Investigating the relationship between sleep problems and Attention-Deficit/Hyperactivity Disorder symptomology.

Proposal details

Title: Investigating the relationship between sleep problems and Attention-Deficit/Hyperactivity Disorder symptomology.
Research Area(s): ADHD and Allied Conditions
Background: Attention-Deficit/Hyperactivity Disorder (AD/HD) is a disruptive behavioural disorder commonly diagnosed in childhood involving deficits in attention, hyperactivity and impulsive behaviour (DSM-IV-TR, 2000). These behaviours can result from many environmental and genetic factors. This makes it difficult to elucidate the aetiology of AD/HD, which could possibly result from other primary problems, such as sleep problems. Sleep problems are common among children with AD/HD, being approximately 20% higher than typically developing children and approximately 15% higher than children diagnosed with other psychopathologies (Chervin., Dillon, J. E., Bassetti, C., Ganoczy, D. A., & Pituch, K. J., 1997; Corkum, Moldofsky, Hogg-Johnson, Humphries, & Tannock, 1999; Cortese, et al., 2005; Hiscock, Canterford, Ukoumunne, & Wake, 2007; Gau et al., 2007; Oosterloo et al., 2006; Van der Heijden, Smits, & Gunning, 2005). Problems in children with AD/HD include: sleep-related breathing disorder (SRBD), periodic limb movement (PLM), restless leg syndrome (RSL), and excessive daytime sleepiness (Van der Heijden et al., 2005). All of these sleeping problems are associated with decreased sleep quality and time (Beebe, 2006; Beebe, Groesz, Wells, Nichols, & McGee, 2003; Cortese et al., 2005; Gottlieb, Whitney, Bonekat, Iber, James, Lebowitz, Nieto, & Rosenberg, 1999; Van der Heijeden et al., 2005). When sleep quality is reduced in healthy typically-developing children, inattentive behaviours during the day increase (Fallone, Acebo, Seifer, & Carskadon, 2005) and vice-versa, when sleeping problems are treated in children diagnosed with AD/HD, hyperactivity, inattention and vigilance improves (Ali, Pitson, & Stradling, 1996; Johnstone, Tardif, Barry, & Sands, 2001; Walters, Mandelbaum, Lewin, Kugler, England, & Miller, 2000). Interestingly, when sleeping problems were treated in an AD/HD sample, 42% no longer meet diagnostic criteria for AD/HD (Walters et al., 2000). What needs to be investigated is the mechanism of this association between ADHD symptomology and sleep quality. Are sleeping problems just a continuation of AD/HD symptomatology into the night, or do the underlying neuropathology associated with sleeping problems result in AD/HD type symptomatology. As yet limited research has been carried out to directly compare children with AD/HD with and without sleeping problems. Therefore, the present study will investigate if the higher prevalence of sleep problems in AD/HD is simply representative of a co-morbid disorder or is of aetiological significance. Different neuropathology is proposed to be associated with AD/HD as compared to reduced sleep quality. A recent meta-analysis by Dickstein et al., (2006) of functional neuroimaging studies reported widely distributed frontal hypoactivity in children with AD/HD in frontal-parietal networks. In contrast Drummond, Gillin and Brown (2001) showed increased activation in frontal-parietal networks after sleep deprivation. Yoo, Hu, Gujar, Jolesz, & Walker (2007) reported that performance on a memory encoding task after sleep deprivation resulted in interruption to neural circuits associated with memory encoding while connections between simple arousal networks, specifically the hippocampus, brainstem and thalamus were stronger. This is in contrast to decreased activity in the left thalamus in AD/HD reported by Dickstein et al., (2006). Therefore it would be expected that electrophysiological measures would differ between these two groups. Electroencephalography (EEG) profiles are shown to be abnormal in AD/HD (Synder and Hall, 2006), as well as sleep problems (Smith, McEvoy, & Gevins, 2002). Further studies also consistently show ERP P3-type components to be abnormal in AD/HD (Johnstone & Barry 1996; Jonkman et al., 1997) and sleep problems (Salmi, Huotilainen, Pakarinen, Siren, Alho, & Aronen, 2005). The nature of these P3-type abnormalities varies slightly however between those diagnosed with AD/HD and sleep disorder populations. Children with AD/HD also show deficits on verbal interference and switching of attention tasks (Frazier, Demaree & Youngstrom, 2004; Mourik, Oosterlann & Sergeant, 2005; Nigg, 2005; Walker, Shores, Trollor, Lee & Sachdev, 2000; Wu, Anderson & Castiello, 2006) as do children with sleeping problems (Wong, Grunstein, Bartlett and Gordon, 2006). A task that does appear to differentiate between sleeping problems and AD/HD is the time estimation task. On this task children with AD/HD are impaired while those with sleeping problems are not (Bohnen and Gaillard, 1994; Kerns, McInerney & Wilde, 2001; Smith, Taylor, Rogers, Newman & Rubia, 2002; Wong et al., 2006). On verbal memory tasks adolescents with AD/HD show errors of interference and decreased recall (Keage, et al., 2006), while those with sleeping problems perform normally (Beebe, 2006; Wong et al., 2006). On verbal fluency tasks children with AD/HD are shown to generate less words when given letter cues but to perform normally when given