簡易檢索 / 詳目顯示

回結果列表
研究生： 李家維
Li, Jia-Wei
論文名稱： 重複性經顱直流電刺激對雄性小鼠的腹部疼痛行為之調節作用
Modulatory effects of repetitive transcranial direct current stimulation on abdominal pain behaviors in male mice
指導教授： 游一龍
Yu, Lung
學位類別： 碩士
Master
系所名稱： 醫學院 - 生理學研究所
Department of Physiology
論文出版年： 2025
畢業學年度： 113
語文別： 英文
論文頁數： 55
中文關鍵詞： 穿顱直流電刺激 、前扣帶皮質 、慢性疼痛 、神經新生
外文關鍵詞： transcranial direct current stimulation, anterior cingulate cortex, neurogenesis, chronic pain
相關次數： 點閱：104  下載：0 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 重複性穿顱直流電刺激 (tDCS) 治療可作為一種調節大腦網絡活動的非侵入式腦功能調節方法，該方法的應用在臨床上可能特別有益於疼痛和認知的症狀治療。本研究以成年雄性小鼠為動物模型，探討陽極性 tDCS 是否可調控急性與慢性內臟的疼痛行為反應，以及其對神經新生的影響。陽極性 tDCS 是指每日施予 0.25 mA、持續 20 分鐘的陽極穿顱直流電刺激，連續給予五天。刺激目標選定與內臟痛感知與神經新生相關的前扣帶迴皮質 (ACC) 與後扣帶迴皮質 (RS)。我們建立兩種慢性疼痛模型，包括: 1) 連續五天餵飲檸檬酸水 (4 g/L)，2) 連續五天餵飲 2.5 % dextran sulfate sodium (DSS)。在急性疼痛實驗中，我們以直腸內注射 0.25 % 辣椒素誘發急性下腹疼痛反應 (包括舔舐腹部及拱背)，下腹部皮膚壓力敏感度以von Frey 測試。小鼠在接受第二次辣椒素注射時表現出比第一次注射時較低的下腹疼痛反應，顯示出辣椒素的刺激會使動物產生行為反應疲化現象。然而， ACC的 tDCS 刺激的介入會使該疲化現象消失，這可能暗示ACC的神經活性可能與該行為疲化現象有關。DSS的前處理可使辣椒素造成的下腹疼痛反應加劇，但ACC的 tDCS 刺激能去除此 DSS 的疼痛反應加劇效果。餵飲檸檬酸水的組別則與對照組不同，ACC 的刺激反而產生了疲化現象。在von Frey測試中發現ACC的tDCS 刺激能降低對照組與DSS組小鼠的壓力敏感度。ACC 的tDCS前處理刺激能增高側腦室下區 (SVZ) 和背側齒狀回 (dDG) 中表達的 Ki67 細胞數量，而RS的tDCS 前處理刺激僅能增加dDG中表達的 Ki67 細胞數量。綜合而言，本研究提供證據指出，tDCS 可透過目標區域選擇，在不同的腹痛生理狀態下，達到行為與神經新生的調控，具潛力發展為下腹部疼痛的非藥物性治療方案。

    Repetitive anodal transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique capable of altering brain network activity, with potential clinical applications in the treatment of pain and cognitive symptoms. In this study, we used adult male mice to investigate whether anodal tDCS may regulate both acute and chronic pain responses, as well as its effects on adult neurogenesis. Mice received daily anodal tDCS (0.25 mA, 20 minutes) for five consecutive days, targeting either anterior cingulate cortex (ACC) or retrosplenial cortex (RS) regions implicated in pain processing and neurogenesis. Two chronic pain models were employed: 1) ingestion of citric acid (4 g/L) in drinking water and 2) administration of 2.5 % DSS (dextran sulfate sodium) via drinking water for five consecutive days. Acute pain was induced by intrarectal injection of 0.25% capsaicin, which reliably triggered abdominal arching and licking behaviors, as well as increased mechanical sensitivity assessed by the von Frey test. In response to repeated capsaicin injections, behavioral habituation was eminent in control mice, but this effect was eliminated by ACC-targeted tDCS. DSS pre-treatment intensified acute pain responses, while ACC-targeted tDCS attenuated such responses. Interestingly, ACC-targeted tDCS enhanced habituation rather than reversed it in citric-treated mice. Moreover, von Frey testing showed that ACC-targeted tDCS reduced mechanical sensitivity in lower abdomen for both control and DSS mice, but not in citric-treated animals. Immunohistochemical analysis revealed that ACC-targeted tDCS increased Ki67⁺ cell proliferation in both the subventricular zone (SVZ) and dorsal dentate gyrus (dDG), whereas RS-targeted tDCS selectively increased proliferation in the dDG. To lump together, these findings demonstrated that tDCS exerted region- and abdominal nociceptive procedure-specific effects on both pain processing and adult neurogenesis. This suggests that specific brain region-targeted tDCS may be used as a promising non-pharmacological add-on intervention for managing lower abdominal pain conditions.

