內側顳葉癲癇症患者大腦結構及功能連結之變化與其臨床意義:多模式磁振造影技術之研究

Altered Structural and Functional Connectivity and Its Clinical Relevance of Mesial Temporal Lobe Epilepsy: A Multi-Modality Magnetic Resonance Imaging Study

石曜嘉(Yao-Chia Shih)

指導教授 ： 林發暄

共同指導教授 ： 曾文毅(Wen-Yih Isaac Tseng)

國立臺灣大學/工學院/醫學工程學研究所/博士(2019年)

https://doi.org/10.6342/NTU201603697

摘要

前言
許多內側顳葉癲癇併發內側顳葉硬化症（mesial temporal lobe epilepsy with mesial temporal sclerosis, MTLE-MTS）的患者即使接受完善的抗癲癇藥物治療後，仍無法抑制癲癇發作，此類癲癇被稱作為頑固型癲癇。有許多頑固型癲癇病患即使切除致癇灶位，如海馬迴，術後依然會持續發作。近期有許多神經影像學的研究指出MTLE-MTS患者除了內側顳葉硬化，內側顳葉外的腦區也有結構與功能上的病變，而這些腦區，都有可能參予癲癇症的不正常放電，形成癲癇腦網絡。然而，關於癲癇腦網絡的範圍、特性，仍尚未有明確的定論。若能了解癲癇腦網絡病變和臨床特徵因子（如病程長度、癲癇發作頻率、發病年齡）之間的關聯性，就可以進一步釐清MTLE-MTS的神經病理機制，有助於改善擬定MTLE-MTS的治療和手術前的評估。

研究目標
本研究利用多模式的磁振造影技術（multi-modality magnetic resonance imaging, MRI），量測MTLE-MTS患者其大腦結構與功能上的變化，包含：海馬迴體積、大腦白質神經纖維束的微結構特性和腦區之間的功能性和有效性連結的強度，來偵測癲癇症病變腦區。另外，本研究更進一步地探討這些腦影像測量值與癲癇症的臨床特徵因子之間的關聯性，希望能進一步了癲癇腦網絡的特性、尋找重要的影像生物標記（imaging biomarkers）。

研究方法
論文中包括三個研究：（一）探討海馬迴硬化是否會造成鄰近神經纖維束：下扣帶迴（inferior cingulum bundle）的退化，形成癲癇腦網絡中一條從海馬迴對外連接大腦皮質的癲癇路徑。（二）將擴散頻譜磁振造影（diffusion spectrum imaging, DSI）量測到的全腦76條主要神經纖維束的微結構特徵，透過機器學習的分析方法可以推估大腦白質的生理年齡，又稱做腦年齡（predicted brain age）。可以利用這項技術探討右側患側MTLE-MTS、左側患側MTLE-MTS和健康對照組之間腦年齡的不同，藉此了解不同患側病患的白質病變分布差異。同時也探討病患的腦年齡與臨床特徵因子之間的相關性，以釐清癲癇腦網絡的特性和臨床意義。（三）從靜息態功能性磁振造影（resting-state functional MRI, rsfMRI）量測到的血氧濃度變化訊號，透過結構方程模型（structural equation modeling, SEM）分析左側和右側MTLE-MTS患者其海馬迴—間腦—扣帶迴腦網絡（hippocampal-diencephalic-cingulate network, HDC network）之間的有效性連結（effective connectivity）強度的變化，希望能找到兩種類型癲癇症共同的病變神經路徑，並進一步探討該神經路徑與癲癇發作頻率之間的關聯性，尋找癲癇反覆性發作的影像生物標記。

結果
【研究一】
15位左側MTLE-MTS成年患者及15位對照組的研究結果發現，患者患側的海馬迴體積和兩側下扣帶迴的微結構強度相較於對照組都呈現顯著的下降。患側海馬迴的體積和下扣帶迴的微結構強度呈現顯著正相關，而海馬迴的體積又與海馬迴—扣帶迴之間的功能性連結強度呈現負相關。

【研究二】
17位右側MTLE-MTS患者、18位左側MTLE-MTS患者和37位對照組的研究結果發現，右側MTLE-MTS患者的腦年齡相較於其他兩個組別呈現顯著老化。右側MTLE-MTS患者的腦年齡和實際年齡的差距（predicted age difference, PAD）分別與病程長度、發病年齡呈現顯著正相關和負相關。

