以事件相關誘發電位探討注意力不足過動症與睡眠問題之關係

Abstract

研究背景及目的 注意力不足過動症是學齡期兒童最常見的神經行為疾病，目前研究認為與額葉執行功能缺損有關。注意力不足過動症兒童常有睡眠問題。縱然多項研究認為睡眠問題兒童也會因睡眠問題而產生注意力不足及過動之症狀及會有較差之認知表現，然而這些兒童可經由治療其睡眠障礙而使其注意力不足及過動之症狀減少。 大腦事件誘發電位檢查可展現出大腦伴隨認知作業而產生的神經電生理活動情形，研究者因而可藉由實驗方法上的操弄來觀察其變化以探討不同人類認知作業下大腦的處理歷程。 由於臨床研究指出睡眠問題之治療可能可減少過動或注意力不集中之行為，我們假設同時有注意力不足過動症及睡眠問題兒童之額葉執行功能缺損比單純注意力不足過動症兒童嚴重，故有更顯著之額葉敏感性之腦活動指標(如失匹配負波)之異常。因此，我們以一般兒童、注意力不足過動症兒童、睡眠問題兒童及同時有注意力不足過動症狀及睡眠問題之兒童同時以注意力轉換及非意識注意下之行為表現(如反應時間、錯誤率)及事件相關腦電位成分(如P1、N2、P3、關聯性負變、失匹配負波)之差異及變化以探討注意力不足過動症與睡眠障礙相關性及探討其病理機轉。如同時有注意力不足過動症及睡眠問題兒童之行為表現及事件誘發電位成分較差，我們應更積極治療同時這兩種問題之兒童。

實驗對象及方法 實驗對象 6-12歲之一般兒童、注意力不足過動症兒童、睡眠問題兒童及同時有這兩種問題者，經其家長或監護人同意後始為研究對象；排除有智力障礙(IQ<80)、精神心理障礙(除注意力不足過動症和睡眠障礙)、發展障礙或神經或行為疾病者。

實驗方法 合乎研究納入條件由其父母簽署受試者同意書、完成問卷(含睡眠習慣問卷、SNAP-IV-中文版)及接受智力測驗後，接受以Posner cueing paradigm及auditory oddball paradigm作評估，記錄其作注意力轉換時之工作行為表現(如反應時間、錯誤率)及事件相關腦電位成分(P1，N2，P3及失匹配負波之振幅與潛時)。使用SAS version 9.1作統計分析，各組間工作行為表現及事件相關腦電位成分以ANOVAs作分析，如有顯著差異再以Fisher’s least significance test作多重比較。ADHD組之ADHD亞型及睡眠問題組之睡眠問題型態以chi-square或Fisher’s exact test作分析。

結果與討論 本研究共收集了62位受測者，包括15位單純注意力不足過動症兒童、17位注意力不足過動症合併睡眠問題兒童、15位單純睡眠問題兒童及15位正常兒童作對照組。四組之年齡分佈及全智商分數皆沒有顯著差異。有注意力不足過動症狀兒童間之SNAP-IV分量表之分數(除IA+HI+OP之總分數外)無顯著差異而睡眠問題兒童間之睡眠問題型態(除睡中腳常動外)也無統計上顯著差異。 從行為表現來看，單純睡眠問題兒童之行為表現如反應時間及錯誤率皆與一般兒童者相仿；注意力不足過動症合併睡眠問題兒童之行為表現則顯著比前兩者差，其反應時間及N2與反應時間差皆較長且有較多anticipation errors。根據事件相關電位成分分析，在Posner cueing paradigm中，單純睡眠問題兒童對target之P1成分之振幅、對target之P3成分之振幅、關聯性負變及失匹配負波之振幅最小。在Auditory oddball paradigm中，單純睡眠問題兒童之失匹配負波之振幅最小。四組之失匹配負波之潛時無顯著差異。注意力不足過動症合併睡眠問題兒童之對target之P1成分之振幅、對target之P3成分之振幅、關聯性負變及失匹配負波幅也較單純注意力不足過動症兒童者小。 注意力不足過動症合併睡眠問題兒童之anticipation錯誤最多顯示其衝動性較强，其反應時間最長可能顯示其注意之指向及動作協調性較差。目前文獻顯示成人之慢性失眠會引起認知缺損，本研究中單純睡眠問題組中有較多之失眠兒童可能與其失匹配負波之振幅最小等有關。

