Sl ee p an d A tte n t i o n D efi ci t H y p e rac t i v i ty Dis o r de r 19

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Sleep and Attention Deficit Hyperactivity Disorder

Louise M. O’Brien and David Gozal

1. INTRODUCTION

A growing number of studies have addressed the prevalence of sleep problems among children with attention deficit hyperactivity disorder (ADHD). As the major symptoms of ADHD (i.e., inattention, impulsiveness, and restlessness) are also characteristic of sleep deprivation, the role of sleep in ADHD is the focus of many investigations. Parental reports of sleep disturbances are common in children with ADHD (1–8), and as such they were so widely presumed to be an intrinsic part of the clinical phenotype of ADHD that sleep problems were included as one of the previous Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) diagnostic criteria for ADHD (9). However, none of the more recent diagnostic manuals (10,11) have included sleep disturbance as a symptomatic criterion for ADHD. Therefore, because parental perception of sleep disturbance helped to define ADHD previously, it is not surprising that studies using earlier diagnostic criteria found a significant association between ADHD and sleep problems.

Sleep arousal disturbances include difficulties in falling asleep, in awakening, and in maintaining adequate alertness for daily activities; such disturbances are frequently reported in children with ADHD. Sleep difficulties have generally been attributed to core difficulties in regulation of arousal. Difficulty in staying alert when not engaged in stimulating activity is commonly reported by children with ADHD, particularly ADHD of the inattentive type.

Alertness difficulties are reported even when sufficient sleep has been obtained the night before, and many individuals with ADHD become aware that they have to keep moving around or changing activities in order to maintain wakefulness. Conversely and as a fre- quently reported phenomenon, a sudden improvement in alertness will occur when children with ADHD start moving around. In such cases, the report is not that they do feel fatigued, as would be anticipated if they had not slept enough, but rather it is perceived as an inability to maintain a sufficient level of alertness or arousal unless engaged in stimulating activities.

Such descriptions have occasionally led to the mislabeling of such individuals as having narcolepsy. Conversely, Navelet et al. (12) and Dahl et al. (13) have reported that some chil- dren with narcolepsy were misdiagnosed as having ADHD. Thus, there seems to be a logical association between the physiology of sleep and the presence of sleep disorders in ADHD, as sleep is an autonomically governed process reflecting cyclical changes in brain arousal (14), while ADHD may result from irregular arousal functioning (15). In 1996, Dahl inferred that the prefrontal cortex may have a critical role in integrative regulation of arousal, sleep,

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From: Attention Deficit Hyperactivity Disorder: From Genes to Patients Edited by: D. Gozal and D. L. Molfese © Humana Press Inc., Totowa, NJ

affect, and attention (16). Indeed, previous neuroimaging studies of regional brain glucose consumption in adult subjects with childhood-onset ADHD documented relatively hypoactive cortical functioning in the frontal lobes concurrent with decreased alertness (17). Similarly, positive associations between physiological indices of arousal obtained during the day and a history of sleep disturbance were reported in a study of children with ADHD (18).

In addition to the potential implications of the putative mechanisms underlying wakefulness and alertness in the context of behavior, attention, and executive function, objective assessment of sleep problems in ADHD may be particularly important because objective disturbances of sleep, such as sleep disordered breathing (SDB) (2,19–23), narcolepsy (24), and periodic limb movement disorder of sleep (PLMS) (25–29) may all present daytime behavioral symptoms that resemble ADHD.

Therefore, in this chapter, we will review the literature pertaining to the subjectively reported and objectively documented sleep characteristics in children with ADHD and con- versely examine the effects of specific sleep disorders on behavior and cognition.

2. SUBJECTIVE MEASURES OF SLEEP DISTURBANCE IN ADHD

The majority of studies investigating the relationships between sleep and ADHD are based on parental reports, and as such are not only markedly subjective, but also convey the inherent bias derived from the interpretation by the parent of their child’s manifestations. Notwith- standing such major limitations in all these studies, the consistent conclusion from such stud- ies indicates a high prevalence of sleep complaints among children with ADHD compared with control children (1,3,5,7,8,30,31). Such sleep complaints are manifest as increased bed- time resistance (7,8), difficulty in falling asleep (1,5,7,8), more frequent nighttime awaken- ings (1,7), and the presence of sleep-related anxiety (3,7), and are commonly reported not only by the parents but also by the ADHD patients themselves. In fact, a relatively recent comprehensive review of the literature (4) revealed that parents of children with ADHD were five times as likely to report that their children have sleep problems compared with parents of healthy children. Often, the child is unwilling to go to bed at night but will also object to tak- ing a nap even when clearly exhausted during daytime. Nonetheless, the inability of children with ADHD to fall asleep either during the day or during the evening hours may reflect a multitude of underlying issues. For example, the absence of a consistent bedtime routine is usually a frequent impediment to regular sleep latencies in healthy children, and the inability to implement this behavioral pattern before sleep may clearly and adversely affect the period between bedtime as imposed by the parents and the actual sleep onset. Another likely and frequent scenario is the occurrence of oppositional behaviors rather than a physiological alteration in the sleep-wake regulatory mechanisms during the evening hours. Intrinsic issues to the child that may generate difficulty in the onset of sleep include amplification of under- lying processes, such as anxiety, which may be linked to fear of separation or of darkness. In addition, disruption of sleep itself through recurring nightmares may trigger an anticipatory objection to the bedtime routine. Therefore, all of these and many other confounding factors make it very difficult to determine the exact nature of the true relationships between ADHD and sleep initiation. A summary of subjective assessments of sleep disturbance in ADHD is shown in Table 1.

