注意力不足過動症與碳酸酐酶之研究

Abstract

注意力不足過動症，於十二歲前發病，其特徵是至少有兩個以上不同環境表現出持續性注意力不足、與（或）過動衝動，其症狀影響其日常作息及發展。目前上市治療注意力不足過動症藥物包括中樞神經興奮劑及正腎上腺素回收阻斷劑；現階段既有之藥物仍無法百分之百有效，而且有部份病患無法忍受其副作用。本研究使用多面向研究方法，進一步了解此一多樣化且複雜的疾病。 注意力不足為注意力不足過動症兒童主要問題之一，其易導致行為及認知功能障礙。是否注意力不足過動症兒童於注意網路任一步驟有缺陷，尚待進一步研究。我們於被動式聽覺刺激模式下，使用純音和國語音調兩種刺激，分析事件相關電位之成份波：包括不匹配負波(mismatch negativity, 簡稱MMN)、P3a、以及晚期不匹配負波(late discriminative negativity, 簡稱LDN)。研究顯示：不論在純音或國語音調情況下，兩者於MMN無差異，而注意力不足過動症兒童相較於健康兒童，其P3a表現下降、LDN表現增強。相關性分析顯示於較大國語音調差異下，較高注意力不足過動症分數伴隨較多P3a振幅下降。總結：不論在純音或國語音調情況下，注意力不足過動症兒童於不自主性注意力導向與注意力重新導向、進一步評估兩步驟，呈現聽覺刺激變化偵測缺損。 除了上述典型注意力不足過動症兒童之研究，我們也針對過敏性鼻炎兒童進行注意力不足過動症相關症狀之研究。研究顯示相較於健康兒童，過敏性鼻炎兒童確實具有較高過動�衝動症狀分數、較高違反錯誤(commission errors)、較短反應時間、較多固持現象（perseveration）。危險因子包括年紀較小、男性、鼻炎症狀分數較高、持續性鼻炎、中重度鼻炎、多重過敏疾病、家族過敏史、以及伴隨注意力不足過動症之可能性。接著於後續前瞻性追蹤研究中，我們進一步證實上述過敏性鼻炎兒童表現出的較高注意力不足過動症相關症狀，可於過敏性鼻炎治療（包括非藥物介入、口服抗組織胺、局部類固醇）後獲得改善。鼻炎症狀分數之改善和違反錯誤與偵測度（detectability）之改善具有正相關。注意力不足過動相關症狀改善之預測因子包括年齡、過敏性鼻炎藥物、過敏性鼻炎類型、以及多種過敏疾病。 碳酸酐酶催化轉化二氧化碳成為重碳酸根和氫離子，參與多種生理作用及病理現象。碳酸酐酶抑制劑已被使用於治療水腫、青光眼、肥胖、腫瘤、癲癇及骨質疏鬆等病症。此外，碳酸酐酶被報告過可影響中樞神經系統的單胺類神經傳導物質；而正腎上腺素和多巴胺失調亦是注意力不足過動症病理機轉之一。因此我們進一步研究碳酸酐酶抑制劑於自發性高血壓大鼠（spontaneously hypertensive rat，簡稱SHR）抑制過動和衝動之效果；自發性高血壓大鼠為迄今最可信的注意力不足過動症動物模式。實驗結果顯示碳酸酐酶抑制劑可以抑制SHR過動和衝動行為，於低劑量使用並無抑制認知功能之副作用。 綜合言之，我們的研究對於注意力不足過動症表徵（事件相關電位研究）、共病（過敏性鼻炎研究）、治療（碳酸酐酶抑制劑研究）提供更進一步了解。而這些結果啟發我們進一步研究，包括使用事件相關電位成份波評估注意力不足過動症藥物療效、尋找出參與過敏性鼻炎兒童注意力不足過動傾向可能的細胞激素或趨化素、以及進行以碳酸酐酶抑制劑治療注意力不足過動症之臨床試劑。

Attention-deficit hyperactivity disorder (ADHD) is characterized by persistent inattention and/or hyperactivity-impulsivity, presenting in more than one setting (e.g., home and school) before the age of twelve, and interfering with functioning or development. Current ADHD medications include CNS stimulants and norepinephrine reuptake inhibitor. Current ADHD drugs still have limited efficacies, and some patients with ADHD cannot tolerate the adverse effects. This study aimed to apply multidimensional approaches to characterize this heterogeneous and complex disorder. Inattention has been a major problem in children with ADHD, accounting for their behavioral and cognitive dysfunctions. Whether children with ADHD would show deficits in any subcomponent of the attention network warrants further investigation. We used mismatch negativity (MMN), P3a, and late discriminative negativity (LDN) as event-related potential (ERP) markers, under the passive auditory oddball paradigm to investigate the auditory change detection of children with ADHD. The results showed no MMN difference, but did show attenuated P3a and enhanced LDN to the large deviants for both pure and lexical tone changes in the ADHD group. Correlation analysis showed that children with higher ADHD tendency, as indexed by parents’ and teachers’ rating on ADHD symptoms, showed less positive P3a amplitudes when responding to large lexical tone deviants. Thus, children with ADHD showed impaired auditory change detection for both pure tones and lexical tones in both involuntary attention switching and attention reorienting for further evaluation. In addition to the above-mentioned study on children with typical ADHD, we also studied the attention and impulsivity in children with AR, age-matched controls and children with ADHD. Children with AR had significantly higher hyperactivity/impulsivity subscale scores, higher commission error, shorter reaction time, and more perseveration, compared to healthy controls. Risk factors for inattention and impulsivity in children with AR included younger age, male gender, higher AR symptom scores, persistent AR, moderate/severe AR, multiple atopic diseases, family history of atopy and possible comorbidity with ADHD. Then, at prospective follow-up study, we showed that higher ADHD scores in children with AR decreased significantly with AR treatment, compared to healthy controls. An improved AR symptom score was positively correlated with improved detectability, and commission error. Significant predictors for the improvement of ADHD scores included age, AR drugs, AR type, and multiple atopic diseases. Carbonic anhydrase (CA) affects monoamine transmission in the central nervous system, and dysregulation of noradrenergic and dopaminergic systems is involved in the pathology of ADHD. We thus investigated the effect of CA inhibitors on the hyperactivity and impulsivity of spontaneously hypertensive rats (SHRs), which is currently the best-validated animal model of ADHD. Our study showed that CA inhibitors can strain-specifically antagonize the hyperactivity and impulsivity of SHRs, without cognition impairment under a low dose. In conclusion, our studies augmented the understanding of this fascinating disease, ADHD, regarding its manifestation (the ERP study in auditory attention control), comorbidity (the AR study), and treatment (the CA inhibitor study). These studies inspire us to use the ERP markers in evaluating anti-ADHD drugs, find out possible cytokines/chemokines participating in the ADHD tendency of children with AR, and carry on the clinical trial of CA inhibitors in patients with ADHD.