semantic cues (Boonstra, Oosterlaan, Sergeant & Buitelaar, 2005; Hurks et al., 2004; Scheres et al., 2004) will those with sleeping problems simply perform worse (Antic et al., 2005; Harrison & Horne, 1997). There are two possible explanations for the high prevalence of sleep problems in children with AD/HD. Firstly, it is possible that the deficits in children with AD/HD, such as hyperactivity, cause sleep problems to occur more frequently. It may be that the higher prevalence of sleeping problems seen in these children are just expressions of there AD/HD symptoms at night (causal link 1). Alternatively, it is possible that sleep problems result in the same behavioural deficits defined as AD/HD, that is, for this group of children the underlying deficit is not AD/HD but a sleeping problem (causal link 2). Reference List American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ? Text Revised. Washington, DC, American Psychiatric Association, 2001. Antic, N., Catcheside, P., Clark, R., Hansen, C., Hensley, M., Naughton, M., Windler, S., & McEvoy, R. D. (2005). Assessing neurocognitive function in patients with moderate to severe obstructive sleep apnea in a multi-centre study. Abstracts presented at the combined Annual Scientific Meeting of the Australasian Sleep Association and the Australasian Sleep Technologists Association, 2004. Internal Medicine Journal, 35 (3), A21?A46. 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Aims: The present study will examine the relationship between sleeping problems and AD/HD by comparing four groups of children: AD/HD with sleeping problems (AD/HD-with), AD/HD without sleeping problems (AD/HD-without), controls with sleeping problems (Controls-with) and controls without sleeping problems (Controls-without). These groups will be compared on EEG profiles, ERP P3-type component latencies and amplitudes in auditory oddball and working memory tasks (targets, non-target and deviant stimuli), and neuropsychological tests (including performance on auditory oddball and working memory tasks, switching of attention, verbal interference, verbal fluency, verbal memory and time estimation tasks). This battery of measures will allow an examination of the contributions of AD/HD and sleep problems to the performance and electrophysiology within the four comparison groups. Comparisons of these measures in the four groups will allow further understanding of the possible role of sleeping problems in the aetiology of AD/HD. Hypotheses 1) Resting brain activity. Controls-without will display decreases in delta, alpha and theta as well as increase in beta as compared with Controls-with. AD/HD-without will display increase in theta and a decrease in beta as compared to Control-without. AD/HD-with is expected to display a combination of these differences to support causal link 1; or the same differences as controls-with vs controls-without to support causal link 2 along with decreased alpha and increased delta as compared to AD/HD-without. 2) Auditory oddball and working memory target and non-target P300s. These two tasks will be examined as they use different modalities (auditory/visual) and different task-demands (need to update in working memory task, no need to update in oddball task; thus working memory task is more difficult), and taking these factors of modality and difficulty into account will provide a greater probability of detecting specific differences. . Controls-without will display shorter latency and larger amplitude than controls-with, following targets and non-targets. AD/HD-without will display smaller amplitude following targets and both smaller amplitude and longer latency non-targets in comparison to controls-without. AD/HD-with is expected to display a combination of these differences to support causal link 1; or the same differences as control-with vs control-without to support causal link 2. 3) Distractor P300a. Controls-without will display smaller amplitude than controls-with. AD/HD-without will display longer latency and smaller amplitude than controls-without. AD/HD-with is expected to display a combination of these differences to support causal link 1; or the same differences as control-with vs control-without to support causal link 2. 4) Oddball and working memory performance. The working memory and oddball task performance measures will be compared for the four groups. Controls-without will display less FNs and shorter RTs than controls-with, no differences are expected for FPs. AD/HD-without will display more FPs and FNs than controls-without, and delay in reaction time. AD/HD-with is expected to display a combination of these differences to support causal link 1; or the same differences as control-with vs control-without to support causal link 2. 5) Psychometric performance. Controls-without will perform better on the, Verbal Fluency, Verbal Interference and Switching of Attention Task than controls-with, no differences in performance are expected for the Time Estimation or Verbal Memory Task. AD/HD-without will perform worse on all five tasks, except the Verbal Fluency semantic condition, than controls-without. AD/HD-with is expected to display a combination of these differences to support causal link 1; or the same differences as control-with vs control-without to support causal link 2.