    論文合格證明書 1 中文摘要 2 Abstract 3 致謝 4 Introduction 9 Materials and Methods 12    1. Animals 12   2. tDCS base mounting procedure 12 3. tDCS stimulation procedure 13 4. Acute pain induction and behavioral assessment 13 5. von Frey test 14   6. Immunohistochemical staining and quantification of cell number 14 7. Fos immunofluorescent staining 15  8. Chronic Pain Models 15 9. Statistical analysis 16 Results 16 Aim 1: To determine whether single-session tDCS induces region- and layer-specific neuronal activation in targeted cortical areas (ACC and RS) Experiment 1-1: Assessing whether tDCS increases neuronal activity in targeted cortical regions 16 Experiment 1-2: Single-session tDCS increased c-Fos expression in a layer-specific manner in the ACC and RS 17 Aim 2: To investigate how repeated tDCS targeting the ACC or RS modulates acute pain behavior and neurogenesis in adult mice Experiment 2-1: Effect of repeated tDCS targeting the ACC or RS on behavioral responses to acute pain 17 Experiment 2-2: Differential modulation of neurogenesis by ACC- and RS-targeted tDCS 18 Aim 3: To evaluate the effects of repeated tDCS on behavioral and neurogenesis under chronic visceral pain conditions Experiment 3-1: Effects of tDCS on pain-related behavior following chronic pain priming 20 Experiment 3-2: Effects of tDCS on referred mechanical hypersensitivity following chronic pain priming 21 Experiment 3-3: tDCS enhances SVZ but not dDG neurogenesis under chronic pain conditions 22 Experiment 4: Social isolation increases mechanical sensitivity; tDCS shows normalizing trend 23 Conclusion 24 Figure 1. Single--session tDCS enhances c-Fos expression in cortical neurons .... 25 Figure 2. Single-session tDCS is associated with layer-specific changes in cortical c-Fos expression 26 - 28 Figure 3. Region-specific effects of repeated anodal tDCS on nocifensive behavior and locomotor activity following capsaicin-induced acute pain in mice 29 - 30 Figure 4. Repeated tDCS induces region-specific changes in neural stem cell proliferation 31 - 32 Figure 5. Effects of repetitive anodal tDCS on pain behavior and locomotion in mice with citric water or DSS treatment 34 - 35 Figure 6. Effects of tDCS on referred mechanical hypersensitivity following chronic pain priming 36 - 37 Figure 7. Effects of repeated anodal tDCS on Ki67⁺ cell proliferation in the SVZ and dorsal dentate gyrus under chronic pain 38 Figure 8. Effects of housing conditions on lower abdominal withdrawal responses to von Frey stimulation 39 - 40 Discussion 41 References 46 Appendix Appendix Figure 1. Water intake and body weight during the 5-day tDCS treatment period across chronic pain conditions 53 Appendix Figure 2. Effects of DSS treatment and tDCS on large intestine length 54

    1. Abdel-Salam, O. M. E., Youness, E. R., Mohammed, N. A., Morsy, S. M. Y., Omara, E. A., & Sleem, A. A. (2014). Citric acid effects on brain and liver oxidative stress in lipopolysaccharide-treated mice. Journal of Medicinal Food, 17(5), 588–598.
