We move to the new website, link here Yi-Jen Wu Lab
Publications
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New Papers & Book
Chin-Hao Chen, Tsung-Chih Tsai, Yi-Jen Wu, Kuei-Sen Hsu*. Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice. JCI insight 2023 May 18;e161874.
Ting-Hsuan Yu, Yi-Jen Wu, Miao-Er Chien and Kuei-Sen Hsu*. Multisession anodal transcranial direct current stimulation enhances adult hippocampal neurogenesis and context discrimination in mice. Journal of Neuroscience 2023; 43(4):635-646. [PDF]
Yi-Ting Fang, Tsung-Lin Lee, Yi-Hsien Tu, Sheng-Hsiang Lin, Miao-Er Chien, Chin-Wei Huang, Kuei-Sen Hsu, Yi-Jen Wu*. Factors associated with mortality in patients with super-refractory status epilepticus. Scientific Reports 2022;12(1): 9670. [PDF]
黃英儒,莊雯莉,呂明桂等人.非侵入性腦刺激術-基礎、臨床與研究.民國111年9月初版.合記. 吳怡真,第11章,經顱直流電刺激的電生理與細胞分子機轉. [Book]
<The book for a general introduction of non-invasive brain stimulation (NIBS) from clinical to basic researches was organized and edited by Prof. Ying-Zu Huang. It was written in Chinese in hope of inspiring a broad audience in Taiwan. In memory of Prof. Ying-Zu Huang, a pioneer and great mentor in the field of NIBS.>
Click here to edit.
Theme 1: Transcranial Direct Current Stimulation, Clinical and Basic Researches
We have been working on the transcranial direct current stimulation (tDCS) application to both healthy people and patients with neurologic disorder, and investigating the neurophysiological mechanism in the disease animal model. In general, tDCS can modulate cortical excitability and neural plasticity by polarity-dependent constant current stimulations, whereby anodal tDCS and cathodal tDCS provide facilitatory and inhibitory effects, respectively. Therefore, tDCS is of therapeutic potential to treat a spectrum of neuropsychiatric disorders. Our research focuses on the therapeutic effects and neurophysiological mechanisms of neuromodulation applied to seizure disorders and cognitive impairments.
1. Anodal tDCS to enhance cognition, from healthy subjects, diabetic patients with mild cognitive impairment, to disease animal model: We reported that anodal tDCS over the dorsolateral prefrontal cortex can facilitate visuospatial working memory in healthy young subjects and the beneficial effect of tDCS also showed in the diabetic patients who concomitantly suffered from peripheral neuropathy and mild cognitive impairment. We found that repeated anodal tDCS improved the spatial working memory in diabetic rats through the potentiation of synaptic plasticity by upregulating BDNF secretion and transcription/translation of NMDARs, and increasing the dendritic spine density.
2. Cathodal tDCS to alleviate seizures, from acute status epilepticus to chronic seizure animal models: Our studies find that in an acute sustained seizure rat model of status epilepticus, repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures, and in a chronic seizure animal model, we reveal an inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicating that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability. In the serial studies, we uncover how cathodal tDCS decreases the brain excitability in an epileptic brain via modulating the endogenous neural oscillations. With these advanced understandings of the neurophysiological basis of tDCS, we can optimize the clinical application of tDCS for the patients with neurological disorders.
