兒童妥瑞氏症之大腦結構改變與臨床表現之相關性

Abstract

研究背景: 妥瑞氏症為兒童神經科非常常見的疾病。常見的症狀包括不自主且重複性的動作和聲音，然而妥瑞氏症的致病機轉仍未被完全解答。過往的研究大多指出妥瑞氏症患者的基底核、前額葉以及連接其之間的神經迴路會產生病理性的變化，但是到底哪部分是此疾病最初的致病原因還沒有被發現。在妥瑞氏症的神經影像研究中發現其實妥瑞症病人的腦部影響非常廣泛，包括基底核、視丘、額葉、運動皮質、感覺皮質甚至枕葉及小腦都有影響。然而因為之前研究的受試者異質性太高，很多變因包括年齡、是否有共病、是否接受過治療、發病時間等皆沒有好好控制，以致於各個研究的結論差異頗大。於是本論文為首個針對無共病無接受治療的兒童妥瑞氏症患者做的腦部微結構異常之核磁共振研究。 研究方法: 本研究為單一醫學中心前驅性研究。收案人數為三十位無共病無接受治療的兒童妥瑞氏症患者及三十位年紀與性別吻合之健康受試者。研究用的核磁共振採用3特斯拉的機器，每位受試者會接受傳統T1及T2掃描以及Diffusion spectrum imaging (DSI)作為微結構病變之評估依據。DSI影像將使用tract-based automatic analysis (TBAA) 系統作為分析軟體並得出四種參數代表不同的微結構變化。除了比較病人組及對照租之間的差異，本研究還會將臨床疾病嚴重度與影像分析所得的數據作單變項及多變項線性迴歸分析，以找出影像變化與臨床疾病嚴重度之間的關係。 研究結果: 本研究發現右側的fronto-striatal tracts連接基底核與背外前額葉及中央前迴,以及雙側連接到背外前額葉的視丘輻射之gFA值在妥瑞氏症患者也顯著升高，而RD值在妥瑞氏患者也看到降低的趨勢，以上發現都暗示妥瑞氏症患者的連結度(connectivity)較高。妥瑞氏症患者在fronto-striatal tracts連接到中央前回這一條神經束的gFA值與病人妥瑞症最嚴重時的total tics severity score有負相關，而左側連接到背外前額葉的視丘輻射的RD值則與當下的motor tics severity scores有正相關。此結果也可能暗示gFA值較能反映出最嚴重時期的狀況而RD值較能反映當下的變化。 結論: 在無共病無接受治療的兒童妥瑞氏症患者在cortico-striatal-thalamo-cortical circuit的連結度是高於健康受試者的。然而在臨床嚴重度及影像結果的關聯性研究來說，反而是疾病程度越嚴重的病人其連結度越低。此結果暗示妥瑞氏症患者的連結度昇高為人體的回饋機制，症狀較輕微的病人是因為回饋機制較顯著,連結度上昇較多所以症狀較不明顯。然而因為本研究的收案人數仍偏少，日後仍須更大規模的樣本數來印證目前的結果。

Background: Gilles de la Tourette syndrome (GTS) is a common pediatric neurological disorder manifested with involuntary movements and sounds with premonitory urge. Although the full pathogenic mechanism is still fully recognized, most studies reported the abnormality of cortico-striato-thalamo-cortical (CSTC) circuits. The neuroimage studies of GTS showed the widespread influence in the whole brain. Besides, the components of CSTC circuits, the involvement of corticospinal tracts, occipital region, or cerebellum were also reported. However, Due to participant heterogeneity such as comorbidities, treatment, disease duration or age, the result could be inconsistent. This study is the first study of microstructural change in treatment naïve pure GTS pediatric patients in diffusion spectrum imaging (DSI). Methods: This is a single center prospective study. We totally enrolled 30 patients and 30 age- and gender-matched healthy volunteers. All of the scans were acquired by 3 tesla scanner with 32-channel phased array coil. MR imaging consisted of sagittal T1-weighted and axial T2-weighted imaging. A total 102 diffusion encoding gradients with the maximum diffusion sensitivity were applied in DSI. The generalized fractional anisotropy (GFA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were analyzed by tract-based automatic analysis and calculated by independent t-test with false discovery rate adjusted q value. The neural fiber tracts with significant difference between patients and healthy controls were selected to calculate clinical association with tics severity scores by simple and multiple linear regression Result: The GFA value of right fronto-striatal (FS) tract of dorsolateral prefrontal cortex (DLPFC), right FS tract of precentral gyrus and bilateral thalamic radiation of DLPFC showed significant higher in the patient group. The RD value of those neural fiber tracts also showed the borderline lower in the patient group. Both of these results suggested increased connectivity in patient groups. The GFA value of right FS tract of precentral gyrus had negative correlation with the total tic severity scores at the most severe condition and the RD value of left thalamic radiation of DLPFC had positive correlation with motor tics severity at presence. Conclusion: The microstructural change of treatment naïve pure pediatric GTS patients showed increased connectivity within the CSTC circuit. The clinical association revealed negative correlation between GFA values of right FS tracts of precentral gyrus and total tics severity score at the most severe condition and positive correlation between RD values of left thalamic radiation of DLPFC and motor tics severity score at presence. The above results suggested the compensatory mechanism