臺灣博碩士論文加值系統

慢性疼痛是指疼痛持續三到六個月以上，不僅影響個人生活品質，也造成社會成本的增加，甚至提高了自殺率。這類的病人有較高的壓力指數和精神疾患，包括憂鬱、焦慮、失眠，也常合併自律神經失調；而憂鬱症、焦慮症、或創傷後症候群的病人也有較高機率產生慢性疼痛。大腦的邊緣系統和自律神經系統，與情緒的產生、壓力的反應和調節、以及疼痛的感知和調解有關。此外，邊緣系統、自律神經系統、和下視丘/腦下垂體/腎上腺軸線的壓力系統等腦部許多區域都有連結。由於疼痛、情緒、壓力三者之間的緊密關聯，暗示了大腦邊緣系統和自律神經系統與慢性疼痛的連結。
邊緣系統中的兩個結構，海馬迴與杏仁體，與壓力的調節和壓力所導致的焦慮關係密切。過去的研究顯示長期或過度的壓力會讓海馬迴萎縮；反之，慢性壓力所伴隨的焦慮則和較大的杏仁體體積有關。而在慢性疼痛的病人中，海馬迴和杏仁體的體積變化則沒有定論。目前我們仍不清楚在疼痛慢性化的過程，邊緣系統如何變化。
本論文選定兩個疼痛相關疾病族群，偏頭痛與纖維肌痛症，來作為研究對象。偏頭痛是一種頭痛疾患，依發作頻率可分為陣發性偏頭痛和慢性偏頭痛。纖維肌痛症則是一種慢性廣泛性疼痛疾病，時常合併疲倦、醒來時沒有睡飽、記憶力或專注力下降、以及憂鬱。本論文分成三個實驗。實驗一，我們探討纖維肌痛症患者的自律神經功能變化。我們發現纖維肌痛症患者有較低的自律神經功能和副交感神經功能；其中，疾病嚴重度較高者的自律神經功能更為低落。在實驗二當中，我們探討邊緣系統如何隨著偏頭痛慢性化而有結構的變化。我們假設每次的偏頭痛發作對大腦是個壓力源(stressor)，針對不同發作頻率的偏頭痛病人，我們測量其海馬迴和杏仁體的體積。結果發現雙側的海馬迴皆會隨著頭痛頻率的增加，體積先變大再變小；此外，較小的右側海馬迴，和兩年後較差的頭痛預後有關，杏仁體則無關。實驗三探討慢性疼痛與自殺的關係。由於偏頭痛和纖維肌痛症互為共病症(comorbidity)，而這兩個疼痛相關疾病都有較健康人高的自殺率，因此我們研究在偏頭痛的族群中，合併纖維肌痛症患者的比例、臨床特徵、以及自殺率。結果發現偏頭痛合併纖維肌痛症的患者有相當高的自殺意念和企圖，且在控制了情緒及其他影響因子後，合併纖維肌痛症和自殺意念仍顯著相關。
總結以上，慢性疼痛與邊緣系統、壓力系統、和自律神經系統密切相關。疼痛慢性化的過程，海馬迴的體積先有適應性增加、後有代償不良的體積萎縮，萎縮的海馬迴伴隨著較差的壓力調節能力，導致疼痛更易發生，這個惡性循環可能是疼痛慢性化的機轉。而慢性疼痛病人邊緣系統與壓力系統的失調，反映到其所輸出及調控的自律神經系統，導致自律神經失衡；較差的壓力調解能力或許也是慢性疼痛病人有較高自殺意念的肇因。