Using the revised DSM-III manual (DSM-III-R) (10) to minimize subject selection bias, Ball and colleagues (3) studied 102 children who met criteria for ADHD and 78 control children.

The control group comprised children who had been referred to neuropsychology assessment

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Ta b le 1 Su bje ct ive Ass e ssm e n ts of R e la ti o nship B etwee n Sl ee p an d ADHD Dia g nosis R ef. A u thors Y ear S u b jects A g eo f ADHD C ontro l sa m p leS leep assess m ent R es ul ts 1 K ap lan 1987 1 . 40 ADHD 3–6 yr Pediatrician 1 . 40 chi ldren 1 . Tw o s leep 1 . 60% ADHD et a l. (non -m edicated ) fro m l oca l day qu estions reported inade qu ate care centers am o u nt of s leep co m pared to 25% contro ls 2 . 1 16 ADHD 3–6 yr Parent report 2 . 88 m al es 2 . Fo u r sl eep 2 . Mean scores (non -m edicated ) p lu s DSM -III fro m l oca l day qu estions si g ni fi cant ly hi g her criteria care centers in ADHD for a ll fo u r qu estions 2 T ro mm er 1988 36 ADHD ; 9 .3 ± 4 Not reported 30 contro ls Qu estionnaires ADHD /ADD report et a l. 12 ADD yr m ore s leep dist u rbance 3 B all et a l. 1997 102 ADHD (28 9 ± 3 yr Parent report 78 chi ldren R etrospective ADHD m ore l ik el y to w ith sti mul ant and for m al referred for revie w of parent report “ prob le m s m edication at psycho lo g ica l assess m ent ; did responses to s leep w ith s leep ;” “ often ti m e of test ) assess m ent not m eet criteria qu estions u p at ni g ht ;” and for ADHD “insists on ni g ht l ig ht ” 32 Da g an 1997 12 ADHD 9 .6 ± 1 .6 Psychiatric 12 hea lthy m al es S leep –w ak eN o dif ferences et a l. m al es yr assess m ent sched ul e, se m i- observed bet w een str u ct u red the t w o g ro u ps intervie w , and sl eep habits qu estionnaires (C ontin u ed)

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Ta b le 1 (C on ti nued) Dia g nosis R ef. A u thors Y ear S u b jects A g eo f ADHD C ontro l sa m p leS leep assess m ent R es ul ts 33 Marcotte 1998 43 ADHD 6–12 yr Ne u ropsych - 86 chi ldren S leep Screenin g No dif ferences et a l. 11 l earnin g o lo g ica l and fro m the l oca lQ u estionnaire bet w een s u b g ro u ps disorder ne u ro lo g ica l co mmu nity for Parents ADHD, LD, 25 ADHD /LD assess m ent ADHD /LD. T ota l w ith DSM -III sa m p le scored hi g her criteria on B reathin g Prob le m s Sca le, S leepiness Sca le, and B ehaviora l Sca le than contro ls 5 R in g 1998 13 ADHD ;8 ± 3 yr Intervie w by Hea lthy sib lin g s Str u ct u red s leep ADHD reported m ore et a l. Methy lphenidate chi ldo f the chi ldren qu estionnaire dif fi cul ties w ith s leep for >4 wk psychiatrist w ith ADHD initiation and m aintenance 34 C or kum 1999 79 u n m edicated 6–12 yr Cl inica l 36 chi ldren fro m C hi ld S leep U n m edicated ADHD et a l. ADHD ; 22 dia g nostic the co mmu nity Qu estionnaire — had l on g er s leep m edicated intervie w s Parent V ersion ; d u ration than other ADHD C hi ld and Fa m il y g ro u ps ; both ADHD S leep History g ro u ps had poorer Qu estionnaire sl eep practices than contro ls ; dysso m nias re lated to co m orbid dia g noses and sti mul ant m edication

7 O w ens 2000 46 ADHD 7 .5 ± 1 .5 For m al 46 m atched C hi ldren ’s S leep ADHD reported hi g her et a l. (non m edicated ) yr psycho lo g ica l chi ldren fro m Habits scores on both assess m ent el em entary Qu estionnaire qu estionnaires schoo l and the S leep Se lf -report qu estionnaire 8 C or kum 2001 25 ADHD 9 .1 ± 1 .4 For m al 25 chi ldren fro mC hi ld S leep ADHD reported hi g her et a l. (m edication yr psycho lo g ica l the co mmu nity Qu estionnaire scores on fi ve of na ïve ) assess m ent si x para m eters 35 O ’B rien 2003 44 ADHD ; 27 5–7 yr C onners ’ 39 contro lsS leep habits ADHD reported et a l. hyperactive Parent R atin gq u estionnaire si g ni fi cant ly m ore Sca le dif fi cul ty initiatin g sl eep, rest less s leep, aw ak enin g s, br ux is m , en u resis, snorin g , and dayti m e sl eepiness than contro ls and w ere l ess w ill in g to g o to bed. Hyperactive chi ldren reported m ore dif fi cul ty initiatin g sl eep and en u resis than contro ls LD, l earnin g disabi lity .