    2. Adams, W., Idnani, S., & Kim, J. (2024). Transcranial direct current stimulation for orthopedic pain: A systematic review with meta-analysis. Brain Sciences, 14(1), 66.
    3. Al Omran, A. J., Shao, A. S., Watanabe, S., Zhang, Z., Zhang, J., Davies, D. L., … Shao, X. M. (2022). Social isolation induces neuroinflammation and microglia overactivation, while dihydromyricetin prevents and improves them. Journal of Neuroinflammation, 19(1), 2.
    4. Alonso, M., Petit, A.-C., & Lledo, P.-M. (2024). The impact of adult neurogenesis on affective functions: of mice and men. Molecular Psychiatry, 29, 2527–2542.
    5. Alwardat, M., Pisani, A., Etoom, M., Carpenedo, R., Chinè, E., Dauri, M., Leonardis, F., & Natoli, S. (2020). Is transcranial direct current stimulation (tDCS) effective for chronic low back pain? A systematic review and meta-analysis. Journal of Neural Transmission, 127(9), 1257–1270.
    6. Auvichayapat, P., Keeratitanont, K., Janyacharoen, T., & Auvichayapat, N. (2018). The effects of transcranial direct current stimulation on metabolite changes at the anterior cingulate cortex in neuropathic pain: A pilot study. Journal of Pain Research, 11, 2301–2309.
    7. Bair, M. J., Robinson, R. L., Katon, W., & Kroenke, K. (2003). Depression and pain comorbidity: A literature review. Archives of Internal Medicine, 163(20), 2433–2445.
    8. Bayer, K.-E., Neeb, L., Bayer, A., Wiese, J. J., Siegmund, B., & Prüß, M. S. (2019). Reduction of intra-abdominal pain through transcranial direct current stimulation: A systematic review and meta-analysis. Medicine, 98(39), e17017.
    9. Boggio, P. S., Zaghi, S., Lopes, M., & Fregni, F. (2008). Modulatory effects of anodal transcranial direct current stimulation on emotion recognition. Neuropsychologia, 47(1), 280–284.
    10. Bragina, O. A., Atochin, D. A., Trofimov, A. O., Nemoto, E., & Bragin, D. E. (2023). Cerebral microcirculation and oxygenation modulation by transcranial alternating current stimulation in awake and anesthetized mice. Advances in Experimental Medicine and Biology, 1438, 9–13.
    11. Bushnell, M. C., Čeko, M., & Low, L. A. (2013). Cognitive and emotional control of pain and its disruption in chronic pain. Nature Reviews Neuroscience, 14(7), 502–511.
    12. Cifre, I., Sitges, C., Fraiman, D., Muñoz, M. Á., Balenzuela, P., González-Roldán, A., Martínez-Jauand, M., Birbaumer, N., Chialvo, D. R., & Montoya, P. (2012). Disrupted functional connectivity of the pain network in fibromyalgia. Psychosomatic Medicine, 74(1), 55–62.
    13. Clara Ros-Simó, & Valverde, O. (2012). Early-life social experiences in mice affect emotional behaviour and hypothalamic–pituitary–adrenal axis function. Pharmacology Biochemistry and Behavior, 102(3), 434–441.
    14. Cummiford, C. M., Nascimento, T. D., Foerster, B. R., Clauw, D. J., Zubieta, J.-K., Harris, R. E., & DaSilva, A. F. (2016). Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients. Arthritis Research & Therapy, 18, Article 40.
    15. Demuyser, T., Deneyer, L., Bentea, E., Albertini, G., Van Liefferinge, J., Merckx, E., De Prins, A., De Bundel, D., Massie, A., & Smolders, I. (2016). In-depth behavioral characterization of the corticosterone mouse model and the critical involvement of housing conditions. Physiology & Behavior, 156, 199–207.
    16. Fagerlund, A. J., Hansen, O. A., & Aslaksen, P. M. (2015). Transcranial direct current stimulation as a treatment for patients with fibromyalgia: A randomized controlled trial. Pain, 156(1), 62–71.