Method: Participants Participants (both male and female) will be between 10-16 years of age, as EEG is relatively stable over this age-span (Satterfield, Schell, Backs, & Hidaka, 1984). They will be divided into four comparison groups: 1) AD/HD without sleeping problems (AD/HD-without), 2) AD/HD with sleeping problems (AD/HD-with), 3) controls without sleeping problems (Control-without), 4) controls with sleeping problems (Control-with). Participants will be matched on age, and body mass index (BMI) due to the link between weight and sleep disordered breathing (Beebe, 2006; Wong et al., 2006). All AD/HD participants have IQs over 80 therefore it is not necessary to match participants on IQ scores. It is hoped that there will be approximately 30 participants in each group. All clinical and control participants will be selected from the Brain Resource International Database (BRID). Children with AD/HD will be accepted into the study if they are medication na?ve due to link between stimulant medication and insomnia (MIMS, 2005). Children with AD/HD will also be accepted into the study if they have a comorbid disorder such as Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), or a learning disorder (LD). Though these comorbid disorders may represent a confound in the EEG measures a key point is that AD/HD is a highly co-morbid disorder rendering pure AD/HD an anomaly and any results in a pure AD/HD group not generalisable to the other AD/HD populations (Brassett-Harknett & Butler, 2007). Therefore the present study will not exclude participants with co-morbid disorders that commonly occur in AD/HD such as ODD and CD. Participants with English as a second language or any history of brain injury or insult will be excluded. Children with AD/HD are referred to the BRID by paediatricians and psychologists in Sydney and Adelaide if they meet the DSM-IV-TR AD/HD diagnostic criteria, while control children are recruited through advertisements in schools and community groups. The participants with sleep problems were identified through Brain Resource Company web-based assessment questionnaire. Psychophysiological data collection A 32-electrode EEG cap (QuickCap, Neuroscan) was used to record EEG data from the Fp1, Fp2, F7, F3,Fz, F4, F8, FC3, FCz, FC4, T3, C3, Cz, C4, T4, CP3, CPz, CP4, T5, P3, Pz, P4, T6, O1,Oz and O2 electrode sites (10-10 International system) while visual/verbal and resting tasks were presented through a computer monitor and headphones. This was referenced to the average of A1 and A2 (mastoid) electrode sites. Eye movements were recorded, horizontally by electrodes 1.5cm to the outer canthus of each eye and vertically by electrodes placed 3mm above and 1.5cm below the left eye. EEG and EOG activity was digitized and amplified by NuAmps, Scan 4.3. Absolute EEG power was recorded for four bands: delta (1.5-3.5 Hz), theta (4-7.5 Hz), alpha (8-13 Hz) and beta (14.5-30 Hz). The ERP P3-type components were defined as those occurring 220-600 ms post-stimulus. Participants used a button-box response pad to respond to task stimuli. The midline sites Fz, Cz and PZ were only used as the study was not interested in the topography of components. The psychophysiology test battery consisted of 10 tasks, three of which included eyes-open/eyes-closed, working memory and an auditory oddball paradigm. All task instructions where presented on the computer monitor and through the headphones with a recorded audio file. Psychophysiological tasks Psychophysiological tasks included EO, EC, oddball and working memory, reported to have high test-retest reliability (Williams, Simms, Clark, & Paul, 2005). Eyes-open / eyes-closed The eyes-open/eyes-closed task required the participant to focus with eyes open, shoulders and jaw relaxed on a red fixation dot in the centre of the computer monitor for three minutes. This was then followed by the eyes closed condition, in which the participant closed their eyes with jaw and shoulders relaxed for a following three minutes. Auditory Oddball The auditory oddball task consisted of two tones ? one high (1000hz) and one low (500hz), presented at 75db for 50ms with a inter-stimulus interval (ISI) of 1-second presented binaurally through headphones. The high tone was the target tone which participants were instructed to respond to by pressing two buttons on the button-box, one with each index finger. Participants were instructed to do this as fast and accurately as possible, while focusing on a red fixation dot in the centre of the computer monitor. Participants were given a brief practice before commencing the