【研究三】
16位右側MTLE-MTS患者、14位左側MTLE-MTS患者和37位對照組的研究結果發現，兩個病患組相較於對照組在海馬迴—間腦—扣帶迴腦網絡間的有效性連結上有著共同的變化。其中，大腦兩側連接前丘腦核—乳頭體的大腦路徑，其有效性連結的強度下降不僅為兩個病患組的共同病變特色，同時也與MTLE-MTS患者的癲癇發作頻率呈現顯著相關。

討論
【研究一】
海馬迴硬化不僅造成海馬迴萎縮也牽連了下扣帶迴，造成其微結構強度的變化，證實了下扣帶迴應與海馬迴之間有強烈的連結。推論當左側MTLE-MTS患者的海馬迴不正常放電，會沿著下扣帶迴傳出、或著是其他的致癲癇灶位會沿著下扣帶迴將癲癇樣放電傳回海馬迴，形成一個癲癇腦網絡路徑，加劇海馬迴和鄰近腦區的退化。

【研究二】
右側MTLE-MTS患者的腦年齡呈現加速老化，代表其白質損傷的程度和範圍都比左側MTLE-MTS患者還大。實際上比較兩個病患組的76條神經纖維束，也得到一樣的研究結果。右側MTLE-MTS患者的PAD和病程長度和發病年齡的強烈關聯性，說明右側MTLE-MTS的患者病程越長、發病年齡越早，全腦白質累積的傷害就越多，代表大腦會隨著病程拉長加速老化。另外，本研究發現右側病患的右側勾束（uncinated fasciculus）的病變為造成右側MTLE-MTS病患腦年齡加速老化的主要因素，代表MTLE-MTS不僅是顳葉相關的疾病，也與前額葉有關。

【研究三】
左、右患側的MTLE-MTS患者的功能性退化都發生在大腦左、右側前丘腦核—乳突體這兩條路徑。這兩條路徑的有效性連結強度與癲癇症發作頻率呈現顯著相關，說明了這個路徑在患者大腦中產生和傳遞癲癇樣放電的神經病理機制上扮演著重要的角色，將治療目標放在這條路徑上，或許會有效地抑制癲癇症的發作。

結論
這三項研究顯示，透過多模式磁振造影技術，可以深入了解癲癇腦網絡的特性，與臨床癲癇發作特徵因子的相關性研究更可進一步釐清單側MTLE-MTS其癲癇腦網絡的發展，希望對於臨床診斷與治療有其貢獻和助益。

關鍵字

內側顳葉癲癇症 ； 癲癇腦網絡 ； 擴散頻譜造影 ； 靜息態功能性磁振造影 ； 體積形態學分析 ； 影像生物標記

並列摘要

Introduction: Many patients with mesial temporal lobe epilepsy with mesial temporal sclerosis (MTLE-MTS) fail to benefit from adequate medication for seizure control. There are many patients with intractable MTLE-MTS who have undergone resection of the epileptogenic focus, such as the hippocampus, but will continue to have seizures after surgery. Recent neuroimaging studies have indicated that in MTLE-MTS patients, in addition to mesial temporal lobe sclerosis, the brain regions outside the mesial temporal lobe also have structural and functional alterations; these regions may comprise a pathologic circuit to generate and spread epileptic activity, namely the epileptic network. However, the affected brain regions and clinical relevance of epileptic network remain unclear. Thus, investigating association between epileptic network and clinical factors (e.g., epilepsy duration, seizure frequency, and age of onset) will be helpful in clarifying the neuropathological mechanism and improving medical treatments and preoperative evaluation of MTLE-MTS.

Objectives: We performed multi-modality magnetic resonance imaging (MRI) to measure brain structure and function in patients with unilateral MTLE-MTS, including hippocampal volume, white matter microstructural properties, and intrinsic effective connectivity (iEC) between brain regions. These measurements can detect potential epileptic networks in unilateral MTLE-MTS. In addition, we further investigated correlations between different brain imaging measurements and clinical factors to identify the important imaging biomarkers, which can be served to improve clinical treatment and diagnosis.