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center for evaluation but who did not fulfill criteria for ADHD. A retrospective review of sleep-related items from the Conners Parent Rating Scale (36) and the Personality Inventory for Children—Revised (7) was conducted. The authors found that significantly more parents of the children with ADHD answered positively to the general question from the Conners scale “problems with sleep,” and also to the more specific question “often up at night” from the Personality Inventory. These results supported those of Kaplan et al. (1) who found that parents of children diagnosed with ADHD by their pediatricians were more likely to be per- ceived as obtaining an inadequate amount of sleep when compared to children without any reported behavior problems who were recruited from local day care centers. However, in the study by Kaplan et al., the authors acknowledged that the children with a diagnosis of ADHD may represent a unique subgroup of children who were taken to a physician for treatment.

Therefore, these investigators conducted a second phase of this study, wherein they recruited children from local day care centers who were believed to be more active or more inattentive than normal and compared this group with a control group of children with no reported behavioral problems. All of the children with reported behavioral disturbances and none of the control children met DSM-III criteria for ADHD (9). Parents answered the following four questions regarding their child’s sleep:

1. Difficulty falling asleep.

2. Wakes during the night.

3. Wakes early.

4. Cries out during the night.

Highly significant differences were observed for each of the four questions between the children with ADHD and the controls. Nonetheless, Kaplan et al. suggested the possibility that parents of children who are unusually active may be more sensitive to their sleep prob- lems. In a third and last phase of their study they attempted to address this issue by obtaining daily logs of sleep habits for three consecutive weeks. Information recorded included bed- time, sleep time, number of times the child got out of bed both before falling asleep and fol- lowing any awakenings, enuresis, night sweats, sleep duration and time out of bed in the morning. This third phase showed that children with ADHD had significantly shorter nap durations, longer sleep time, more awakenings during the night, more bed-wetting episodes, and more night sweats than control children. Taken together, these data further support the rela- tionship between ADHD and sleep disturbance, even when some objective measures are intro- duced. However, although one of the strengths of the study by Kaplan et al. was the attempt to record objective sleep measurements, sleep diaries are still highly prone to reporting biases because they are reliant on parental report. For example, if parents of children with ADHD are more sensitive and more acutely aware to their child’s sleep disturbance, they may be less able to sleep at night, may be more likely to wake up during otherwise insignificant and physiological awakenings, and therefore will be more likely to be aware of their child’s behaviors and to report them in the diaries.

3. OBJECTIVE ASSESSMENT OF SLEEP IN CHILDREN WITH ADHD

To prevent the potential problems imposed by parental reporting, objective measures of sleep disturbance were necessary. Several investigators have utilized actigraphs—i.e., small watchlike accelerometer recording devices that permit somewhat accurate derivation of sleep-wake state, latency to sleep onset, duration of sleep, and other sleep-related measures—to document sleep in

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children with ADHD. In addition, the gold-standard test, overnight polysomnography, was also used, and although labor-intensive and expensive, has provided valuable information and allow investigation of sleep architecture and sleep stage distribution in ADHD patients.

Despite the high frequency of sleep-related complaints, earlier objective assessments of sleep in children with ADHD have shown inconsistent findings, such that a very nebulous picture emerges from such studies. Furthermore, small sample sizes and inconsistent criteria in subject inclusion, as well as in the incorporation of control subjects, make comparisons of these studies difficult. The disparity between subjective and objective findings is best high- lighted by Corkum et al. (8), who compared 25 children with ADHD with 25 age-matched controls (mean age = 9 yr) utilizing parent and child reports of sleep quality and 7-d acti- graphic recordings. Parents of children diagnosed with ADHD reported significantly more problems with sleep onset, morning awakenings, restless sleep, and bedtime resistance than children in the control group. However, when both actigraphy recordings and the children’s reports of their own sleep were analyzed, the only variable that was significantly different between the two groups was bedtime resistance. Corkum and colleagues hypothesized that the significant difficulties that parents of children with ADHD report with their children’s sleep may be related to the difficult and often oppositional behaviors manifesting as bedtime resistance rather than representing primary sleep disorders in ADHD. In addition, these objective-subjective incongruencies could also be related to differences introduced by retro- spective and prospective collection of sleep measures.