actual task. Throughout the task 280 non-target and 60 target tones were presented over six minutes with no two targets ever occurring consecutively. Working Memory Task The working memory task involved a series of letters (B, C, D and G, in white Ariel font on a black background) presented on the computer screen randomly interspersed with a checkerboard pattern (black and white 1cm by 1cm checks). Letters were presented for 200milliseconds with an ISI of 2.5 seconds. The participant?s task was to use the button-box, simultaneously with both left and right index fingers to respond to any letters that were repeated in a row. Both speed and accuracy were emphasised in the task instructions. The task began after a short practice. In total 85 non-target letters, 20 random targets letters and 20 distracter checkboard stimuli were presented over 8 minutes. Behavioural measures Performance on auditory oddball and working memory tasks. The behavioural measures examined in the auditory oddball and working memory tasks were the reaction time (RT) and standard deviation of reaction time (SDRT) to target stimuli. Also recorded were FP (errors of commission) and FN (errors of omission) identifications of target stimuli. Psychometric performance. The neuropsychological test battery was presented through a touch screen computer. Twelve tasks formed the battery, five of which included switching of attention task (a form of the Trail Marking Task; Lezak, 1995), verbal interference (a form of the Stroop Task; Lezak, 1995), time estimation test, verbal memory task, and a verbal fluency task which have been shown to be valid, reliable measures of cognitive function (Paul, Lawrence, Williams, & Clark, 2005; Williams et al., 2005). Switching of Attention Task The switching of attention task contains two tests of the participant?s attention. Trial one, presented after a practise trial, required the participant to link 25 numbers in sequential order. Following this, trail two required the participant to link a series of letters and numbers in order one after the other (eg 1-a-2-b-3-c etc). Both speed and accuracy were emphasised. The difference in total time to completion and number of errors between trail one and two were proposed as measures of distraction (Keage et al., 2006). Verbal Interference Test The verbal interference test involved the presentation of the names of colours, presented in a different colour on the monitor (eg the word red presented in green text-colour). Beneath this were four different colour options, (red, yellow, green, blue) in four boxes for the participant to select their response. On trial one the words were presented in black, on trial two they were presented in conflicting colours. On trial two the participant was asked to identify not the word itself but the colour of the word. This task indexes the ability to inhibit well-learned responses. This ability to inhibit is measured by the difference between trial one and two in correct responses, the number of incorrect responses and the reaction time to respond. Time Estimation Test In the time estimation test a circle appears on the computer screen for an interval from 1 to 12 seconds. The participant then has to select from the options (1-12) presented on the bottom screen to indicate how long they believe the interval lasted for. The test measures the ability to attentively monitor and sustain concentration. This is measured by examining the proportional bias, the average of the difference between the duration of the period and the users estimate of the period length (Clark, Paul, Williams, Arns, Fallahpour, Handmer & Gordon, 2006). Verbal Memory Task In this task the participant is presented verbally with a list of twelve concrete words that they are asked to remember. The list is presented four times and after each presentation the participant is asked to recall as many words as they can. Memory recall is indexed by the total number of words recalled on trials 1-4. A measure of intrusion, or poor verbal memory, is indexed by the number of intrusions of words recalled on trials 1-4 that were not included in the original list. Verbal Fluency Task This task involves that participant generating as many words as possible in one minute that start with a given letter (F,A, or S) or fit a semantic category (animals). The participant is instructed not to use proper nouns or to simply vary to prefix, suffix or tense of a word (eg run, running, ran). The total score for verbal fluency for the letter conditions is the average number of generated words for the three letters. For the