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研究生：	朱冠丞 Zhu, Guan-Cheng
論文名稱：	神經鬆動術對於糖尿病疼痛神經病變之感覺異常與神經退化之治療效果: 動物模型基礎研究 The effect of neural mobilization in sensory dysfunction and peripheral nerve degeneration relate to painful diabetic neuropathy: a pre-clinical animal study
指導教授：	洪菁霞 Hung, Ching-Hsia
學位類別：	博士 Doctor
系所名稱：	醫學院 - 健康照護科學研究所 Institute of Allied Health Sciences
論文出版年：	2020
畢業學年度：	109
語文別：	英文
論文頁數：	60
中文關鍵詞：	糖尿病神經病變、神經病理性疼痛、物理治療、臨床神經科學
外文關鍵詞：	Diabetic neuropathy, Neuropathic pain, Physical therapy, Clinical neuroscience
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糖尿病神經病變所造成的神經病理性疼痛(糖尿病疼痛經病變)是造成糖尿病患長期疼痛最常見的原因之一。目前研究指出大約有25-50%的糖尿病患者患有糖尿病疼痛神經病變，其臨床上的表現包括了自發性疼痛以及對外部機械性刺激與熱刺激的過度敏感。目前學界及醫界對糖尿病疼痛神經病變的生理機轉仍不甚清楚，但目前的研究指出負責供應神經之微血管網功能退化、周邊神經的發炎和退化是造成糖尿病神經病變的主要因素。糖尿病疼痛神經病變所造成的感覺異常會嚴重影響患者的生活品質。但目前臨床上缺乏非藥物的介入手段來改善患者的生活品質。目前臨床上主要以抗癲癇與抗憂鬱藥物來緩解患者的疼痛，但是其效果在個別病人身上的差異較大。另外，雖然藥物可以在一些患者身上有效的抑制疼痛，但這些藥物對造成感覺異常的根源:周邊神經的退化並沒有直接的效果。在臨床上，物理治療師會透過許多非藥物治療去緩解神經病變造成的感覺異常。其中神經鬆動術是一個常用來治療由神經損傷、壓迫造成疼痛的手法。其基本概念是透過對神經組織施以間歇性張力來促進神經組織間液體的流動及促進局部神經血液循環以達到改善神經生理平衡的效果。在理論上，神經鬆動術應也可以改善由糖尿病神經病變所造成的感覺異常及周邊神經退化。但目前研究也指出在糖尿病患者由於其微血管系統已經遭受一定程度的破壞，因此對神經施以張力仍然有一定的危險性。因此在這份研究中，我們選擇在糖尿病疼痛神經病變的動物模型上分析神經鬆動術在其感覺異常及周邊神經退化的效果。另外，也透過分析神經組織中的促發炎介質物的濃度來研究神經鬆動術的生理機轉。
在這份研究中，我們使用鏈脲佐菌素(STZ)誘發糖尿病的大鼠模型來分析神經鬆動術對糖尿病疼痛神經病變的效果。在感覺異常的部分，我們透過分析大鼠的機械性疼痛敏感度及熱覺敏感度來評估感覺異常的嚴重程度。在周邊神經退化的部分，我們分析了大鼠足底皮膚的表皮內神經纖維密度(IENFD)以評估周邊神經退化的嚴重程度。此外，我們也分析了大鼠神經組織內的促發炎介質物的濃度來研究神經鬆動術的生理機轉。分析結果顯示，神經鬆動術治療可以有效的改善糖尿病神經病變所引起的機械性過度敏感。另外，我們也發現了單次治療的效果約可維持48小時，但若要產生顯著的症狀改善則需要接受多次治療。在足底皮膚的表皮內神經纖維密度(IENFD)的分析結果顯示接受治療的大鼠其治療側的表皮內神經纖維密度(IENFD)顯著高於非治療側以及未接受治療的糖尿病大鼠。此結果顯示神經鬆動術確實可以有效延緩周邊神經的退化或是促進神經的再生。但為什麼神經鬆動術有這樣的效果?本研究對神經組織內促炎性物質濃度的分析顯示有接受治療的神經組織其促炎性物質濃度顯著低於未接受治療的神經組織，這可能與神經鬆動術的止痛效果和促進神經再生有關。但是由於促發炎介質物的生理訊號傳遞極為複雜，因此需要進一步的研究才能釐清神經組織中發炎介質物濃度的變化與疼痛、神經纖維再生之間的因果關係。
最後總結，本研究的結果證明神經鬆動術可有效的改善糖尿病神經病變造成之痛覺過度敏感以及延緩周邊神經的退化。其原理可能是透過降低神經組織內促進神經敏感化及神經退化的促發炎介質以達到其效果。但是各種促發炎介質的訊號傳遞路徑與疼痛、神經纖維退化的因果關係仍有待後續研究釐清。