In their review of the published literature on objective sleep characteristics in ADHD, Corkum et al. (4) inconsistent findings were the rule. Indeed, there was either an absence of any discernible differences in sleep variables among ADHD subjects and controls, or instead significant changes emerged in the sleep parameters. Contrary to information gained from studies utilizing subjective data, increased sleep onset latency is not commonly found.

Although studies using sleep diaries (1,8) and actigraphy (38) reported longer sleep duration in children with ADHD, use of electroencephalogram (EEG) to determine sleep times yielded conflicting results. For example, Ramos Platon et al. (39) found prolonged sleep duration in ADHD, whereas Greenhill et al. (40) reported longer sleep duration in children who were medicated, but did not find any differences in nonmedicated children. Longer sleep onset latencies have been found in studies on both medicated (40–42) and nonmedicated children (38); shorter sleep latencies have also been reported in two studies in nonmedicated children (39,41). Despite the heterogeneous definitions of ADHD employed in these studies (ranging from formal psychological assessment to reports on a parent-based rating scales), and the medication status of the children, no consistent alterations in sleep onset latency have been found in the vast majority of the studies (8,32,35,43–49). A summary of objectively assessed sleep disturbances are shown in Table 2.

Clinically, parents of children with ADHD complain of hyperactive and oppositional behaviors that occur throughout the day and into the evening. The extension of these behaviors to bedtime is the most likely explanation for the higher probability that parents of children with ADHD will report that their children have bedtime resistance and sleep- onset delay. Thus, children with ADHD may be displaying oppositional behaviors that pre- vent them from following rules and engaging in appropriate bedtime behaviors. On the basis of the aforementioned findings, the overall higher frequency of bedtimes and sleep- related problems appears to reflect more sleep limit-setting issues rather than representing sleep disorders per se.

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Ta b le 2 Obje ct ive Ass e ssm e n ts of R e la ti o nship B etwee n Sl ee p an d ADHD Dia g nosis R ef. A u thors Y ear S u b jects A g eo f ADHD C ontro l sa m p leS leep assess m ent R es ul ts 41 S m all 1971 T hree 8 .4 ± 0 .6 Psychiatric Seven a g e-m atched Five ni g hts of ADHD had shorter et a l. hyperactive yr ex am ination contro ls EEG ( no sl eep l atency and chi ldren ;m edications ); mu sc le activity before 1 m o on d u rin g sl eep in and d u rin g sti mul ants base line condition. m edication fo ll o w ed by Medicated : ADHD three ni g hts had red u ced n um ber EEG then of s leep cyc les, three ni g hts increased s leep of p lacebo latency , decreased aw ak enin g s, increased R EM l atency 44 Feinber g 1974 Fo u r m al e 8 .6 ± 1 yr Physician - Si x m al e ag e- EEG recordin g s Medication associated et a l. hyper k inetic dia g nosed m atched for one ni g ht w ith l on g er R EM chi ldren ( no contro ls latency sti mul ants ) and fo u r hyper k inetic chi ldren on lon g- ter m sti mul ants 42 Hai g 1974 Si x 8–14 yr Inter - Si x nor m al EEG recordin g s Medicated hyperactive et a l. hyperactive discip linary m al es for fi ve ni g hts chi ldren had increased m al es cl inic sl eep l atency and (m edicated ); dia g nosis increased R EM l atency fo u r chi ldren re lative to contro ls. No rest u died dif ferences fo u nd for postdr ug . on and of f dr ug co m parisons

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50 Nahas and 1977 Fo u r 7 .3 ± 2 .5 Dia g nosis of P u b lished va lu es EEG recordin g s Hyperactive g ro u p K rynic k i hyperactive yr hyperactive decreased R EM and m al es ( before im p ul se sta g e 4; increased sta g e and d u rin g disorder 2 and state chan g es. m edication ) No m edication ef fects observed 43 Bu sby 1981 1 1 non -1 0 .6 ± 1 .7 Presence of 11 m al es ne g ative EEG recordin g s Hyperactive g ro u p had et a l. m edicated yr core on C onners for fi ve ni g hts increased R EM l atency hyper k inetic sy m pto m s m al es for DSM -III and e levated hyperactivity scores on C onners 51 K ahn 1982 16 hyper - 6–12 yr Ne u ro lo g ica l 12 m al es EEG recordin g s Shortened R EM l atency k inetic and in nine hyper k inetics m al es psycho lo g ica l assess m ent 40 Greenhi ll 1983 Nine ADHD 8 .6 ± 1 .4 Psycho lo g ica l1 1 chi ldren ( fo u r EEG recordin g s Pre m edication ; no et a l. m al es ( before yr assess m ent ;m al es ) ne g ative for t w o ni g hts dif ferences. and d u rin g DSM -II for m enta l pre -m edication On m edication, ADHD m edication ) criteria disorder then t w o ni g hts h ad l on g er s leep l atency , of EEG recordin g an d increased s leep after 6 m o of ti m e, w ith increased dr ug therapy sta g e chan g es and increased R EM cyc les (C ontin u ed)

