臺灣博碩士論文加值系統

女性疼痛的議題近年來逐漸被重視，原發性痛經(Primary dysmenorrhea, PDM)是指沒有骨盆腔病變下所引發的月經疼痛，在育齡女性中一直是個困擾的疾病。當中有10到20 %的PDM女性是屬於嚴重程度的痛經，這些患者大多無法藉由常規的止痛藥物與物理治療緩解疼痛，並且會因為嚴重痛經對其日常生活造成影響。而痛經的女性在日後發展成慢性疼痛（例如：纖維肌痛症）的比例較無痛經女性高。
過去研究中發現環境壓力一直是痛經的危險因子，長期痛經困擾的女性在心理狀態上會有較高的焦慮與憂鬱特質，且會造成疼痛感知、疼痛調控與情緒處理等相關腦區之結構與功能異常，其中也包含壓力調控相關神經迴路（如：下視丘、海馬迴）。海馬迴是神經新生重要腦區且易受環境壓力影響，腦源性神經滋養因子(Brain-derived neurotrophic factor, BDNF)是一種幫助細胞生長、存活的蛋白質，且高濃度分布與基因表現於海馬迴組織中。環境壓力產生時BDNF表現會受到抑制，進而導致海馬迴細胞受到損害。過去研究中已經證實，BDNF基因中的Val66Met多態性與海馬迴結構與焦慮、憂鬱之心理狀態有所關連。過去痛經相關研究中也發現，BDNF Val66Met多態性與痛經女性在疼痛感知、疼痛抑制與情緒調節處理迴路異常有關，但對於不同BDNF Val66Met基因型在原發性痛經女性的海馬迴結構差異目前尚未釐清。本研究除了探究BDNF Val66Met基因型對於原發性痛經女性海馬迴結構的影響之外，更深入討論與痛經嚴重程度的關聯性。
此外，過去研究中已經發現藉由刺激大腦運動皮質區，能夠有效緩解疼痛。我們使用經顱直流電刺激(Transcranial direct current stimulation , tDCS)介入，藉由刺激運動皮質區，進而減緩嚴重原發性痛經受試者疼痛感受。除了討論臨床止痛效益外，我們也針對下行性疼痛抑制系統中大腦導水管旁灰質(Periaqueductal gray matter, PAG)其功能性連結，進而探討tDCS對於疼痛緩解的調控機轉，尤其是PAG與運動皮質區域之間連結的探討。
本論文主要研究目的將討論不同痛經程度對於大腦神經適應與可塑性之影響。論文分成兩大部分，第一部分將討論不同痛經程度患者在大腦結構網路（研究一）以及BDNF Val66Met基因多態性在海馬迴結構之差異（研究二）。第二部分我們探討嚴重原發性痛經女性，經由運動皮質區tDCS刺激介入後，對於疼痛的緩解以及其大腦下行性疼痛抑制系統的影響進行探討（研究三）。此外，本論文也提出我們在進行大腦磁振造影實驗中的腦部結構影像的意外發現（研究四）。
研究一我們使用擴散頻譜影像探討不同嚴重程度痛經女性在大腦白質神經束完整性以及大腦結構網路之差異。我們發現痛經女性和無痛經女性相比較，大腦白質神經束與大腦結構網路均無顯著差異且與嚴重程度無關，這和我們過去針對痛經女性在大腦功能性網路中的發現一致。雖然痛經會導致區域性的結構或功能上的影響，但在整體大腦網路結構中並沒有顯著差異，這或許可以印證痛經女性在非疼痛期間可維持正常社會心理功能，且並不會表現出顯著的認知與情感等障礙。
研究二我們使用大腦結構影像，從巨觀到微觀角度探討歷經長期痛經女性其海馬迴體積變化與BDNF Val66Met基因型之關聯，同時也探討不同嚴重程度的痛經是否會影響BDNF Val66Met基因型與海馬迴體積之變化。我們發現中等疼痛程度的痛經女性在左前以及右後局部海馬迴會隨著所攜帶Val等位基因的數量增加而體積增加，反之在嚴重疼痛的痛經女性，不論帶有何種BDNF Val66Met基因型，體積的大小均沒有顯著差異。這樣的結果可以推斷BDNF Val等位基因具有神經保護作用避免海馬迴受環境壓力而萎縮，然而該保護作用會隨著環境壓力增強而減弱。
研究三我們採用雙盲與真假刺激隨機分組之實驗設計，討論嚴重難治型原發性痛經女性在經期前給予運動皮質區tDCS刺激後對於痛經的緩解，以及藉由PAG與運動皮質區其功能性連結，探討下行性疼痛抑制系統經神經調節後之可塑性機轉。大多數接受真刺激的嚴重痛經女性其痛經均有達到緩解，而在假刺激組則發現有安慰劑效應。我們發現PAG與輔助運動區域(Supplementary Motor Area, SMA)有異常的病理性連結，尤其是骨盆肌肉控制區域。而tDCS介入會削減PAG與SMA之間的功能性連結，同時其疼痛也隨之緩解。我們認為運動皮質區tDCS刺激，有效削減嚴重痛經女性其PAG與SMA之間的病理性連結，達到臨床止痛成效。
研究四我們觀察到痛經女性在大腦結構正常變異與異常的比例均高於無痛經女性，然而其背後機轉有待未來更深入研究。
本研究證實了BDNF Val66Met基因多態性的神經保護機制會因為嚴重痛經而減弱，進而對於海馬迴結構產生影響。同時我們也證實運用tDCS在運動皮質區的刺激，對於嚴重難治型痛經女性將可達到臨床疼痛緩解效益，對於未來臨床止痛開創新的可能性。而藉由減少嚴重疼痛對於神經系統所帶來之負面影響，將有效提升女性生活品質以及減低未來疼痛慢性化的可能性。