Painful diabetic neuropathy (PDN) is one of the most common causes of chronic pain in patients with diabetes. The current literature suggests that approximately 25-50% of patients with diabetes are affected by painful diabetic neuropathy. The clinical manifestation of painful diabetic neuropathy includes hypersensitivity to mechanical or thermal stimuli and spontaneous burning, pinprick-like pain as well as sensory loss. The physiological mechanism of painful diabetic neuropathy is still unclear at the moment. However, current literature indicates that a dysfunction of the microvascular system, inflammation of the peripheral nervous system and the degeneration/regeneration of peripheral nerves are major contributing factors in the development of painful diabetic neuropathy.
Sensory dysfunction related to painful diabetic neuropathy can severely affect the patients’ quality of life. The current first-and second line management for sensory dysfunction related to painful diabetic neuropathy are medications including anti-convulsants, serotonin and norepinephrine re-uptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Although widely used in clinics, the effect of these medication varies from patient to patient. In addition, the medications cannot mitigate the degeneration of peripheral nerves, which is the cause of sensory dysfunction in most patients. For long term diabetic care, non-pharmacological intervention for painful diabetic neuropathy is more ideal. However, currently there is no effective non-pharmacological treatment for painful diabetic neuropathy.
The aim of this study is to evaluate the effect of neural mobilization (NM), a physical therapy technique, in managing sensory dysfunction and peripheral nerve degeneration in animals with painful diabetic neuropathy. Neural mobilization is a technique used by physical therapists to manage neuropathic pain related to nerve damage. The basic idea of neural mobilization is to apply intermittent tension on nerve tissue in order to facilitate the dispersion of fluid within nerve tissue and improve local nerve circulation thus restoring homeostasis in the nerve tissue. Current literature suggests that neural mobilization is effective in managing spinal referred leg and arm pain. Animal studies that investigated the neurophysiological effect of neural mobilization also showed it is effective in attenuating neuropathic pain related to nerve injury. In addition, the animal studies indicated that neural mobilization could facilitate the regeneration of nerves that were damaged by nerve injury. In theory, neural mobilization may be able to mitigate the degeneration and sensory dysfunction related to painful diabetic neuropathy. However, there is still the risk of neural mobilization inflicting additional neural injury in patients with diabetic neuropathy. Thus, streptozocin (STZ) induced painful diabetic neuropathy rat model was used in this study to evaluate the effect of neural mobilization.
To evaluate the effectiveness of neural mobilization on sensory dysfunction related to painful diabetic neuropathy, mechanical and thermal pain sensitivity in rats with painful diabetic neuropathy were measured. In addition, concentration of pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1β (IL-1β) in the nerve tissue was also measured to explore the possible mechanism of neural mobilization’s treatment effect. For the evaluation of neural mobilization’s effect on nerve degeneration, the intra-epidermal nerve fiber density of the paw skin was measured. The results of this study showed that neural mobilization is effective in attenuating mechanical allodynia in rats with painful diabetic neuropathy. It was also discovered that the treatment effect of a single neural mobilization session could persist for 48 hours. Results from this study also suggest that it may require multiple neural mobilization session to produce significant treatment effects or to enhance the effect of previous treatment sessions.
In terms of neural mobilization’s effect in mitigating degeneration of peripheral nerves, the result showed intra-epidermal nerve fiber density in the paw skin of rats receiving neural mobilization is higher compared to the rats that did not receive neural mobilization. The higher intra-epidermal nerve fiber density was only shown on the treatment side, indicating the effect was specific to the treatment the rats received. In summary, this study demonstrated neural mobilization is effective in attenuating pain and nerve degeneration related to painful diabetic neuropathy and does not seem to induce axonal injury. The decreased concentration of pro-inflammatory cytokines may contribute to the effects of neural mobilization, but it requires further study to investigate the cause-effect relationship between the reduction of pro-inflammatory cytokine concentration and the effects of neural mobilization.