Ta b le 2 (C on ti nued) Dia g nosis R ef. A u thors Y ear S u b jects A g eo f ADHD C ontro l sa m p leS leep assess m ent R es ul ts 52 Porrino 1983 12 hyper - 6–12 yr Psycho lo g ica l 12 ag e and 24- h m otor Hyperactive g ro u p had et a l. active m al es assess m ent ; cl assroo m activity m onitor hi g her l eve l of (on and DSM -III m atched m al es for 1 wk m ove m ent d u rin g of f m edication ) criteria sl eep 53 Bu sby and 1985 16 hyperactive 8–12 yr DSM -III Ei g ht contro ls fro m EEG and Aro u sa l responses to Pivi km al es ( ei g ht criteria and loca l schoo ls respiration for sti mul i not dif ferent ; m edicated )C onners ’ fo u r ni g hts (fi rst ho w ever a l o w er Parent and tw o ni g hts for thresho ld in T eacher adaptation ) non m edicated chi ldren R atin g sca les observed in sta g e 2 1 K ap lan 1987 25 m al es 3–6 yr Parent report 27 m al es fro m S leep l o g s for ADHD chi ldren m ore et a l. w ith ADHD p lu s DSM -III loca l day care 21 consec u tive l ik el y to have shorter (m edication criteria centers days naps, l on g er s leep at free ) ni g ht, m ore aw ak enin g s, bed w ettin g , ni g ht s w eats 39 R am os 1990 13 ADD 9 ± 1 .7 For m al P u b lished EEG recordin g s ADD had decreased P laton chi ldren yr psycho lo g ica l data on w ith respiration sl eep l atency , increased et a l. (m edication assess m ent 43 chi ldren and E C G for sl eep ti m e and n um ber free ) and DSM -III tw o ni g hts of a w ak enin g s, and criteria increased S W S. ADD had decreased R EM and sta g e 1 sl eep. O lder ADD had l on g er R EM l atency

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54 Pa lm 1992 10 chi ldren 6–12 yr Physician, 18 contro ls PSG, MSL T , and Inde x chi ldren had a et a l. w ith de fi cits psycho lo g ist reaction ti m es l on g er l atency to s leep in attention, and physio - for t w o ni g hts onset d u rin g ni g ht one. m otor contro l, therapist No other dif ferences in and perception sl eep observed ; inde x (m edication free ) had chi ldren si g ni fi cant ly l on g er reaction ti m es 45 T irosh 1993 10 ADHD 6–12 yr Previo u s 10 m atched Acti g raphy d u rin g D u rin g m edication there et a l. (before and dia g nosis contro ls base line, p lacebo w as a shorter s leep d u rin g of ADHD and d u ration m edication ). m ethy lphenidate for 8 d each 32 Da g an 1997 12 ADHD 9 .6 ± 1 .6 Psychiatric 12 hea lthy m al es Acti g raphy for ADHD had poorer s leep et a l. m al es (fi ve yr assess m ent three ni g hts ef fi ciency , l ess m edicated ) qu iet s leep, and increased activity 38 Gr u ber 2000 38 ADHD 9 .6 ± 2 .7 DSM -IV 64 m al es fro m a Acti g raphy for ADHD had l on g er s leep et a l. m al es yr criteria based nor m ative fi ve ni g hts onset l atency , (m edication on teacher sa m p le and dai ly increased s leep na ïve ) and parent sl eep l o g s. d u ration and increase ratin g st ru e sl eep. No dif ferences fo u nd in the s leep l o g data. (C ontin u ed)

Ta b le 2 (C on ti nued) Dia g nosis R ef. A u thors Y ear S u b jects A g eo f ADHD C ontro l sa m p leS leep assess m ent R es ul ts 46 Lecendre ux 2000 30 ADHD 7 .8 ± 1 .6 Psychiatric 22 m atched 1 wk of No dif ferences in et a l. m al es ; ( psycho - yr assess m ent contro ls presentin g hospita li zation ; overni g ht st u dy . MLS T sti mul ant u sin gw ith readin g EEG and E C G sho w ed shorter s leep na ïve ) DSM -IV disorder recordin g s latency in ADHD ; criteria overni g ht and ADHD chi ldren had d u rin g MSL T; m ore dayti m e sl eep co m p u teri zed episodes. ADHD test of a lertness perfor m ed w orse on tests of reaction ti m e 8 C or kum 2001 25 ADHD 9 .1 ± 1 .4 For m al 25 chi ldren fro m1 . Acti g raphy 1 . No dif ferences et a l. (m edication yr psycho lo g ica l the co mmu nity for 7 d bet w een g ro u ps na ïve ) assess m ent 2 . S leep diary 2 . ADHD l on g er s leep ti m e and m ore bedti m e resistance 47 K onofa l 2001 30 m al e ADHD 5–10 yr Psychiatric 19 contro ls w ith PSG and video ADHD chi ldren had et a l. (m edication - assess m ent learnin g disorders perfor m ed on hi g her l eve ls of free )w ith DSM -IV m atched for a g e the 3 rd ni g ht noct u rna l activity ; criteria and se x fo ll o w in g sl eep architect u re adaptation other w ise not dif ferent 35 O ’B rien 2003 44 ADHD ; 27 5–7 yr C onners ’ 39 contro ls fro m PSG for one R EM l atency l on g er in et a l. hyperactive Parent R atin g the co mmu nity ni g ht ADHD than in hyper Sca leo r contro ls ; R EM % shorter in ADHD than in hyper or contro ls

