Abstract
Human sleep is considered to be a global phenomenon, orchestrated by central nervous system neuronal networks, and a local phenomenon. Sleep and wakefulness may be restricted to small groups of neurons, to individual cortical columns, or to larger brain regions. Cognitive impairment and performance deficits induced by sleep deprivation (reduced attention and vigilance, decision-making ability, and memory functions) may reflect the occurrence of cortical and subcortical local “islands of sleep” in participants who are behaviorally fully awake.
The similarity between the spectrum of cognitive consequences of sleep loss and the profile of ADHD makes the relationship between sleep and ADHD an intriguing issue for basic researchers and clinicians on account of its implications in the diagnosis and choice of therapies. Data on the occurrence of “islands of sleep” during wakefulness in ADHD are based on electroencephalography (EEG) studies of oscillatory power during the resting state, which point to abnormally high slow oscillatory activity (i.e., theta) and reduced fast oscillatory activity (i.e., alpha and beta), as well as on neuroimaging studies, which have detected hypoactivation in systems involved in executive function (frontoparietal network) and attention (ventral attentional network).
In their review, Owens and coauthors explain the functions of the three main sleep regulatory processes: the circadian process, named “Process C,” which couples the timing for sleep and wakefulness with the light–dark cycle; the homeostatic process, named “Process S,” which modulates sleep intensity and is strongly dependent on the duration of and activity during wakefulness; and, finally, the ultradian process, which regulates the intrasleep non-rapid eye movement (NREM)–REM alternation. The authors describe the main neurotransmitters involved in the regulation of sleep, arousal, vigilance, and attention. The review by Owens et al. is the outcome of a meeting held in November 2010, by a multidisciplinary group of experts in pediatric sleep medicine and ADHD. The aim of the meeting was to review the current literature, identify gaps in knowledge, and formulate recommendations regarding future research directions and priorities. The participants at the meeting summarized the similarities between the cognitive, emotional, and behavioral consequences of sleep loss and ADHD. This is a fundamental field of research when differentiating ADHD participants with major sleep disorders (such as restless legs syndrome [RLS], periodic leg movements, and obstructive sleep apnea, which all result in sleep loss) from those without sleep problems. Moreover, they raised the question of whether participants with ADHD have a chronobiological vulnerability, expressed by a delayed endogenous circadian pacemaker. I personally believe that Question Number 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 the efficacy and tolerability of specific pharmacologic therapeutic choices for the treatment of ADHD?”) is the question that most urgently needs to be addressed. Delineating different sleep phenotypes of ADHD may reduce the heterogeneity and complexity of the sleep–ADHD relationship.
With regard to sleep phenotypes, the authors who wrote the second article (Modestino & Winchester) wanted to study the relationship between ADHD and hypersomnia, hypothesizing that in some cases ADHD may be part of a primary disorder of vigilance, and the core symptoms of ADHD may be an attempt to stay alert, to counteract daytime sleepiness. This overlap between ADHD and symptoms of hypersomnia is often ignored by clinicians, notwithstanding some cases of adults with narcolepsy receiving a diagnosis of ADHD during childhood has been described. According to this hypothesis, the authors investigated the presence of symptoms of childhood ADHD in a large population of 161 adults with a diagnosis of narcolepsy (age range from 18 to 86 years, 109 female), by means of the retrospective self-report questionnaire Wender Utah Rating Scale (WURS). The authors found that more than 37% of patients have had symptoms of ADHD during childhood, and that the score of WURS correlated positively with the mean sleep latency measured by the Multiple Sleep Latency Test (MSLT). Daytime sleepiness has been investigated in children with ADHD, by objective measures such as MSLT and by questionnaires, with contradictory results, which can be explained by the fact that a disorder of vigilance may be present only in a subgroup of children with ADHD and that hypersomnolence usually is more evident in adulthood. The same differences may be reported in participants with obstructive sleep apnea syndrome: Adults often showed clear daytime sleepiness and sleep attacks, whereas children manifest symptoms of ADHD. The results of this study confirm the hypothesis that a subgroup of children with ADHD display a primary disorder of vigilance, narcolepsy being the extreme sleep phenotype.