Chronic pain is pain that lasts longer than 3 to 6 months. It has huge impact on the individual and the society, and is even associated with higher suicide risk. Patients with chronic pain are usually associated with higher stress level, anxiety, depression, sleep disturbance, and autonomic dysfunction, while patients with psychiatric disorders and post-traumatic stress disorder are more likely to suffer from chronic pain. The limbic system and autonomic nervous system are responsible for emotion, stress response and modulation, and pain processing and modulation. In addition, the two systems and the hypothalamus-pituitary-adrenal axis are anatomically and functionally connected. Given the mutual relationships among stress, emotion, and pain, imply the altered structure or function of the two systems in patients with chronic pain.
Two limbic structures, hippocampus and amygdala, are closely related to stress and stress-related anxiety. Previous studies have shown that overt or chronic stress can cause hippocampal atrophy; in contrast, chronic stress with increased anxiety level is associated with increased amygdala volume. In patients with chronic pain, the changes of hippocampal and amygdala volume are inconsistent in different studies. Up till now, it remains elusive how the limbic structures adapt to pain chronificaton.
The current study focused on two pain disorders, migraine and fibromyalgia. Migraine is a headache disorder, and is characterized into episodic migraine and chronic migraine based on the frequency of headache attack. Fibromyalgia is a chronic wide spread pain disease, commonly associated with fatigue, unrefreshing sleep, cognitive function decline, and depression. There are three dimensions of our study. First, we investigated the heart rate variability in patients with fibromyalgia, and the results reflected that these patients have autonomic dysfunction, particularly the parasympathetic nervous system, and those with more severe overall symptoms have worse autonomic function. In the second study, we investigated how the limbic structures adapt to the process of pain chronificaton. We assume each migraine attack is a stressor to the brain and explored the volumes of hippocampus and amygdala in migraine patients with different attack frequency. It showed that the bilateral hippocampus and left amygdala increased followed by decreased in volume with increasing headache frequency. Further, a smaller volume of the right hippocampus predicted poorer headache outcome. In the third study, we investigated the suicide risk in migraine patients comorbid with fibromyalgia. We found that migraineurs comorbid with fibromyalgia carried high suicide ideation and attempt; in addition, fibromyalgia is an independent predictor for suicide when controlling other psychiatric factors.
In conclusion, chronic pain is closely related to the limbic system, the stress system, and the autonomic nervous system. With repetitive pain, hippocampus adaptive increases followed by maladaptive decreased in volume. And the decreased volume may be associated with vulnerability to stress .This viscous cycle may underlie the mechanism of pain chronification. The dysfunction and dysregulation of the limbic and the stress system affect its output and modulation of the downstream autonomic nervous system, resulting in autonomic dysfunction. The vulnerability to stress may also be responsible for the higher suicide risk in patients with chronic pain.

Table of Contents
Acknowledgments……………………………………………......……..I
Chinese abstract……………………………………………….…….…II
English abstract……………………………………………….…….…IV
Abbreviations……………………………………………….………….VI
Table of Contents……………………………………………………..VII
List of Tables …………………………………………...………….….XI
List of Figures………………………………………………..……….XII

Chapter 1. Introduction ……………………………………..…………1
1.1 Chronic pain……………………………………………………………………...1
1.1.1 Definition, prevalence, and social impact of chronic pain …………..…..1
1.1.2 Clinical manifestation of chronic pain ………………………...………….1
1.1.3 Mechanism of chronic pain—links to stress and limbic structures……..2
1.1.4 Migraine and chronic migraine……………………………………………3
1.1.5 Firbomyalgia………………………………………………………………..3
1.2 Stress………………………………………………………………………………4
1.2.1 Definition of stress, allostasis, and allostatic load………………………...4
1.2.2 Stress and the autonomic nervous system…………..…………………….4
1.2.3 Stress and the HPA axis……………………………………………………5
1.2.4 Stress and hippocampus…………………………………………………...6
1.2.5 Stress and amygdala………………………………………………………..6
1.2.6 Stress and chronic pain…………………………………………………….7
1.2.7 Stress and migraine…………………………...……………………………8
1.3 Autonomic nervous system in response to pain and stress…………………….8
1.3.1 Autonomic nervous system………………….…………………..……...….8
1.3.2 Central modulation of the autonomic nervous system…………………..9
1.3.3 Autonomic dysfunction in patients with fibromyalgia…………………..9
1.3.4 Heart rate variability……………………………………………………..10
1.4 Limbic plasticity in response to stress and pain………………………………11
1.4.1 The limbic system…………………………………………………………11
1.4.2 Neural plasticity…………………………………………………….……..11
1.4.3 Hippocampal plasticity in response to stress, migraine, and chronic pain………………………………………………………………………………12
1.4.4 Amygdala plasticity in response to stress, migraine, and chronic pain………………………………………………………………………………13
1.5 Chronic pain and suicide……………………………………………………….13
1.5.1 Suicide……………………………………………………………………..13
1.5.2 Chronic pain and suicide…………………………………………………14
1.5.3 Migraine, fibromyalgia, and suicide risk………………………………..15
1.6 Motivation and thesis objective………………………………………………...15