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48 O ’B rien 2003 87 ADHD (53 6 .5 ± 1 .4R eport of 53 contro ls fro m PSG for one Decreased R EM % in et a l. m edicated ) yr con fi rm ed the co mmu nity ni g ht ADHD ; Medicated dia g nosis of ADHD had trend ADHD to w ard l on g er R EM latency 49 O ’B rien 2003 47 ADHD 8 ± 1 .6 Dia g nosis by 53 contro ls fro m PSG for ADHD had increased et a l fro m cl inica l yr physician or the co mmu nity one ni g ht R EM l atency , (c linica l; psycho lo g ist decreased R EM % sa m p le 53 sa m p le ) for c linica l than contro ls ADHD fro m 6 .6 ± sa m p le ; co mmu nity 0 .4 yr - parenta l sa m p le (co mmu report of nity ADHD sa m p le ) to g ether w ith score >2 SD on C onners for co mmu nity sa m p les MSL T , mul tip le s leep l atency test ; S W S, s lo w-w ave s leep ; E C G, echocardio g ra m; PSG, po lyso m no g ra m; SD, standard deviation.

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4. SLEEP ARCHITECTURE IN ADHD

The proportion of time spent in different sleep stages in children with ADHD has been investigated in a number of studies dating back to the 1970s. Nahas and Krynicki (50) found a decreased percentage of rapid-eye-movement (REM) sleep and stage 4 sleep ( Δ sleep) in nonmedicated hyperactive males when compared with published values in normal children.

These changes were accompanied by a reciprocal elevation of stage 2 sleep. Conversely, increased Δ sleep was reported by Ramos Platon et al. (39) in a group of 13 medication-free attention deficit disorder children in comparison to published data. Clearly, the use of pub- lished normative values for comparison of findings in selected ADHD cohorts is not very valuable and does not allow for assessments of real differences that may exist in sleep archi- tecture between the ADHD and control children. Notwithstanding these considerations, reported differences in REM sleep between ADHD and control children appear to be more reliably present. Indeed, Busby et al. (43) performed overnight polysomnography in a small number of children with ADHD (n = 11) and controls (n = 11) and found that REM sleep latency was significantly increased in the ADHD group, a finding that is in agreement with those of Haig et al. (42) and Feinberg et al. (44). In contrast, Kahn (51) found decreased REM sleep latencies, and Ramos Platon et al. (39) found no significant differences in hyper- active and control children. Further, the studies by Haig et al. (42) and Feinberg et al. (44) found that the increase REM latency was present only in children who were medicated with stimulants. Despite such findings, it needs to be emphasized that a first-night effect could be one of the factors that may affect REM sleep latency, such that the putatively prolonged REM sleep latency among ADHD children could essentially reflect the fact that ADHD chil- dren are more sensitive to changes in the environment, and therefore more prone to develop a first-night effect in the sleep laboratory. However, when sleep EEG dynamics were followed in ADHD children for four consecutive nights, there was a tendency to maintain prolonged REM sleep latency across all nights (43). In addition, the proportion of time spent in REM sleep has been found to decrease (39,50) in nonmedicated children with ADHD. More recently, in a series of more extensive studies from our laboratory, we confirmed that a pro- longed REM latency is clearly present in children with significant symptoms suggestive of ADHD (35), and that such delayed onset of REM findings were still present in children with reports of a diagnosis of ADHD obtained from both a clinical population and a community population (49). Furthermore, O’Brien, et al. (48) also found a trend toward a longer REM latency in medicated children with ADHD compared with controls. Interestingly, we found on all three of these studies that the proportion of REM sleep as a function of total sleep duration was decreased in the ADHD groups. What are the implications of such findings?

O’Brien et al. (35) found significant correlations between the magnitude of REM sleep dis- turbance and the degree of disturbance in neurocognitive measures, particularly in those associated with executive function. Such associations suggest that disruption of REM sleep may exert small effects on daytime functioning, a not-so-surprising finding, given that REM sleep plays important roles in memory consolidation of learned tasks (55).

