臺灣博碩士論文加值系統

疼痛是一種人人都有的經驗。疼痛可以概分為生理性和病理性兩種。生理性的疼痛是使人能存活的重要功能之一；反之，病理性的疼痛是一種極為普遍的疾病，幾乎可以影響身上的任何部位。根據聯合國世界衛生組織所表的2010全球疾病負擔普查，張力性頭痛、偏頭痛(migraine)和下背痛的盛行率都排名在前十名之內。這些疼痛通常是陣發性的，但有時也可以是慢性而令患者更加難以忍受。疼痛如何從陣發性轉換成慢性是疼痛研究領域的重要課題之一。
偏頭痛是一種常見的頭痛，其特徵是單側、搏動式頭痛，嚴重度是中至重度，身體活動時會加重。合併出現的症狀包括噁心、嘔吐、怕光、怕吵等等。雖然大多數的人的偏頭痛是陣發性的，有些人則是慢性的，其定義是每個月頭痛十五天以上，持續超過三個月以上。雖然陣發性轉換慢性的機制未明，但內生性疼痛控制不良、中樞神經敏感化、止痛藥過度使用等等都可能有相關。止痛藥過度使用的定義是每個月使用止痛藥達十或十五天(依不同止痛藥而定)，持續三個月以上。過去的研究指出，慢性偏頭病人約有半數合併止痛藥過度使用。
首先，我們嘗試研究偏頭痛病人的腦幹內生性疼痛控制機制。我們以氫離子核磁共振頻譜分析(1H- magnetic resonance spectroscopy)研究腦幹中的大腦導水管旁灰質(periaqueductal gray)和兩側橋腦背部(dorsal pons)。本研究對收錄19個陣發性偏頭痛，53個慢性偏頭痛(30人合併止痛藥過度使用，23人不合併止痛藥過度使用)，以及16個對照組。結果發現陣發性偏頭痛的病人，對比於慢性偏頭痛和對照組，在橋腦背側有最高的N-乙醯天門冬酸(N-acetylaspartate)/肌酸(creatine)對比值。在偏頭痛病人族群中，N-乙醯天門冬酸/肌酸對比值和頭痛頻率 (右側 r = -0.350，P = 0.004；左側 r = -0.284，P = 0.019) 以及頭痛強度 (右側r = -0.286，P = 0.019；左側r = -0.244，P =0.045) 成反比。止痛藥的過度使用與磁振造影頻譜分析的數值則無明顯相關。上述增加的N-乙醯天門冬酸/肌酸對比值可能代表陣發性偏頭痛病人的橋腦背部有神經增生現象。我們認為陣發性偏頭痛在轉變成慢性偏頭痛的過程中，此區域的腦部可能有功能不良，這樣的推論可以從該比值與頭痛的頻率和強度成反比得到佐證。
在上述的研究之後，我們進一步想要研究偏頭痛對整個腦造成的神經可塑性的改變。我們執行了另一個以體素為基礎的形態測量(voxel-based morphometry)方法來分析磁振共振影像(magnetic resonance imaging)的研究。此研究共收錄了66個慢性偏頭痛患者(半數有止痛藥過度使用)，33個陣發性偏頭痛以及33個對照組。偏頭痛的病人，相較於對照組，有多處灰質體積減少。這些腦區域都出現在所謂的「疼痛基質」(pain matrix)的腦區域。我們進一步發現，慢性偏頭痛病人中合併止痛藥過度使用者，相對於未合併止痛藥過度使用者，在眶額葉(orbitofrontal cortex)及左側中枕葉腦迴(middle occipital gyrus)的灰質體積減少，而左側顳葉頂/海馬旁(temporal pole/parahippocampus)則有灰質體積增加。灰質體積減少可以解釋止痛藥使用頻率的變異性達31.1%。病人對治療反應良好者，在眶額葉有比較高的灰質體積。
總結來說，我們的研究顯示偏頭痛及其慢性化的過程中，牽涉到不同的神經可塑性的變化。這些發現可以幫助我們進一步了解偏頭痛對腦部的影響；而這樣的結果可能可以外推到其它的慢性疼痛疾病，雖然不同的疼痛疾病仍可能有各自不同的特性。

Pain is a universal experience that could be physiological or pathological. Physiological pain is a vital function in the survival of almost any individuals. On the other hand, pathological pain is a group of pandemic disorders involving almost every parts of our body. According to the Global Burden of Disease Survey 2010 conducted by World Health Organization (WHO), tension-type headache, migraine and low back pain rank the top ten most prevalent diseases of the human kind. These pain disorders are episodic in nature, but they could be chronic and thus more disabling. The mechanisms of how acute and physiological pain turns into a chronic and pathological condition are important issues in the research fields of pain.