中文摘要(CHINESE ABSTRACT)	i
英文摘要(ENGLISH ABSTRACT)	iii
致謝 (ACKNOWLEDGEMENT)	v
縮寫(ABBREVIATION)	vi
INTRODUCTION 	1
1 Background and general aim of the study	1
2 Literature review 	3
2.1 Definition of painful diabetic neuropathy	3
2.2 Clinical manifestation of painful diabetic neuropathy	4
2.3 Epidemiology	4
2.4 Pathophysiological mechanisms of painful diabetic neuropathy	5
3 Research aims and hypothesis	10
MATERIAL AND METHODS (STUDY I)	12
1 Research objectives (Study I)	12
2 Animal model and groups in Study I	12
3 General procedure of study I	13
4 Behavioral test: mechanical pain sensitivity	14
5 Behavioral test: thermal pain sensitivity	14
6 Neural mobilization	14
7 Sample collection, preparation and cytokine assay	15
8 Statistical analysis	16
RESULTS (STUDY I) 	17
1 Total number of animals used in study I	17
2 Rats with painful diabetic neuropathy showed a significant decrease of mechanical, but not thermal response thresholds	17
3 Neural mobilization alleviates mechanical hypersensitivity on the treatment side 	17
4 No significant differences in thermal response threshold in rats with painful diabetic neuropathy after neural mobilization	19
5 Rats in the PDN Group Had Higher Concentrations of IL-1β But Not TNF in the Sciatic Nerve Branches and Sciatic Nerve Trunk	19
6 Rats in the PDN-MN Group Had Lower Concentrations of Both IL-1β and TNF in the Sciatic Nerve Branches and Sciatic Nerve Trunk on the Treatment Side	19
7 Summary of findings in Study I	20
8 Summary of limitations in Study I	22
MATERIAL AND METHODS (STUDY II)	23
1 Research objectives (Study II)	23
2 Changes in methodology compared to study I	24
3 Animal model and groups in the Study II study	24
4 General procedure of the Study II study	24
5 Behavioral tests, neural mobilization treatment protocol and isoflurane anesthesia	25
6 Evaluation of intra-epidermal nerve fiber density (IENFD)	26
7 Statistical analysis	27
RESULTS (STUDY II) 	28
1 Total number of animals used in study II	28
2 Rats with painful diabetic neuropathy showed significantly decreased mechanical, but not thermal response threshold	28
3 Single neural mobilization session attenuates, but does not fully reverse mechanical allodynia in rats with painful diabetic neuropathy	28
4 The effect of duration and additive effect of multiple neural mobilization sessions	29
5 Neural mobilization induces higher intra-epidermal nerve fiber density on the treatment side	30
DISCUSSION 	32
1 The effectiveness of neural mobilization in managing painful diabetic neuropathy and optimal treatment regime for the treatment of painful diabetic neuropathy	32
2 The effect of neural mobilization on the degeneration of peripheral nerves and its underlying physiological mechanism	34
CONCLUSION 	36
1 Conclusion	36
2 Future work	36
3 Acknowledgements 	36
REFERENCE 	37

Table 1. Treatment protocol for neural mobilization 	44
Table 2. List of antibodies used in Study II 	45

Figure 1. Timetable of the general procedure of study I 	46
Figure.2 Behavioral test methods used in this study 	47
Figure 3. Demonstration of neural mobilization treatment in this study 	48
Figure 4. Mechanical and thermal response threshold data from baseline to the end of the experiment in study I 	49
Figure 5. The concentration of interleukin 1β (IL-1β) and tumor necrosis factor (TNF) measured in the sciatic nerve branches and sciatic nerve trunk 	51
Figure 6. The general procedure of Study II 	53
Figure 7. Demonstration of the criteria for intra-epidermal nerve fibers 	54
Figure 8. Daily behavioral data in Study II 	55
Figure 9. Behavior data of the time-course test in study II 	57
Figure 10. Demonstration of IENFD on the paw skin of the treatment side and contralateral side of the rats in PDN-NM group 	59
Figure 11. IENFD data of the left and right paw skin in the vehicle, PDN-Iso and PDN-NM groups 	60




                                    

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