Theme 2: Seizure and Epilepsy, Clinical and Basic Studies
Theme 3: Neuromodulation & Neurosciences
Book Chapter
研究成果
(1)經顱直流電刺激用於促進認知功能的效應與機轉研究 陽極經顱直流電刺激雖廣泛被用於認知與學習的神經心理學實驗,而其神經生理尚未完全清楚。基於對認知功能的興趣一開始實驗室利用經顱直流電刺激施予背外側前額葉於一般正常受試者,測試其對視知覺空間工作記憶的影響,並搭配動作干擾的實驗設計,研究證實陽極經顱直流電刺可促進前額葉的空間工作記憶功能,尤其是在有干擾的狀況下直流電刺激的效應更加顯著(2014 Brain and Cognition)。此研究的進行奠定了研究團隊在認知神經科學上的基礎,也幫助將這方面的研究帶進臨床運用在病人身上。吳醫師在日常的神經科病患診視中發現糖尿病患者在神經方面的表現不僅只有周邊神經病變,也有認知功能的缺損,透過認知評估發現這群病人合併有輕度認知功能障礙(mild cognitive impairment, MCI),其空間工作記憶也有缺損,透過右背外側前額葉施予陽極經顱直流電刺激可以提升這群病人的空間工作記憶缺失,此一研究開啟了運用非侵襲性微量電流改善疾病相關的認知功能障礙的可能性(2016 Frontiers in Human Neuroscience)。為了解陽極經顱直流電刺激對糖尿病認知功能提升的神經生理機制,研究團隊利用糖尿病疾病動物模式證實此由顱外提供的非侵襲性弱電流刺激可以藉由改善疾病動物中受損的神經可塑性,促進調節神經可塑性相關的神經傳遞物質與神經滋養因子的表現,並增加樹突棘數目,穿顱直流電刺激除了活化電導極下方的神經元活性,也活化了其旁鄰區域與功能性連結的遠方區域。上述研究發現都是此領域重要而尚未清楚的議題,也提供未來臨床運用於神經精神疾患重要的基礎依據(2017 Brain Stimulation,2020 Neuropharmacology)。
(2)癲癇重積症的臨床研究 癲癇是腦部神經元異常興奮放電的表現,癲癇重積症是癲癇持續發作無法自行停止的神經科急重症,病人在持續嚴重的癲癇發作之下往往需要呼吸道插管使用呼吸器、使用抗癲癇藥與麻醉鎮定藥物合併多種治療,往往伴隨高死亡率與併發症,而死亡相關的原因多重複雜尚未被清楚了解。我們回顧成大醫院13年期間收治的超級難治型癲癇重積症患者,剖析致病原因、病程進展、治療與反應、抗癲癇與麻醉鎮定藥物的使用、及併發症等各種與死亡相關的因素,並提出可能減少死亡率的治療建議,提供第一線治療難治型癲癇重積症具體實際的幫助(2022 Scientific Reports)。
(3)經顱直流電刺激用於治療癲癇重積症的效應與機轉研究 為了解決上述藥物難治型癲癇重積症此一重要臨床問題,實驗室運用陰極經顱直流電刺激(transcranial direct current stimulation, tDCS)於嚴重持續發作的急性癲癇重積症動物模式。為了進行相關研究,實驗室在科技部研究計畫經費的支持下建立癲癇動物模式,並建置活體清醒動物配合行為同步腦部電生理記錄的軟硬體設施,以及活體經顱直流電刺激合併同時腦部電生理活動記錄的技術。我們的研究發現經顱直流電刺激可以減少嚴重癲癇的發作、亦可調節癲癇腦波頻譜共振、並減少其神經後遺症(2020 Experimental Neurology)。在後續系列研究中則以慢性自發性癲癇動物模式探討機制,驗證經顱直流電刺激可以藉由增強腦內自生性的低頻腦波共振作為抑制癲癇興奮性的神經生理機制,此研究結果揭示非侵襲性微量陰極直流電對癲癇興奮性調節的病態生理機制,獲刊登於領域代表期刊(2021 Brain Stimulation, IF 8.955, 6.01% in Clinical Neurology, 6.78% in Neuroscience)。神經調節術因為科技的進步,未來將有越來越多的機會被運用到疾病的治療,因此神經調節的效應與機制更顯重要,此兩篇研究對非侵襲性腦刺激術調節癲癇提供重要的轉譯研究證據,也為目前最具挑戰的難治型癲癇的臨床困境提供新的治療契機,並提供學理上的神經生理機制作為後續臨床試驗的基礎。
We have been working on the transcranial direct current stimulation (tDCS) application to both healthy people and patients with neurologic disorder, and investigating the neurophysiological mechanism in the disease animal model. In general, tDCS can modulate cortical excitability and neural plasticity by polarity-dependent constant current stimulations, whereby anodal tDCS and cathodal tDCS provide facilitatory and inhibitory effects, respectively. Therefore, tDCS is of therapeutic potential to treat a spectrum of neuropsychiatric disorders. Our research focuses on the therapeutic effects and neurophysiological mechanisms of neuromodulation applied to seizure disorders and cognitive impairments.