semantic condition it is the total number of animal names generated. Procedure All participants attended a recording session in a laboratory in either Sydney or Adelaide. All participants had a parent or guardian give consent on their behalf and in the case of children under the age of 12 the parent or guardian also completed the BRC web-based assessment questionnaire (appendix a). The child was fitted with the EEG recording cap and then completed the brain function test battery, including auditory oddball, working memory, and EO, EC paradigms, in a light and sound attenuated room. The cognitive test battery of neuropsychological function was then completed using the touch screen system to record responses to the switching of attention and verbal interference tasks. The web-questionnaire was completed with a parent if the child was under 12 and individually if the child was over 12 before coming in for testing. Self- and parent- report sleep measures have been found to be reliable in discriminating those with and without sleeping problems (Chervin, Hedger, Dillion, & Pituch, 2000). In the questionnaire the participants where asked two questions about sleep quality which if positive referred them to one of two sleep history questionnaires. The first sleep question asked participants, ?In the last month, have you experienced or have you been told about any of the following sleep symptoms ? difficulty in falling asleep at night; frequent night awakenings; breathing difficulties, snorting, gasping or loud snoring?? Participants that agreed with this question were referred to sleep history questionnaire 8a, with 8 questions based on an apnea risk index created by Maislin et al., (1995). The second question asked participants, ?In the last month, have you experienced problems staying awake during the day?? Participants that agreed with this question were referred to sleep history questionnaire 8b, with 8 questions indexing excessive daytime sleepiness. Both sleep history questionnaires used Likert-type response formats, with a score of 2 or more (indicating that they experienced the symptom twice or more in a week) representing experience of the sleep problem in question (see appendix a). The current study will accept those that have answered positively to either 1 or both 1 and 2, that is, it will not accept those that only answered 2 as this may indicate a different pathology not related to a nocturnal sleeping problem. Statistical Analysis EEG and ERP data will be analysed from central electrodes Fz, Pz and Cz. Differences across the groups in EEG, latency and amplitude in ERP components, and behavioural measures will be analysed using a one-way analysis of variance (ANOVA). ERP Analyses For ERP data 10, 4(group: AD/HD-with, AD/HD-without, controls-with, controls-without) x 3(electrode: Fz, Pz, Cz) one-way ANOVAs will be run on each ERP component measure: oddball target (amplitude and latency), oddball non-target (amplitude and latency), working memory target (amplitude and latency), working memory non-target (amplitude and latency), and distracter (amplitude and latency). If a significant result is found then Tukey post-hoc planned comparisons will be carried out. Main effects of electrode will no be investigated, as they are not relevant to research aims. EEG Analyses For EEG data 4, 4(group: AD/HD-with, AD/HD-without, controls-with, controls-without) x 3(electrode: Fz, Pz, Cz) one-way ANOVAs will be run on the absolute power measures of the four EEG band: alpha, delta, theta, and beta. If a significant result is found then Tukey post-hoc planned comparisons will be carried out. Main effects of electrode will no be investigated, as they are not relevant to research aims. Behavioural Measures Analysis. For behavioural measures, 15, 4 (group: AD/HD with, AD/HD without, controls with, controls without) one way ANOVAs will be run on each performance measure from each cognitive task: working memory (false positive, false negative, reaction time), auditory oddball (false positive, false negative, reaction time), switching of attention (difference in total time to completion, number of errors between trail 1 and 2), verbal interference (difference in reaction time, difference in errors and correct responses), time estimation (proportional bias), Verbal Memory Task (total no recalled trials 1-4, total number of intrusion trials 1-4), and Verbal Fluency (average number of words generated in letter condition, total number generated in ?animal? condition.) If a significant result is found then Tukey post-hoc planned comparisons will be carried out.