5. SDB AND ADHD: TRUE, FALSE OR UNRELATED?

A large body of evidence has now documented that children with either snoring or SDB

often present with problems of attention and behavior that are remarkably similar to those

observed in children with ADHD (2,7,8,23,56–58). In addition, three separate population

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surveys encompassing almost 3300 children showed the presence of daytime sleepiness, hyperactivity, and aggressive behavior in children who snored (2,59,60). It has been further suggested that up to one third of all children with frequent, loud snoring will display signifi- cant hyperactivity and inattention (2). Based on the available literature, the relatively high prevalence of SDB (3% of children) and ADHD (5–6%) would predict that their coexistence may also be relatively frequent. However, the actual prevalence of SDB in children with ADHD far exceeded that predicted by the simple probability if these two disorders were mechanistically unrelated coexisting disorders. In fact, it has been suggested that up to 25%

of children with a diagnosis of ADHD may actually have SDB (23). Although such rather elevated figure estimates of the overlap between SDB and ADHD is probably less prominent if medication status and psychiatric comorbidity are accounted for in the analysis, the phe- nomenon still holds true but only for a subgroup of children with hyperactivity. In a recent study by our team (35), we found that the prevalence of SDB in a cohort of children with ADHD does not appear to differ from the prevalence in the general population. However, an unusually high frequency of SDB was found among children with mild-to-moderate increases in hyperactivity, who did not meet the more stringent criteria necessary for the diagnosis of ADHD. This suggests that although SDB may induce significant behavioral effects manifesting as increased hyperactivity and inattention, it will not overlap with true clinical ADHD when the latter is assessed by more objective tools than just parental perception.

6. EFFECT OF STIMULANT MEDICATION ON SLEEP IN ADHD

Stimulant medications have long been the first line of treatment for children with ADHD, and routinely yield clear benefits in both behavioral patterns and attention deficits, indepen- dent of whether the assessments are part of laboratory research or field trials (31). In addition to the improvements in the cardinal symptoms of inattention, impulsivity, and hyperactivity, substantial cognitive improvements have also been noted (61). However, many of the puta- tive sleep problems in children with ADHD have been attributed to the use of stimulants.

Insomnia has long been reported to be a side effect of stimulant therapy despite the fact that the majority of studies have been based on parental report, rather than truly assess sleep latency and maintenance. Stein (6) found that almost one third of families with stimulant- treated children reported insomnia or increased sleep latency compared with 10% of untreated children with ADHD. Similarly, both Barkley (31) and Ahamenn et al. (62) found that stimulant medication was associated with insomnia. In contrast, Pataki et al. (63) did not find insomnia to be reported with significantly greater frequency in children medicated with methylphenidate compared to baseline or placebo periods.

There is some evidence that the medication schedule may influence sleep measures

(64–66). For example, delays in the first REM period and decreased proportion of REM sleep

have been reported following nocturnal administration of stimulants (64). Additionally, the

type and dosage of the stimulant may affect sleep characteristics in children. Efron et al. (67)

conducted a double-blind, crossover trial of methylphenidate and dexamphetamine, and

reported that the latter caused more severe insomnia that methylphenidate. Tirosh et al. (45)

reported that only sleep duration was affected (reduced) by methylphenidate hydrochloride

compared with placebo, whereas others have reported prolongation of REM latency (41,44),

increases in the number of REM cycles (40), or decreased proportion of REM (64). We

recently examined the potential effect of stimulants on objective sleep measures and found no

differences in sleep parameters between children taking methylphenidate or dexamphetamine

compared with nonmedicated children (48). These results support earlier findings of Haig et al.

(42) and Nahas and Krynicki (50), who found no differences in sleep parameters in a small group of children before and during stimulant therapy. Thus, if stimulant medication is indeed associated with disrupted sleep, the disruptions are likely to be minimal and of little clinical consequence. Moreover, some of observed sleep disturbances could be related to drug rebound effects rather than medication effects per se.

The relationship(s) between ADHD, medication, and sleep is far from being a trivial one.

However, small sample sizes, lack of control subjects, and skewed clinical populations drawn from tertiary referral centers potentially detract from the validity of any of the potential findings, and make it difficult if not impossible to compare across studies. Furthermore, these obstacles are further compounded by not knowing whether studies on nonmedicated children were conducted in children who never received psychostimulants vs children who had previ- ously been on stimulant therapy, in whom sleep characteristics may have been influenced by residual medication effects. As a result of all these methodological issues, whether psychos- timulant use is associated with sleep disturbance remains an unanswered question despite the widespread use of such medications for the treatment of ADHD symptoms.

7. SLEEP MOTOR HYPERACTIVITY AND ADHD

Studies using both actigraphy (32,52), overnight polysomnography (41,43), and more recently video analysis of nighttime motion (47) have reported that hyperactive children show an increased frequency of body movements during sleep. PLMS has been reported in greater frequency among children with ADHD compared to controls (26,27), raising the speculation that PLMS and ADHD may share neurobiological mechanisms (27,28). Indeed, children with PLMS are reported to have hyperactive behavior (25) and PLMS may be com- mon among hyperactive children (26–28,60). In one study by Picchietti et al. (27), 15 out of 16 children with frequent PLMS (>25 per hour of sleep) had ADHD. Chervin and Archbold (68) further reported a dose-dependent association between hyperactivity, measured by the Conners Parent Rating Scale (36) and PLM index. Furthermore, treatment of PLMS will often lead to substantial behavioral improvements in hyperactivity (69). However, most of these studies were conducted in tertiary-referral patient cohorts (25–28,60,68). To further examine the possibility that skewed ADHD populations may lead to an overrepresentation of PLMS, O’Brien et al. (49) studied a community sample of children diagnosed with ADHD and compared it to both a group of control children and to a group of children referred for subspecialty evaluation at a tertiary medical center. Although this study did not find an increase in PLMS in the community sample of ADHD children, PLMS was found in 40% of children referred to the tertiary clinic. Of interest almost half of these children had arousals associated with PLMS events. These findings further raise the question of whether those chil- dren attending the clinical setting actually represent a subgroup of children with ADHD who are also more likely to have a nighttime disorder (i.e., PLMS). In other words, ADHD chil- dren referred to a tertiary specialty clinic may represent a subset of ADHD children who are at high risk for PLMS and associated sleep fragmentation, which in turn may exacerbate day- time behavior. This possibility is further substantiated by data from Crabtree et al. (29) who found that children with PLMS and ADHD had significantly more PLMS events associated with arousals than children without ADHD. As such, the number of arousals elicited by PLMS events during sleep may be more directly linked with hyperactivity rather than the overall number of PLMS per se. As such, children who exhibit an elevated PLMS index may