The growing interest in the distinction of sleep phenotypes associated with ADHD also emerges from the study design adopted in the third article by Fargason et al. The authors investigate sleep quality by means of a standardized scale administered to a “pure” ADHD subtype of adults without referred insomnia or other circadian rhythm disorders, and with no psychiatric comorbidities. The participants’ age ranged from 19 to 65 years, two thirds were below 40 years of age, 53% were men, and the participants were composed of four groups: ADHD + stimulants (n = 39), ADHD + nonstimulants (n = 15), ADHD-no medication (n = 26), and controls (n = 25). The authors found that the ADHD participants did not display any circadian delay but did suffer unrecognized subclinical sleep problems and prolonged sleep latency, which appeared to be independent of medications. Moreover, positive correlations between the later timing of stimulant medications and higher stimulant dosages, which in turn led to delayed sleep onset, were observed. By contrast, only ADHD participants on stimulants did not display any daytime dysfunction due to sleepiness, thus resembling controls. This finding suggests that daytime sleepiness may be a core deficit of ADHD. The authors should have excluded not only participants who complain of insomnia but also those with other major sleep disorders (such as RLS, periodic limb movements, obstructive sleep apnea, nocturnal seizures), to obtain a “pure” group of ADHD participants. Indeed, any correlation between stimulants and sleepiness that might have emerged from a “pure” ADHD group would have been more interesting as it might be related to a “primary” condition of hypoarousability, as it is observed in narcolepsy.
It is somewhat surprising that the authors of these three articles discuss sleep phenotypes but do not mention alterations in sleep quality due to either epilepsy or interictal epileptiform discharges. Sleep activates focal and generalized spikes in about one third of all individuals with epilepsy. Some types of epilepsy are closely related to sleep, with the clinical onset occurring exclusively or mainly during sleep (i.e., rolandic epilepsy and nocturnal frontal lobe epilepsy). A large body of data in the literature point to a high prevalence of interictal or ictal discharges during sleep in ADHD children (approximately 50% of those who underwent a full-night video-polysomnography for suspected sleep disorders, with seizures occurring in fewer than 10%). One in four nonepileptic children examined for ADHD had epileptiform discharges (focal in more than half), which were detected by means of sleep EEG recording and sleep-deprivation EEG recording. The majority of the EEG abnormalities occurred in the sleep and sleep-deprived recordings, whereas the highest prevalence of epileptiform discharges was usually observed in prolonged sleep recordings.
On the basis of all these findings that point to the need to distinguish between different sleep phenotypes, the fourth article attempts to describe each ADHD sleep phenotype and its clinical and therapeutic implications by presenting case reports of children with ADHD and learning disabilities who had been referred to a sleep center for suspected sleep disorders according to the following classification: (a) the hypoarousal state of the “primary” form of ADHD, (b) the sleep phase advanced disorder, (c) sleep disordered breathing (SDB), (d) RLS and/or periodic limb movements disorder (PLMD), and (e) epilepsy. The first case report is an example of ADHD and SDB, with resolution of sleep apnea and daytime hypersomnolence after continuous positive airway pressure therapy. The second case highlights the efficacy of melatonin on delayed sleep phase advanced disorder and cognitive performance. The third case report describes the association between ADHD and PLMD, with a significant improvement following iron supplementation. The other two cases are examples of ADHD associated with epilepsy (nocturnal frontal lobe epilepsy and benign occipital epilepsy), which improved after the start of antiepileptic treatment.
In conclusion, the sleep model of the hypoarousal state resembling narcolepsy of the primary ADHD phenotype may be related to alterations in the ultradian process, which regulates the intrasleep NREM–REM alternation; the model of sleep loss with varying levels of arousal (such as the obstructive sleep apnea syndrome phenotype, the RLS and periodic limb movements phenotype, the sleep occurrence of ictal and interictal epileptiform discharges during sleep) may instead be related to an alteration in the homeostatic “Process S”; and, finally, the sleep-onset delay insomnia in ADHD is a sleep model related to an alteration in the circadian “Process C.” Not only does this hypothesis have numerous research implications, which are not limited to clinical aims, but also it provides a better definition of our genetic, biochemical, and basic knowledge of ADHD (see Table 1).
The Relationship Between Sleep Process and ADHD.
Note. NREM = non-rapid eye movement.