注意力不足過動症兒童青少年患者情緒調節困難之相關神經機轉

The Neural Substrates of Emotion Dysregulation in Children and Adolescents with ADHD

蔡佳叡(Chia-Jui Tsai)

指導教授 ： 高淑芬

共同指導教授 ： 吳文超(Wen-Chau Wu)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2022年)

https://doi.org/10.6342/NTU202200884

摘要

背景
注意力不足過動症(Attention-Deficit/Hyperactivity Disorder, 以下簡稱ADHD)是常見的兒童青少年精神疾病，盛行率約5%。ADHD為大腦異常的神經發展疾患，患者的大腦體積、白質完整性、特定腦區的活化程度，及不同腦區間的連結程度都跟一般族群有些差異，然而結果在各研究間並不一致，造成結果差異的原因很多，包括收案族群本身特徵、異質性表現、治療、共病、研究工具等等。情緒調節困難(emotion dysregulation, ED)為常見的ADHD相關特徵，不只影響ADHD患者生理、症狀表現，也是造成ADHD異質性表現及功能與預後不佳的重要因子。本研究主要探討ED對ADHD兒童青少年患者腦部結構及靜息態腦部功能連結的影響及其關聯性。
研究目的與方法
本研究收集了140個7-18歲ADHD兒童青少年患者以及140個典型發展孩童對照組(typically developing control, TDC)的不同模態腦部MRI影像來進行分析，並根據模態所需不同的篩選條件選取個案。使用體積形態學分析voxel-based morphometry (VBM)探討局部腦區體積，透過擴散頻譜影像diffusion spectrum imaging (DSI)的造影方法來分析白質纖維束完整性，使用靜息態功能性磁振造影resting-state functional MRI (rsfMRI)來分析功能性腦網絡的連結強弱。並以Child behavior checklist情緒調節量表(Dysregulation Profile of CBCL, CBCL-DP)，來評估情緒調節困難程度的高低(ED程度)。
本研究有兩個研究目標。第一，比較ADHD和TDC兩組受試者腦部神經區的差異，在控制或者不控制情緒調節能力程度時，是否會受到影響。第二，了解ADHD和TDC兩組受試者的大腦結構、腦部活性，在哪些腦部神經區的區域大小、活性以及白質束完整性，會和情緒調節困難的程度有相似或者相異的關聯，特別是在過去認為與情緒調節相關的位置、白質束和功能網絡，是否會與情緒調節困難程度之間有高度關聯性，或是在不同組會出現不同方向的改變。
研究結果
在未考慮ED程度時，ADHD和TDC在局部大腦體積、白質束完整性和靜息態腦網絡內在功能連結(iFC)強弱均有找到顯著組間差異。而在控制了ED程度之後，兩組的局部腦體積差異未受到明顯影響，但白質束完整性和靜息態功能連結原先的組間差異大多消失或變得不顯著，尤其是白質束中arcuate fasciculus (AF)、uncinate fasciculus (UF)的纖維完整性，和功能性網絡default-mode network (DMN)、frontoparietal network (FPN)、dorsal attention network (DAN)及與precuneus所連結的區域網絡間的iFC異常，其中發現ED程度對DMN靜息態的功能連結有著高度影響。
至於在情緒調節困難程度與大腦結構/功能關聯性高低的探討，我們發現ADHD組與TDC組在特定的腦區隨著情緒調節困難程度的變化，有著不同方向的變化關係。包含dorsolateral prefrontal cortex (DLPFC)的灰質體積大小、牽涉到一整組top-down與bottom-up調節情緒白質束之完整性、及DMN的iFC高低。另外，我們也發現在anterior cingulate cortex (ACC)、middle occipital gyrus (MOG)和inferior frontal gyrus (IFG)的灰質體積隨著情緒調節困難程度的變化上，ADHD組與TDC有相同方向的改變，都隨著ED而增加體積，但在TDC組較為明顯。
討論
過去探討ADHD大腦影像研究結果不一致的現象，有一部分可能是受到ED程度的影響，特別是白質束完整性及靜息態腦網絡的iFC異常，在考慮了ED的嚴重程度後，ADHD和TDC許多組間差異會完全消失，這些差異的改變雖然不能直接就等於ED在ADHD中的問題位置，但值得作為深入探討在ADHD的情緒調節異常可能的相關神經區。我們過去所發現的ADHD特定腦區、白質束完整性異常及功能網絡連結強弱等結果，並非完全由ADHD的診斷做解釋，部分可能是情緒調節困難的嚴重程度在中間扮演著調節效果。
研究結果也顯示ADHD和TDC在情緒調節困難程度和特定腦區與白質束的變化、靜息態功能連結的好壞大多存在著不同的趨勢，例如在局部腦區大小(如：DLPFC)、白質纖維束(AF、UF、CC所連結相關腦區的白質束)以及DMN內的功能性連結，在兩組間隨著情緒調節困難程度有著不同方向的變化，而這些相關的腦區、白質束、功能網絡與在機轉上與情緒調節相關，意味著ADHD和TDC在調節情緒時，可能是採用不同的機制，這些變化可能是專屬於ADHD情緒調節的問題。然而，跟過去的研究結果不同，我們也發現ADHD和TDC情緒調節困難程度和腦區的關係，像是在ACC、MOG和IFG的灰質體積，在兩組均會隨情緒調節困難程度而增加，這些腦區可能代表的是一般調節情緒所牽涉到的腦區。
我們所採用的三種MRI影像模組分析雖然因分析方式，影像處理，個案組成、理論基礎的不同，無法直接做比較。但在其中所找到的異常區域和位置，彼此之間有許多相關聯或重疊的地方，例如區域體積中找到的DLPFC，白質束中的CC of SMA、CC of superior parietal lobule、SLF、cingulum of hippocampal component，及靜息態研究中找到的DMN、FPN，可能可在未來作為ADHD情緒調節異常的幾個關鍵位置與腦部網絡指標。另外我們在兩個研究目標間也同時發現AF、UF、TR to precentral gyrus、ILF的白質完整性、和DMN的內在功能聯結，都在第一部份組間差異的分析中受到控制ED程度的影響，且也都在第二部份關聯性的分析中發現它們在ADHD和TDC與ED程度會有不同方向的變化。因此推測這幾個相關神經區在情緒調節困難與ADHD之間扮演十分重要的角色。
結論
過去探討ADHD大腦影像研究結果出現不一致的現象，有部分可能是受到情緒調節困難程度的影響。藉由本研究系統性的探討，我們可更清楚情緒調節困難對ADHD異質性表現的影響與可能牽涉的神經病理機轉和相關神經區。未來在治療ADHD和其相關症狀時，就能有更全面的考量以及更明確的指標，來幫助達到ADHD孩童的最大利益，讓更多的ADHD孩子和家長受益。