450 O’Brien and Gozal

have a reduced risk of presenting symptoms of ADHD if the PLMS events are not associated with arousals.

An alternative possibility may be that children presenting to sleep disorders centers are more likely to exhibit PLMS, whether or not they are diagnosed with ADHD. In this context, PLMS- associated arousals could be a result of the underlying pathophysiology of ADHD, rather than represent a pathophysiological mechanism facilitating the emergence of hyperactive behaviors and attention deficits. Chervin and Archbold (68) found that 26% of children presenting to their sleep disorders center who underwent polysomnography had a PLMS index greater than or equal to 5, and found no association between PLMS and inattention–hyperactivity in children.

Conversely, Picchietti and Walters (27) found that 91% of children with PLMS in their clinic had a diagnosis of ADHD. The disparities among the various studies are therefore difficult to recon- cile, and further support the need for additional research on the prevalence and significance of PLMS in children with ADHD.

8. ADHD, COMORBIDITY, AND SLEEP

In a setting of ADHD, comorbid psychiatric diagnoses, such as anxiety and behavioral disorders, may impose significant effects on the occurrence of sleep disturbances as reported by parents. However, the data are scanty on this issue, and the few studies available have not consistently included a clinical comparison group. Furthermore, the results of such studies are conflicting. Day and Abmayr (70) found that ADHD children with comorbid conditions were more likely to report problems with settling and going to sleep, as well as disruptions during sleep, whereas Marcotte et al. (33) found that the frequency of sleep- related problems did not differ between children with ADHD and those with a learning dis- order. Corkum et al. (34) attempted to unravel the potentially complex relationships between ADHD comorbidities and medication status and sleep. These investigators reported that although children with ADHD were more likely to have more problematic sleep issues than their normally developing peers, they were not different from other children with psy- chiatric diagnoses (anxiety disorder, depression, conduct disorder, oppositional defiant dis- order). The combined subtype of ADHD (presence of both hyperactive and inattentive behaviors) was associated with the presence of dyssomnias and sleep-related involuntary movements. However, post hoc analyses revealed that the dyssomnias were associated with stimulant medication and oppositional defiant disorder rather than ADHD per se, whereas sleep-related involuntary movements were highly associated with anxiety. More recently, Mick et al. (71) have provided additional data supportive of the findings by Corkum et al.

(34), and have suggested that the majority of sleep difficulties observed in ADHD children are accounted for by comorbid anxiety and pharmacotherapy with stimulants. Furthermore, comorbid anxiety was associated with a decreased likelihood of going to bed willingly, of falling asleep easily, and also with an increased likelihood of waking during the night.

These findings suggest that bedtime struggles often reported in ADHD may be more closely related to the presence of comorbidities than ADHD per se. Thus, the relationship between ADHD and sleep disturbance is complex, and may depend on numerous factors that include the type of sleep problem, the presence of comorbidity, and the medication status. Further studies that include control groups recruited from psychiatric or neurologic subspecialty clinics may provide additional information on the sleep characteristics of these children, and help determine whether the differences observed are unique to ADHD or are shared by neuropsychiatric diseases in general.

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9. SUMMARY

In conclusion, the associations between sleep disturbance and ADHD are complex and quite poorly defined at present. Parental report-based studies invariably yield findings of sig- nificantly more reported sleep disruptions in children with ADHD, whereas objective assess- ments have yet to uncover striking and consistent differences. Despite such considerations, it seems prudent to assess children with ADHD for the presence of sleep disturbances because identification of specific sleep disorders may facilitate improved control of ADHD-ascribed symptoms in these children. Future studies utilizing large sample sizes of rigorously diag- nosed children and appropriately matched controls are required and need to include careful selection processes that incorporate information on comorbid disorders and medication history and schedules.

ACKNOWLEDGMENTS

The authors are supported by National Institutes of Health grant HL-65270, Department of Education Grant H324E011001, Centers for Disease Control grant E11/CCE 422081–01, and The Commonwealth of Kentucky Research Challenge Trust Fund.

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