Primary dysmenorrhea (PDM) refers to menstrual pain of which the pathological cause(s) are unknown. About 20% of PDM subjects have extreme pain intensity and describe their suffering as severe and distressing. PDM may cause adaptive/maladaptive functional and structural alterations in pain, emotion, stress-related brain regions (e.g., hippocampus, hypothalamus, and periaqueductal gray matter (PAG)). Brain-derived neurotrophic factor (BDNF) is a neurotrophin highly expressed in the hippocampus, which plays a vital role in the processing of pain-laden stress. We previously reported that BDNF Val66Met polymorphisms are associated with stressful PDM. The current study examined the associations among BDNF Val66Met polymorphisms, menstrual pain severity, and hippocampal volume among young PDM subjects. Previous studies have also demonstrated that motor cortex stimulation effectively relieves pain via the descending pain modulation system. Transcranial direct current stimulation (tDCS) is a novel form of non-invasive neuromodulation technology. In the current study, we applied anodal tDCS stimulation over the primary motor cortex (M1) in severe PDM subjects to evaluate the effect on menstrual pain relief, and investigate the functional connectivity (FC) changes in descending pain modulatory system (DPMS) via PAG-seeded resting-state functional magnetic resonance imaging, especially in FC between PAG and motor area.
The general aims of this dissertation were to investigate the means by which gene (e.g., BDNF Val66Met) and motor cortex stimulation (e.g., tDCS intervention) contribute to the adaptive and maladaptive neuroplasticity, and how these effects are modulated by pain severity in PDM subjects. There were two study cohorts with PDM and four studies in this dissertation.
In the first study, we aimed to explore the effect of different severity of dysmenorrhea on white matter tract integrity and structural connectome using diffusion spectrum imaging. We observed no significant difference in white matter tract integrity and structural connectome in PDM females, and those changes were irrelevant to pain severity. Those negative findings of the brain structural network concur with our previous functional network study. Our negative findings supported that PDM is essentially dissimilar to major neurological and psychiatric diseases because PDM females usually do not exhibit overt cognitive, affective, and psychosocial liability and disability.