關鍵字

注意力不足過動症 ； 情緒調節困難 ； 體積形態學分析 ； 擴散頻譜影像 ； 靜息態功能性磁振造影

並列摘要

Background
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent and childhood-onset neurodevelopmental disorder. The differences between ADHD and typically developing controls (TDC) were inconsistent across brain imaging studies, and heterogeneity of ADHD might be part of the cause. ADHD has high prevalence of co-occurring emotion dysregulation (ED), reported as 40–70% across studies. Youths with ADHD and ED are more likely to have more ADHD symptoms and poor outcomes longitudinally. There’s a lack of study focusing on neural correlates of ED in ADHD.
Methods
The brain imaging of 140 children and adolescents with ADHD and 140 typically developing control (TDC), aged 7 to 18 years old, were collected. ED severity was estimated according to the dysegulation profile of Child Behavior Checklist (CBCL-DP). We explored the impact of ED on the neural mechanism of ADHD using several MRI methods including voxel-based morphometry (VBM) for regional brain volume, diffusion spectrum imaging (DSI) for white matter tract integrity, and resting-state functional MRI (rsfMRI) for intrinsic functional connectivity (iFC). First, we explored whether there is significant group difference change between ADHD and TDC when ED is included in the model or not. Second, we explored whether ADHD and TDC had similar or distinct neural correlates underpinning ED.
Results
Controlling ED did not have much influence on the regional brain volume differences, but have much impact on the group differences of the WM tract integrity and iFC. The group differences of WM intergrity between AF, UF and TR of precentral tracts disappeared, and an additional abnormality over ILF emerged. As for rsfMRI, many RSNs abnormalities disappeared after controlling ED, especially the iFC of default-mode network (DMN). It was thought to be highly influenced by ED in ADHD.
As for the relationship between neural correlates and ED severity, we found some regional brain volume had similar patterns of change with ED between ADHD and TDC. In the anterior cingulate, middle occipital gyrus, IFG, both groups had volume increased with ED. However, in the regional volume of DLPFC, group-by ED interaction was noted. In the DSI analysis, the integrity of a set of WM tracts found in CCA which interconnect regions principally involved in emotion processing, regulation, and cognitive control, had distinct pattern of change with ED. Also, in the rsfMRI analysis, the iFC of DMN with angular gyrus had different patterns with ED severity between ADHD and TDC.
Discussion
Our result found the inconsistency of previous ADHD brain imaging studies might be partly moderated by the degree of ED. Controlling ED had limited influence to regional GM volume differences, but had prominent effects on the differences of WM integrity of WM tracts and the iFC of RSNs, especially in DMN. We found ADHD and TDC had different trends of WM integrity and iFC change with ED. Compared to normal controls, ADHD might have different neuro-mechanism while regulate emotions. Thus, it is worth to take some ADHD-specific interventions for their ED problems. However, we also found some brain regions that had similar patterns of change with ED.
Besides, we found inter-correlated correlates across different MRI techniques and also same neural correlates across two study aims of current thesis. These neural correlates might be highly correlated with ED in ADHD, and could play as possible neural correlates of ED in ADHD.
Conclusion
The inconsistent results of ADHD MRI studies may be explained by the effects of ED, and should be considered in the future analysis. In addition, ADHD and TDC had similar and distinct neural mechanisms underpinning ED, which may facilitate the development of targeted intervention toward their ED problems in the future.

並列關鍵字

Attention-Deficit/Hyperactivity Disorder (ADHD) ； emotion dysregulation (ED) ； voxel-based morphometry (VBM) ； diffusion spectrum imaging (DSI) ； resting-state functional MRI (rsfMRI)

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