Methods: This dissertation includes three studies: (1) explore whether hippocampal sclerosis causes the degeneration of inferior cingulum bundle (iCB), which could be a potential epileptic pathway connecting the hippocampus with cortical regions. (2) We performed diffusion spectrum imaging (DSI) to obtain the white matter features of 76 major fiber tracts over the whole brain. We estimated the differences between brain-predicted age and chronological age (PAD scores) based on these white matter features via a machine-learning-based analysis. Therefore, this technique can be used to assess difference in PAD between the right MTLE-MTS patients, the left MTLE-MTS patients, and healthy controls, so as to explore different epileptic networks between two subtypes of unilateral MTLE-MTS. The correlation between PAD and clinical factors of patients can help clarify the progression of epilepsy networks and their clinical relevance. (3) We performed structural equation modeling (SEM) analysis to analyze resting-state functional MRI (rsfMRI) blood-oxygen-level dependent imaging (BOLD) signals, and estimate intrinsic effective connectivity (iEC) within the hippocampal-diencephalic-cingulate network (HDC) network. We aimed to identify the common iEC alterations related to seizure recurrence in patients with left and right MTLE-MTS.

Results: (1) Patients with left MTLE-MTS showed that the hippocampal volume and microstructural of bilateral iCB of patients were decreased as compared to healthy controls. There was a significant positive correlation between the volume of ipsilateral hippocampus and the structural connectivity of ipsilateral iCB; There was a significant negative correlation between the volume of ipsilateral hippocampus and the intrinsic functional connectivity (iFC) between the hippocampus and posterior cingulate cortex. (2) In 17 patients with right MTLE-MTS, 18 patients with left MTLE-MTS, and 37 patients with MTLE-MTS, we found that right MTLE-MTS patients had older brain age compared to other two groups. The brain predicted age difference (PAD) was positively and negatively correlated with epilepsy duration and age of onset in patients with right MTLE-MTS, respectively. (3) In 16 patients with right MTLE-MTS, 14 patients with left MTLE-MTS, and 37 patients with MTLE-MTS, we found the common iEC alterations in the HDC network in both patient groups. The decreased iEC on bilateral mammillothalamic connections were not only the common alterations, but also associated with seizure frequency in both patient groups.

Discussion: (1) The hippocampal sclerosis lead to the degeneration of ipsilateral iCB, indicating that the iCB tightly connects to the hippocampus. Thus, iCB is assumed to receive antegrade epileptic activity from secondary epileptogenic regions and propagate back to the hippocampus. (2) Right MTLE-MTS patients showed accelerated aging, implying more extensive and severe white matter damages than left MTLE-MTS patients. In fact, when comparing the white matter properties of 76 tract bundles between two patient groups, the same result was obtained. The strong relationships of PAD with epilepsy duration and age of onset in patients with right MTLE-MTS indicate that patients with longer epilepsy duration or earlier age of onset had more aggravated white matter damages, representing the accelerated brain aging along disease course. The right uncinate fasciculus was the white matter feature that most contributed to the increased PAD scores, suggesting that MTLE-MTS is not only a disease related to temporal lobe, but also involved the brain regions of frontal lobe. (3) Aberrant iEC on bilateral mammillothalamic connections is the common neuropathological change of unilateral TLE-MTS, and might be a potential imaging biomarker to predict seizure recurrence in patients.

Conclusion: Multi-modality MRI analyses can facilitate the discovery of epileptic network pathways and the development of novel targeted therapies for left and right TLE-MTS.

並列關鍵字

mesial temporal lobe epilepsy ； epileptic network ； diffusion spectrum imaging ； resting-state functional magnetic resonance imaging ； volumetric study ； imaging biomarkers

參考文獻

Abdi, H., Williams, L.J. (2010) Principal component analysis. Wiley Interdisciplinary Reviews: Computational Statistics, 2:433-459.

Aggleton, J.P., O’Mara, S.M., Vann, S.D., Wright, N.F., Tsanov, M., Erichsen, J.T. (2010) Hippocampal–anterior thalamic pathways for memory: uncovering a network of direct and indirect actions. The European Journal of Neuroscience, 31:2292-2307.

Aggleton, J.P., Saunders, R.C., Wright, N.F., Vann, S.D. (2014) The origin of projections from the posterior cingulate and retrosplenial cortices to the anterior, medial dorsal and laterodorsal thalamic nuclei of macaque monkeys. Eur J Neurosci, 39:107-23.

Aggleton, J.P., Wright, N.F., Rosene, D.L., Saunders, R.C. (2015) Complementary Patterns of Direct Amygdala and Hippocampal Projections to the Macaque Prefrontal Cortex. Cereb Cortex, 25:4351-73.

Aggleton, J.P., Wright, N.F., Vann, S.D., Saunders, R.C. (2012) Medial temporal lobe projections to the retrosplenial cortex of the macaque monkey. HP, 22:1883-900.