In the second study, we aimed to investigate how BDNF Val66Met polymorphisms contribute to the structural plasticity of the hippocampus and its subfields, and how these effects are modulated by pain severity in PDM subjects. Significant interactions between PDM severity and BDNF Val66Met genotype were observed in the right whole hippocampus, subiculum, and molecular layer. Post-hoc analysis revealed that the average hippocampal volume of Val/Val moderate PDM subjects was greater than that of Val/Val severe PDM subjects. Note that right hippocampal volume was greater in the Val/Val group than in the Met/Met group, particularly in the right posterior hippocampal region. Dosage effect analysis revealed a positive dosage-dependent relationship between the Val allele and volume of the right whole hippocampus, subiculum, molecular layer, and voxel-based morphometry (VBM)-defined right posterior hippocampal region in the moderate PDM subgroup only. These findings indicate that Val/Val PDM subjects are resistant to intermittent moderate pain-related stress, whereas Met carrier PDM subjects are susceptible. When confronted with years of repeated PDM stress, the hippocampus can undergo differential structural changes in accordance with the BDNF genotype and pain severity. Our results provide evidence for Val allele dosage-dependent protective effects on the hippocampal structure; however, in cases of the Val variant, these effects were modulated in accordance with the severity of menstrual pain.
In the third study, we aimed to investigate the effect of transcranial direct current stimulation intervention on pain relief and neuromodulation of descending pain modulation system with severe dysmenorrhea patients. Our data revealed an analgesic effect in real anodal-M1 tDCS stimulation with pain improvement, and especially the effect is significant in the one month after tDCS intervention. We observed a significant tDCS effect of decreased functional connectivity between the PAG seed and the right supplementary motor area (SMA) after actual tDCS intervention. The functional connectivity value of PAG and SMA was positively correlated with menstrual pain intensity and McGill Pain Questionnaire total score. We indicated that tDCS disrupts the pathological coupling between PAG and SMA (especially in the pelvic-motor control area) for pain alleviation and restores the normal functionality of PAG and SMA.
In the fourth study, we observed that PDM subjects are associated with a high prevalence of normal variants but not brain abnormalities. However, our observations invite further epidemiological and neuroscientific studies.
This triad study on PDM (i.e., combining genotype with endophenotype imaging results and clinical phenotypes) underscores the potential neurobiological consequences of PDM, which may prefigure in neuroimaging abnormalities associated with various chronic pain disorders, and underpin the importance of treating PDM aggressively as early as possible. We have also demonstrated that tDCS stimulation will be another treatment option for pain relief with severe PDM subjects who were ineffective of analgesic or physical therapy.

Table of Contents
Acknowledgement .................... i
Chinese Abstract ................... iv
English Abstract ................... vi
Table of Contents .................. viii
List of Figures .................... xi
List of Tables ..................... xii
Abbreviations ...................... xiii
1. Introduction 1
1.1 Primary dysmenorrhea 1
1.2 Brain-derived neurotrophic factor 2
1.3 Motor cortex stimulation for pain relief 3
1.3.1 Descending pain modulation system 3
1.3.2 Non-invasive brain stimulation techniques 5
(A) Transcranial magnetic stimulation 5
(B) Transcranial direct current stimulation 5
1.4 Aims and hypotheses of the dissertation 7
2. Materials and Methods 9
2.1 Participants 9
2.2 Study design 11
2.2.1 Neuroimaging studies of PDM (Study I, II, and IV) 11
2.2.2 tDCS intervention for the treatment of severe PDM (Study III) 12
2.3 MRI data acquisition 15
2.4 Data analyses 16
2.4.1 White matter tract integrity and whole-brain connectome analyses (Study I) 16
2.4.2 Hippocampal volumetric and morphometric analysis (Study II) 21
2.4.3 PAG-seeded functional connectivity analysis (Study III) 22
2.4.4 Assessment of incidental findings (Study IV) 24
2.5 Statistical analyses 24
2.5.1 Demographic data and BDNF Val66Met genotyping 24
2.5.2 White matter tract integrity and whole-brain connectome analyses (Study I) 25
2.5.3 Volumetric analysis of the whole hippocampus and hippocampal subfields (Study II) 25
2.5.4 Voxel-based morphometry analysis on hippocampus (Study II) 25
2.5.5 tDCS outcome measurement (Study III) 26