結論 縱然單純睡眠問題兒童臨床上無行為表現問題，但是其事件相關電位成分分析與注意力不足過動症合併睡眠問題兒童者相仿，皆比單純注意力不足過動症兒童或一般兒童者較差。單純睡眠問題兒童之額葉功能相關之事件相關電位成分(失匹配負波)振幅最小，推論其額葉功能可能與注意力不足過動症合併睡眠問題兒童同樣較差。注意力不足過動症合併睡眠問題兒童之損傷可能比單純注意力不足過動症兒童較嚴重，臨床上也可能更需要積極之治療。

Background and objectives Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurobehavioral disorders. Recent neuropsychological work has suggested that ADHD children may suffer from deficits in the frontal executive function on motor control. Sleep problems are frequently observed in children with ADHD but their relationship remains unclear. As some sleep problems can be treated instead of stimulants, assessment and treatment of sleep problems in potential ADHD patients before starting the long-term use of stimulants should be considered. Event-related potentials (ERP) recording gives a spatio-temporal approach helping us to know variations of brain activity associated with the processes of attending to, anticipating, and detecting environmental targets as well as reflecting preparation to make a motor response. Our objectives were to study the ERP components of these children (ADHD with sleep problems, ADHD only, sleep problems only and normal controls) so as to investigate the relationship of ADHD and sleep problems and the pathogenic mechanisms of ADHD and sleep problems.

Materials and methods Materials Children aged 6 to 12 years with the diagnosis of ADHD with or without sleep problems, sleep problems only and normal children were included, excluding those with IQ<80 or underlying psychiatric, mental or neurological disorders or developmental disabilities. Methods After completing the questionnaires, informed consents and neuropsychological tests, subjects took the EEG examination for the ERP measurements with the Posner cueing paradigm and the auditory oddball paradigm. Combined analysis of electrophysiological components (like P1, N2, P3, mismatch negativity (MMN) and contingent negative variation (CNV)) and behavioral data (reaction time (RT) and the number and percentage of errors) were done in the 4 groups. The behavioral data and ERP results will be assessed using repeated measures analysis of variance (ANOVA) and Fisher’s least significance test for multiple comparisons by the SAS 9.1 version.

Results and Discussion The behavioral performance and ERP results of the 62 subjects were analyzed (15 with ADHD only, 17 with ADHD and sleep problems, 15 with sleep problems and 15 controls). No significant differences in age and FIQs were noted among these 4 groups. No significant differences in the SNAP-IV subscales (inattentive (IA), hyperactive/impulsive (HI)) were noted in the groups with ADHD except the total SNAP-IV (IA+HI+OP) scores. No significant differences in the proportions of the subtypes of sleep problems were noted in the groups with sleep problems except frequent leg movements during sleep. About the behavioral performance, subjects with ADHD and sleep problems have the longest mean reaction time and more anticipation errors, suggesting greater impulsivity, poorer attention orienting and probably poorer coordination. Subjects with sleep problems have similar behavioral performance as our controls. However, for the analysis of the ERP components, the amplitudes of the target-P1, the target-P3 components, MMN and CNV of the children with sleep problems only were the smallest. Besides, in those with ADHD, subjects with sleep problems had smaller amplitudes of the target-P1, target-P3, MMN and CNV than those without sleep problems. There was a smaller increment in the target-P1 amplitudes from valid to invalid condition in ADHD groups (22.7% and 31%) than non-ADHD groups (49% and 58%), suggesting poorer function in attention shifts in those ADHD subjects. As subjects with sleep problems (with or without ADHD) have smaller target-P1, target-P3 and MMNs (MMN was considered as a frontal lobe sensitive ERP component), ADHD and sleep problems may both have frontal lobe deficits which may be associated with poor attention maintenance and disorders in arousal. Conclusion Though subjects with sleep problems showed similar behavioral performances as the controls, their ERP measurements were poorer than the controls and seemed to be similar to those with ADHD and sleep problems. Considering the behavior and electrophysiological results, the ADHD patients with sleep problems might have more severe frontal executive deficits than those with ADHD only and thus they might need more attention and aggressive intervention including behavioral therapy and stimulants. Besides, early insomnia might be an important sleep problem that might lead to ADHD-like symptoms and neurocognitive impairment. Further investigation with more confirmative diagnostic tools like K-SADS and polysomography (to lessen the heterogeneity of sampling) and increased sample size and tasks might help us to have better understanding of the relationship between ADHD and sleep problems.