    17. Gan, Z., Li, H., Naser, P. V., Han, Y., Tan, L. L., Oswald, M. J., & Kuner, R. (2021). Repetitive non-invasive prefrontal stimulation reverses neuropathic pain via neural remodelling in mice. Progress in Neurobiology, 201, 102009.
    18. Gill, J., Shah-Basak, P. P., & Hamilton, R. (2015). It's the thought that counts: Examining the task-dependent effects of transcranial direct current stimulation on executive function. Brain Stimulation, 8(2), 253–259.
    19. González-Cano, R., Tejada, M. Á., Artacho-Cordón, A., Nieto, F. R., Entrena, J. M., Wood, J. N., & Cendán, C. M. (2017). Effects of tetrodotoxin in mouse models of visceral pain. Marine Drugs, 15(6), 188.
    20. Guo, T., Fang, J., Tong, Z. Y., He, S., & Luo, Y. (2020). Transcranial direct current stimulation ameliorates cognitive impairment via modulating oxidative stress, inflammation, and autophagy in a rat model of vascular dementia. Frontiers in Neuroscience, 14, Article 28.
    21. Hamner, J. W., Villamar, M. F., Fregni, F., & Taylor, J. A. (2015). Transcranial direct current stimulation (tDCS) and the cardiovascular responses to acute pain in humans. Clinical Neurophysiology, 126(5), 1039–1046.
    22. Hervik, J. A., Vika, K. S., & Stub, T. (2024). Transcranial direct current stimulation for chronic headaches: A randomized, controlled trial. Frontiers in Pain Research, 5.
    23. Huang, L., Liu, J., Wang, M., Hu, Z., & Chen, J. (2022). Dietary citric acid improves intestinal health and reduces inflammation by regulating gut microbiota in mice. Journal of the Science of Food and Agriculture, 102(5), 1978–1986.
    24. Ihle, K., Rodriguez-Raecke, R., Luedtke, K., & May, A. (2014). tDCS modulates cortical nociceptive processing but has little to no impact on pain perception. Pain, 155(10), 2080–2087.
    25. Jayathilake, N. J., Phan, T. T., Kim, J., Lee, K. P., & Park, J. M. (2025). Modulating neuroplasticity for chronic pain relief: Noninvasive neuromodulation as a promising approach. Experimental & Molecular Medicine, 57, 501–514.
    26. Kronberg, G., Bridi, M., Abel, T., Bikson, M., & Parra, L. C. (2017). Direct current stimulation modulates LTP and LTD: Activity dependence and dendritic effects. Brain Stimulation, 10(1), 51–58.
    27. Laird, J. M. A., Martínez-Caro, L., Garcia-Nicas, E., & Cervero, F. (2001). A new model of visceral pain and referred hyperalgesia in the mouse. Pain, 92(3), 335–342.
    28. Lengu, K., Ryan, S., Peltier, S. J., Tyszkowski, T., Kairys, A., Giordani, B., & Hampstead, B. M. (2021). Effects of HD-tDCS on local GABA and glutamate levels among older adults with and without mild cognitive impairment: An exploratory study. Journal of Alzheimer's Disease, 84(3), 1091–1102.
    29. Li, L. M., Violante, I. R., Leech, R., Ross, E., Hampshire, A., Opitz, A., Rothwell, J. C., Carmichael, D. W., & Sharp, D. J. (2018). Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation. Human Brain Mapping, 39(10), 4077–4092.
    30. Liao, Y.-H., Sun, L.-H., Su, Y.-C., Yao, W.-J., & Yu, L. (2023). Medial and dorsal lateral septum involving social disruption stress-primed escalation in acid-induced writhes. Frontiers in Molecular Neuroscience, 16, Article 1158525.
    31. Lim, M., Kim, D. J., Nascimento, T. D., & DaSilva, A. F. (2024). High-definition tDCS over primary motor cortex modulates brain signal variability and functional connectivity in episodic migraine. Clinical Neurophysiology, 161, 101–111.
    32. López-Estévez, S., López-Torrellardona, J. M., Parera, M., & Martínez, V. (2022). Long-lasting visceral hypersensitivity in a model of DSS-induced colitis in rats. Neurogastroenterology & Motility, 34(12), e14441.
