question 1: What is the relative contribution of various systems involved in sleep regulation (i.e., homeostatic, circadian, and environmental facilitators/inhibitors of sleep) to observed sleep onset delays and/or night wakings in children with ADHD? How do these systems interact and what biological markers (i.e., melatonin levels, slow-wave sleep density, and arousal threshold) may be useful in delineating these interactions?

Research Question 2: Do alterations in circadian rhythms contribute to emotional lability in ADHD?

Research Question 3: Do basic sleep needs at various ages differ in children with ADHD compared with healthy controls? A common clinical observation by caregivers is that their child with ADHD “just doesn’t need much sleep.” Although polysomnographic and actigraphy studies do not consistently find that children with ADHD in general have shorter sleep durations, there may be a subgroup (possibly genetically determined) that does have decreased sleep requirements.

Research Question 4: Are there specific phenotypes of ADHD that may be delineated in which sleep problems such as delayed sleep onset and/or night wakings are more or less prominent, and does their identification have a significant impact on efficacy and tolerability of specific pharmacologic therapeutic choices for the treatment of ADHD?

Research Question 5: What is the contribution of known genetic markers associated with ADHD in predicting the occurrence of sleep problems in these children? Alternatively, are there genetic markers that confer relative resistance to developing sleep problems?

Research Question 6: Does the presence of genetic markers that are linked to specific sleep disorders such as narcolepsy (human leukocyte antigens [HLAs]) and obstructive sleep apnea contribute to the pathophysiology of ADHD?

Research Question 7: What is the role of “good sleep hygiene” or healthy sleep practices as a prevention measure and/or therapeutic intervention for managing sleep problems in children with ADHD?

Summary

ADHD is the most commonly diagnosed childhood mental health disorder in North America, and sleep problems constitute one of the most prominent clinical comorbidities found in this population. Given the multiple overlaps and interactions described in this review, some might question whether sleep problems are best understood as a comorbidity commonly associated with ADHD or, perhaps, as a fundamental characteristic of ADHD itself as was assumed by Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; DSM-III; American Psychiatric Association, 1980). Furthermore, sleep loss resulting from sleep disruption in these children may contribute to the core manifestations of cognitive, mood, and behavioral symptoms. While sleep issues complicate clinical management, treatment of sleep problems may improve behavior and decrease the need for stimulant medication in children with ADHD. Thus, an enhanced understanding of the underlying neural systems and complex relationships between the regulation of sleep and attention, genetic vulnerabilities, and environmental influences on sleep in ADHD may shed light on basic mechanisms and eventually pave the way for the development of more refined and novel therapeutic approaches.

Despite progress in the diagnosis, assessment, and treatment of children with ADHD, a number of controversies exist, and many open research questions remain unaddressed regarding the relationship between ADHD and sleep in children. This article summarizes expert consensus proceedings and recommendations regarding basic and translational science research on sleep and ADHD in children, which may help to guide future research in this area. Ultimately, the importance of pursuing these lines of investigation rests in the expectation that this will result in optimizing treatment delivery and maximizing therapeutic effects.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This Conference was supported by an unrestricted educational grant from Shire Pharmaceuticals.

Author Biographies

Judith Owens, MD, MPH, is a professor of pediatrics at George Washington School of Medicine and Health Sciences and the director of Sleep Medicine at Children’s National Medical Center in Washington, DC.

Reut Gruber, PhD, is an assistant professor of psychiatry at McGill University and a sleep researcher at Douglas Hospital Research Centre in Montreal, Canada.

Thomas Brown, PhD, is an assistant clinical professor of psychiatry at the Yale University School of Medicine and is associate director of the Yale Clinic for Attention and Related Disorders.

Penny Corkum, PhD, is an associate professor in the Department of Psychology at Dalhousie University, Nova Scotia, Canada. She is also the director at the Colchester East Hants ADHD Clinic and Scientific Staff at the Izaak Walton Killam (IWK) Health Centre.

Samuele Cortese, MD, PhD, completed his MD, child neuropsychiatry residency, and PhD in biomedical imaging at the University of Verona (Italy). He is currently a postdoctoral research fellow at the Institute for Pediatric Neuroscience of the New York University Child Study Center, New York City.

Louise O’Brien, PhD, is an associate professor in the Sleep Disorders Center, Department of Neurology, and an associate research scientist, Department of Oral and Maxillofacial Surgery, at the University of Michigan.

Mark Stein, PhD, is a professor of psychiatry and pediatrics at University of Illinois at Chicago, where he directs the ADHD Clinical Research Program.

Margaret Weiss, MD, PhD, is a clinical professor of child psychiatry at University of British Columbia.

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