Chapter 2. Autonomic dysfunction in fibromyalgia patients……….18
2.1 Aims and hypothesis………………………………………………………….…18
2.2 Material and methods…………………………………………………………..18
2.2.1 Study design and target population…………………………………….18
2.2.2 Diagnosis of FM………………………………………………………….19
2.2.3 Questionnaires……………………………………………………...……19
2.2.4 Measurement of HRV…………………………………………...………20
2.2.5 Statistical analysis……………………………………..………………...21
2.3 Results…………………………………………………………………………...22
2.3.1 Demographics……………………………………………………………22
2.3.2 FM profiles and impacts in the 3 subgroups of FM patients and HC..22
2.3.3 Psychiatric features and sleep quality in the 3 subgroups of FM patients and HC………………………………………………………………..24
2.3.4 Autonomic profiles in the 3 subgroups of FM patients and HC……....25
2.4 Discussion………………………………..………………………………………25
2.5 Limitation………………………………………………………………………..27

Chapter 3. Hippocampus and amygdala volume in relation to migraine frequency and prognosis……………………………………28
3.1 Aims and hypothesis…………………………………………………………….28
3.2 Material and methods…………………………………………………………..29
3.2.1 Study design……………………………………………………………...29
3.2.2 Participants………………………………………………………………30
3.2.3 Follow-up…………………………………………………………………31
3.2.4 MRI data acquisition……………………………………………………31
3.2.5 Volumetric estimation of global brain tissues………………………….31
3.2.6 Subcortical volumetric analysis of structural brain MRI…………….32
3.2.7 Statistical analysis……………………………………………………….32
3.3 Results…………………………………………………………………………...33
3.3.1 Demographics and distribution of headache frequencies…………….33
3.3.2 Volumetric changes of hippocampus in relation to headache frequency……………………………………………………………………….35
3.3.3 Volumetric changes of amygdala in relation to headache frequency……………………………………………………………………….36
3.3.4 Association between limbic structural volumes and migraine outcome………………………………………………………………………...37
3.4 Discussion………………………………………………………………….…….37
3.5 Limitation………………………………………………………………………..40

Chapter 4. Suicide risk in patients with migraine and comorbid fibromyalgia……………………………………………………………41
4.1 Hypothesis and aims…………………………………………………………….41
4.2 Material and methods…………………………………………………………..41
4.2.1 Study design……………………………………………………………...41
4.2.2 Participants..……………………………………………………………..41
4.2.3 Diagnoses of migraine and FM…………………………………………42
4.2.4 Questionnaires…………………………………………………………...42
4.2.5 Statistical analysis……………………………………………………….44
4.3 Results…………………………………………………………………………...45
4.3.1 Migraine classification and clinical features…………………………...48
4.3.2 Frequency and clinical features of comorbid FM in migraine patients…………………………………………………………………………48
4.3.3 Suicide risk in subtypes of migraine and its association with comorbid FM………………………………………………………………………………48
4.3.4 Suicide risk and its association with depression, comorbid FM, and other covariates………………………………………………………………...49
4.4 Discussion………………………………………………………………………..52
4.5 Limitation………………………………………………………………………..54
Chapter 5. Summary and Future works……………………………...56
Chapter 6. References……………………………………..…………..58

List of Tables
Table 1. Demographics, FM profiles, clinical impacts, and autonomic profiles in patients with FM and HC…………........………………………………..23
Table 2. Clinical profiles and imaging data in patients with migraine and healthy control subjects…………………………………………………….……..34
Table 3. Demographic data, headache characteristics, clinical impacts, comorbidity of FM and suicide risk in migraine patients …..………...46
Table 4. Different models for suicide risk associated with comorbid FM in patients with migraine….………………………………………………..51
Table 5. Independent risk factors for suicidal ideation and attempt in migraine patients……………………………………………………………………52

List of Figures
Figure 1. Stress may affect the central nervous system (limbic structures), the peripheral nervous system (autonomic nervous system), and behavior of an individual…………………………………………………...………17
Figure 2. Bidirectional relationship between headache frequency and hippocampus volume……………………………………………………..28
Figure 3. Volumetric changes of the bilateral hippocampi with headache frequency………………………………………………………………….35
Figure 4. Volumetric changes of the bilateral amygdala with headache frequency
……………………………………………………………………………..36
Figure 5. Suicide risk in migraine patients, migraine with comorbid depression, and with comorbid depression and FM..…………….....………………50
Figure 6. Chronic pain changes the volumes of stress-related limbic structures, impairs the function of the autonomic nervous system, and increases suicide risk……………………………………………………………..…57

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