    33. Lu, H., Liu, Q., Guo, Z., Zhou, G., Zhang, Y., Zhu, X., & Wu, S. (2020). Modulation of repeated anodal HD-tDCS on attention in healthy young adults. Frontiers in Psychology, 11, Article 564447.
    34. Martin, D. M., Liu, R., Alonzo, A., Green, M., & Loo, C. K. (2014). Use of transcranial direct current stimulation (tDCS) to enhance cognitive training: Effect of timing of stimulation. Experimental Brain Research, 232(10), 3345–3351.
    35. Matsumoto, K., Kurosawa, E., Terui, H., Hosoya, T., Tashima, K., Murayama, T., Priestley, J. V., & Horie, S. (2009). Localization of TRPV1 and contractile effect of capsaicin in mouse large intestine: High abundance and sensitivity in rectum and distal colon. American Journal of Physiology-Gastrointestinal and Liver Physiology, 297(2), G348–G360.
    36. Mishima, T., Nagai, T., Yahagi, K., Akther, S., Oe, Y., Monai, H., Kohsaka, S., & Hirase, H. (2019). Transcranial direct current stimulation (tDCS) induces adrenergic receptor-dependent microglial morphological changes in mice. eNeuro, 6(5), ENEURO.0204-19.2019.
    37. Mutso, A. A., Radzicki, D., Baliki, M. N., Huang, L., Banisadr, G., Centeno, M. V., Radulovic, J., Martina, M., Miller, R. J., & Apkarian, A. V. (2012). Abnormalities in hippocampal functioning with persistent pain. Journal of Neuroscience, 32(17), 5747–5756.
    38. Omran, A. J. A., Shao, A. S., Watanabe, S., Zhang, Z., Zhang, J., Xue, C., Watanabe, J., Davies, D. L., Shao, X. M., & Liang, J. (2022). Social isolation induces neuroinflammation and microglia overactivation, while dihydromyricetin prevents and improves them. Journal of Neuroinflammation, 19(2).
    39. Ong, W.-Y., Stohler, C. S., & Herr, D. R. (2018). Role of the prefrontal cortex in pain processing. Molecular Neurobiology, 56(2), 1137–1166.
    40. Podda, M. V., Cocco, S., Mastrodonato, A., Fusco, S., Leone, L., Barbati, S. A., Colussi, C., Ripoli, C., & Grassi, C. (2016). Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression. Scientific Reports, 6, 22180.
    41. Qiu, Y., Lian, Y. N., Wu, C., Liu, L., Zhang, C., & Li, X. Y. (2024). Coordination between midcingulate cortex and retrosplenial cortex in pain regulation. Frontiers in Molecular Neuroscience, 17, 1405532
    42. Reichmann, F., Hassan, A. M., Farzi, A., Jain, P., Schülgoi, R., & Holzer, P. (2015). Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala–hippocampus network of mice. Scientific Reports, 5, Article 9970.
    43. Reis, G. M., Dias, Q. M., Silveira, J. W. S., Del Vecchio, F., Garcia-Cairasco, N., & Prado, W. A. (2010). Antinociceptive effect of stimulating the occipital or retrosplenial cortex in rats. The Journal of Pain, 11(10), 1015–1026.
    44. Rikard, S. M., Strahan, A. E., Schmit, K. M., & Guy, G. P. Jr. (2023). Prevalence of pharmacologic and nonpharmacologic pain management therapies among adults with chronic pain—United States, 2020. Annals of Internal Medicine, 176(11), 1571–1575.
    45. Schneider, J., Algharably, E. A. E., Budnick, A., Wenzel, A., Dräger, D., & Kreutz, R. (2021). High prevalence of multimorbidity and polypharmacy in elderly patients with chronic pain receiving home care are associated with multiple medication-related problems. Frontiers in Pharmacology, 12, 686990.
    46. Shackman, A. J., Salomons, T. V., Slagter, H. A., Fox, A. S., Winter, J. J., & Davidson, R. J. (2011). The integration of negative affect, pain and cognitive control in the cingulate cortex. Nature Reviews Neuroscience, 12(3), 154–167.