Migraine is a common pain disorder characterized by unilateral and throbbing headache with moderate to severe intensity and aggravation by physical activity. Associated features include nausea, vomiting, phonophobia, photophobia, and so on. While most patients with migraine have episodic attacks (i.e. episodic migraine, EM), some of them may have chronic migraine (CM), defined as headache frequency ≥ 15 days per month, for more than three months. Though the mechanisms responsible for the transformation remains speculative, the dysfunctions in endogenous pain modulation, central sensitization and medication overuse (MO) have been proposed. Medication overuse is defined as using analgesics for ≥ 10 or 15 days per month, for more than 3 months. It has been reported that about half patients with CM have concomitant MO.
At first, we tried to explore the possible dysfunction of endogenous pain modulation in patients with migraine. We aimed to investigate the 1H- magnetic resonance spectroscopy (MRS) metabolite ratios at the periaqueductal gray and bilateral dorsal pons, the areas known to play important roles in the pain modulation. A total of 19 patients with EM, 53 patients with CM (with MO n = 30, without MO n = 23) and 16 control subjects completed the study. Patients with EM had the highest N-acetylaspartate (NAA)/creatine (Cr) ratio at the dorsal pons (right, P = 0.014; left, P = 0.034) in comparison with those with CM and controls. Among migraine patients, NAA/Cr ratios at dorsal pons were inversely correlated with headache frequency (right, r = -0.350, P = 0.004; left, r = -0.284, P = 0.019) and intensity (right, r = -0.286, P = 0.019; left, r = -0.244, P =0.045). Of note, MO was not associated with brainstem MRS ratios in patients with CM. The increased NAA/Cr levels may suggest neuronal hypertrophy at the dorsal pons in patients with EM. We proposed a progressive dysfunction of this region may occur during the transformation from EM to CM since the NAA/Cr levels declined with increasing headache frequency and intensity.
Based on the previous study, we further tried to explore the neural plasticity changes associated with migraine in a whole brain range. We conducted another brain magnetic resonance imaging (MRI) study analyzed by voxel-based morphometry. A total of 66 patients with CM (half with MO), 33 patients with EM and 33 controls completed the study. Gray matter volume (GMV) loss was noted in patients with migraine, as compared with controls. The involved brain regions were compatible with the so-called “pain matrix” brain areas. We further tested the effect of MO in patients with CM and the result showed GMV decrease in the orbitofrontal cortex and left middle occipital gyrus as well as a GMV increase in the left temporal pole/parahippocampus. The GMV changes explained 31.1% variance of the analgesics use frequency. The patients who responded to treatment had a greater GMV in the orbitofrontal cortex (P = 0.028).
In conclusion, our study showed different forms of neural plasticity changes associated with migraine and its chronification. These findings may help in understanding the effect of migraine to the brain that may be extrapolated to chronic pain, though differences may exist in different types of pain disorders.