2.5.6 PAG-seeded functional connectivity analysis (Study III) 26
2.5.7 Prevalence of incidental brain findings (Study IV) 27
3. Results 28
3.1 Demographic data and grouping using behavioral and genetic information for genetic neuroimaging study cohort (Study I and II) 28
3.2 Study I: No significant difference changes on white matter tract integrity and structural connectome in PDM female 33
3.3 Study II: BDNF Val66Met polymorphism on hippocampus is modulated by the severity of menstrual pain 36
(A) Association of global hippocampal volume and genotypes as modulated by PDM severity 36
(B) Association between subfield volume and genotypes, as modulated by PDM severity 39
(C) Association between VBM volume and genotypes, as modulated by PDM severity 40
3.4 Study III: tDCS intervention for the treatment of severe PDM 44
(A) Demographic and menstrual pain experience assessments for tDCS intervention cohort 44
(B) Clinical pain reduction with real and sham tDCS intervention 45
(C) Real tDCS intervention is associated with decreases in functional connectivity between PAG and SMA 49
3.5 Study IV: High prevalence of incidental brain findings in PDM 52
4. Discussion 53
4.1 Unaltered intrinsic structural brain architecture maintains normal psychosocial outcomes in PDM females 53
4.2 The brief nature of cyclic PDM episodes would not necessarily prompt global structural changes in the hippocampus 54
4.3 The hippocampus can undergo differential adaptive or maladaptive structural changes in accordance with the BDNF genotype and pain severity 54
4.4 BDNF Val allele exhibits an adaptive neuroprotective effect on hippocampal volume but undermines when severe distressful pain 56
4.5 Analgesic benefit of tDCS intervention over motor cortex for female with severe PDM 57
4.6 Decoupling the pathological functional connectivity between the PAG and pelvic-motor area might indicate potential analgesic mechanisms after tDCS intervention in severe PDM 57
4.7 PDM subjects have many times of high incidence of normal anomalies 59
4.8 Limitation 60
5. Conclusions 61
6. References 62
7. Appendices 73

List of Figures
Figure 1-1. Illustration of descending pain modulation system. 4
Figure 1-2. The overall research framework of present dissertation. 7
Figure 2-1. Flow-chart for subject selection in the cohort of genetic neuroimaging study. 10
Figure 2-2. Flow-chart for subject selection and allocation in the cohort of tDCS intervention study. 11
Figure 2-3. Experimental design of tDCS intervention study. 13
Figure 2-4. (Left) The portable one-channel tDCS device and (Right) the placement of anodal (red) and cathodal (blue) electrodes is schematically stimulation location. 14
Figure 2-5. Flow chart of TBAA analysis. 17
Figure 2-6. The PAG mask overlaid on the MNI152 template. 22
Figure 2-7. An example of fMRI BOLD signals change for each scan. The PAG mask (repressed in red) overlayed on the preprocessed fMRI data. 23
Figure 3-1. Post-hoc genotype analysis of PDM severity on global (A) and subfield (B) hippocampal volumes. 38
Figure 3-2. Post-hoc analysis on VBM-defined hippocampal volumes for PDM vs. CON and PDM severity. 41
Figure 3-3. Post-hoc analysis of PDM severity on genotype-VBM-defined hippocampal volumes. 43
Figure 3-4. Change of menstrual pain intensity after tDCS intervention in severe dysmenorrhea patients. 46
Figure 3-5. Change of menstrual pain intensity trajectory after (top) real and (down) sham tDCS intervention. 48
Figure 3-6. (A) Decreased functional connectivity between the PAG (seed in green) and right SMA (pelvic-motor area) in T3 compared with baseline after real tDCS intervention. (B) The change of functional connectivity value between the PAG and right SMA after real and sham tDCS intervention. 50
Figure 3-7. Correlation between change in functional connectivity of the PAG - right SMA at T3 and (A) menstrual pain intensity (B) total scores MPQ at MENS-Post 2. 51
Figure 3-8. Categorical distribution of incidental findings of brain MRIs in PDM and HC. 52

List of Tables
Table 1. Demographic data and clinical assessment results in PDM and CON groups 29
Table 2. Psychological assessment results in PDM and CON groups 31
Table 3. whole brain tractography-derived index in PDM and CON groups and severe PDM and moderate PDM subgroups 34
Table 4. Global network metrics in PDM and CON groups and severe PDM and moderate PDM subgroups 35
Table 5. Demographic data and clinical assessment results in the real and sham tDCS intervention group 44
Table 6. The effects of tDCS intervention on pain relief in severe dysmenorrhea patients 45
Table 7. Individual data on the menstrual pain change after tDCS intervention using visual analogue scale 47

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