    47. Todd, T. P., & Bucci, D. J. (2015). Retrosplenial cortex and long-term memory: Molecules to behavior. Neural Plasticity, 2015, 414173.
    48. Uskur, T., & Kurt, B. F. (2025). Polypharmacy and drug-drug interactions in elderly patients with gastrointestinal bleeding: A single-center retrospective study. Cureus, 17(1), e77866.
    49. Vitali, R., Prioreschi, C., Rebenaque, L. L., Colantoni, E., Giovannini, D., Frusciante, S., ... & Pazzaglia, S. (2022). Gut–Brain Axis: Insights from Hippocampal Neurogenesis and Brain Tumor Development in a Mouse Model of Experimental Colitis Induced by Dextran Sodium Sulfate. International Journal of Molecular Sciences, 23(19), 11495.
    50. Wang, S., Du, S.-H., Wang, X.-Q., & Lu, J.-Y. (2024). Mechanisms of transcranial direct current stimulation (tDCS) for pain in patients with fibromyalgia syndrome. Frontiers in Molecular Neuroscience, 17.
    51. Weber, E. M., Dallaire, J. A., Gaskill, B. N., Pritchett-Corning, K. R., & Garner, J. P. (2021). Exploring refinement strategies for single housing of male C57BL/6JRj mice: Effect of cage divider on stress-related behavior and hypothalamic-pituitary-adrenal-axis activity. Frontiers in Behavioral Neuroscience, 15, 743959.
    52. Wiech, K., & Tracey, I. (2009). The influence of negative emotions on pain: behavioral effects and neural mechanisms. NeuroImage, 47(3), 987–994.
    53. Xiao, X., & Zhang, Y.-Q. (2018). A new perspective on the anterior cingulate cortex and affective pain. Neuroscience & Biobehavioral Reviews, 90, 200–211.
    54. Yamawaki, N., Radulovic, J., & Shepherd, G. M. G. (2016). A corticocortical circuit directly links retrosplenial cortex to M2 in the mouse. The Journal of Neuroscience, 36(36), 9365–9374.
    55. Yu, T.-H., Wu, Y.-J., Chien, M.-E., & Hsu, K.-S. (2019). Transcranial direct current stimulation induces hippocampal metaplasticity mediated by brain-derived neurotrophic factor. Neuropharmacology, 144, 358–367.
    56. Yu, T.-H., Wu, Y.-J., Chien, M.-E., & Hsu, K.-S. (2023). Multisession anodal transcranial direct current stimulation enhances adult hippocampal neurogenesis and context discrimination in mice. Journal of Neuroscience, 43(4), 635–646.
    57. Yuan, T. F., Dong, Y., Zhang, L., Qi, J., Yao, C., Wang, Y., Chai, R., Liu, Y., & So, K. F. (2021). Neuromodulation-based stem cell therapy in brain repair: Recent advances and future perspectives. Neuroscience Bulletin, 37(5), 735–745.
    58. Zahlan, G., De Clifford-Faugère, G., Nguefack, H. L. N. N., Guénette, L., Pagé, M. G., Blais, L., & Lacasse, A. (2023). Polypharmacy and excessive polypharmacy among persons living with chronic pain: A cross-sectional study on the prevalence and associated factors. Journal of Pain Research, 16, 3085–3100.
    59. Zhang, Y., Li, X., Qiu, S., Jin, R., & Peng, W. (2025). Preemptive transcranial direct current stimulation mitigates susceptibility to persistent pain. Communications Biology, 8, Article 865.
    60. Zortea, M., Ramalho, L., Alves, R. L., Alves, C. F. S., Braulio, G., Torres, I. L. da S., Fregni, F., & Caumo, W. (2019). Transcranial direct current stimulation to improve the dysfunction of descending pain modulatory system related to opioids in chronic non-cancer pain: An integrative review of neurobiology and meta-analysis. Frontiers in Neuroscience, 13, Article 1218.

    下載圖示
    2026-08-31公開
    QR CODE