Acknowledgments --------------------------------------------------------------------------- i
Chinese Abstract----------------------------------------------------------------------------- ii
English Abstract ----------------------------------------------------------------------------- iv
Table of Contents---------------------------------------------------------------------------- vi
List of Figures ------------------------------------------------------------------------------ ix
List of Tables ------------------------------------------------------------------------------- x
Chapter 1. Introduction ---------------------------------------------------------------------1
1.1 Background---------------------------------------------------------------------- 1
1.1.1. Overview of physiological and pathological pain-------------------- 1
1.1.2. Neural plasticity changes associated with pain----------------------- 1
1.1.2.1. Sensitization, central and peripheral------------------------------ 2
1.1.2.2. Habituation ----------------------------------------------------------- 3
1.1.2.3. Defective endogenous pain modulation -------------------------- 3
1.1.2.4. Neuroimaging and pain matrix ------------------------------------ 4
1.2 Migraine ------------------------------------------------------------------------- 5
1.2.1. Overview of migraine ---------------------------------------------------- 5
1.2.2. Neural plasticity changes associated with migraine ----------------- 8
1.2.2.1. Cutaneous allodynia and sensitization --------------------------- 8
1.2.2.2. Habituation ----------------------------------------------------------- 9
1.2.2.3. Defective endogenous pain modulation -------------------------- 10
1.2.3. Neuroimaging studies in migraine ------------------------------------- 11
1.2.3.1. Functional neuroimaging studies---------------------------------- 11
1.2.3.2. Structural neuroimaging studies----------------------------------- 12
1.2.3.2.1. Gray matter------------------------------------------------------ 12
1.2.3.2.2. White matter ---------------------------------------------------- 14
1.2.3.3. Biochemical neuroimaging studies ------------------------------- 15
1.3. Medication overuse and medication overuse headache ------------------ 15
1.4. Motivation and thesis objectives -------------------------------------------- 18
1.4.1. Motivation ----------------------------------------------------------------- 18
1.4.2. Thesis objectives---------------------------------------------------------- 19
Chapter 2. Brainstem 1H-MR Spectroscopy in Episodic and Chronic Migrain-----20
2.1. Aims and hypothesis -----------------------------------------------------------20
2.2. Methods --------------------------------------------------------------------------21
2.2.1. Subjects ---------------------------------------------------------------------21
2.2.2. Multi-voxel 1H-MRS of PAG and bilateral dorsal pons -------------21
2.2.3. Statistical analysis ---------------------------------------------------------23
2.3.3. Medication overuse-----------------------------------------------------------27
2.4. Discussion -----------------------------------------------------------------------28
Chapter 3. Gray matter changes related to medication overuse in patients with chronic
migraine--------------------------------------------------------------------------------------- 32
3.1. Aims and hypotheses -----------------------------------------------------------32
3.2. Methods --------------------------------------------------------------------------33
3.2.1. Participants -----------------------------------------------------------------33
3.2.2. Magnetic resonance imaging data acquisition -------------------------34
3.2.3. Voxel-based morphometry (VBM) analysis ---------------------------34
3.2.4. Statistical analyses of VBM data ----------------------------------------36
3.2.5. Clinical correlations -------------------------------------------------------37
3.2.6. Statistical analyses of clinical data --------------------------------------37
3.3. Results----------------------------------------------------------------------------38
3.3.1. Demographics --------------------------------------------------------------38
3.3.2. VBM results on MO and clinical correlations -------------------------40
viii
3.3.3. VBM results on CM compared with HCs -------------------------------43
3.4. Discussion-------------------------------------------------------------------------45
Chapter 4. Conclusions-----------------------------------------------------------------------50
4.1 Summary and implications ------------------------------------------------------50
4.2 Limitations--------------------------------------------------------------------- ----51
4.3 Future directions ------------------------------------------------------------------53
References --------------------------------------------------------------------------------------56
Appendices -------------------------------------------------------------------------------------76
List of Figures
Figure 1.1 The main areas of the pain matrix. ------------------------------------------------5
Figure 2.1 The selected voxels of interest in the MRS study. -----------------------------22
Figure 3.1 Gray matter volumes differences between chronic migraine with and
without medication overuse. --------------------------------------------------------------------40
Figure 3.2 Gray matter volume decrease in patients with chronic migraine, without or
with medication overuse. ----------------------------------------------------------------------- 43
List of Tables
Table 1.1 Diagnostic criteria of episodic migraine (migraine without aura and migraine
with aura) and chronic migraine.----------------------------------------------------------------6
Table 1.2 Diagnostic criteria of medication overuse headache. ---------------------------16
Table 2.1 Comparisons of demographics and headache profiles between episodic
and chronic migraine patients and normal controls.-----------------------------------------23
Table 2.2 Comparisons of the metabolite ratios of 1H-MR spectroscopy among controls
and patients with episodic and chronic migraine. -------------------------------------------26
Table 2.3 Comparisons of demographics and headache profiles between chronic
migraine patients with and without medication overuse. -----------------------------------27
Table 2.4 Comparisons of the metabolite ratios of 1H-MR spectroscopy between
chronic migraine patients with and without medication overuse. -------------------------28
Table 3.1 Demographics and headache profiles of the participants.c---------------------39
Table 3.2 Regions of gray matter volume change in chronic migraine with or without
medication overuse. ------------------------------------------------------------------------------41
Table 3.3 Baseline demographics and headache profiles of patients with chronic
migraine and medication overuse, with or without good treatment responses. ----------42
Table 3.4 Regions of gray matter volume decrease in patients with chronic migraine,
without or with medication overuse. ----------------------------------------------------------44

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