1. Anodal tDCS to enhance cognition, from healthy subjects, diabetic patients with mild cognitive impairment, to disease animal model: We reported that anodal tDCS over the dorsolateral prefrontal cortex can facilitate visuospatial working memory in healthy young subjects and the beneficial effect of tDCS also showed in the diabetic patients who concomitantly suffered from peripheral neuropathy and mild cognitive impairment. We found that repeated anodal tDCS improved the spatial working memory in diabetic rats through the potentiation of synaptic plasticity by upregulating BDNF secretion and transcription/translation of NMDARs, and increasing the dendritic spine density.
2. Cathodal tDCS to alleviate seizures, from acute status epilepticus to chronic seizure animal models: Our studies find that in an acute sustained seizure rat model of status epilepticus, repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures, and in a chronic seizure animal model, we reveal an inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicating that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability. In the serial studies, we uncover how cathodal tDCS decreases the brain excitability in an epileptic brain via modulating the endogenous neural oscillations. With these advanced understandings of the neurophysiological basis of tDCS, we can optimize the clinical application of tDCS for the patients with neurological disorders.
- Yu TH, Wu YJ, Chien ME, Hsu KS*. Multisession anodal transcranial direct current stimulation enhances adult hippocampal neurogenesis and context discrimination in mice. Journal of Neuroscience 2023;43(4):635-646. (IF 6.709, 82.73% in Neurosciences) [Link]
- Wu YJ*, Chien ME, Chiang CC, Huang YZ, Durand DM, Hsu KS*. Delta oscillation underlies the interictal spike changes after repeated transcranial direct current stimulation in a rat model of chronic seizures. Brain Stimulation 2021;14(4):771-779. (IF 8.955, 93.99% in Clinical Neurology, 93.22% in Neuroscience, *corresponding and first author) [PDF] [Link]
- Wu YJ*, Chien ME, Huang CH, Chiang CC, Lin CC, Huang CW, Durand DM, Hsu KS*. Transcranial direct current stimulation alleviates seizure severity in kainic acid-induced status epilepticus rats. Experimental Neurology 2020;328:113264. (IF 5.33, Neurosciences 70/273, 74.54%, *corresponding and first author) [PDF] [Link]
- Wu YJ, Chiang CC, Chien ME, Huang CH, Hsu KS, Durand DM (2019, Oct). Transcranial direct current stimulation ameliorates status epilepticus in rats: From seizure severity, EEG, neuronal firing to epileptogenesis. Oral presentation, Neuroscience 2019, Society of Neuroscience, Chicago, USA.
- Wu YJ, Chien ME, Huang CH, Lin CC, Hsu KS (2018, Nov). Transcranial direct current stimulation ameliorated seizure severity and altered ictal EEG in the status epilepticus rats. Oral presentation, The Asian Oceanian Congress of Neurology, Seoul, Korea.
- Yu TH, Wu YJ, Chien ME, Hsu KS*. Transcranial direct current stimulation induces hippocampal metaplasticity mediated by brain-derived neurotrophic factor. Neuropharmacology 2019;144:358-367. (IF 5.251, Pharmacology & Pharmacy 54/276, 80.62%; Neurosciences 72/273, 73.81%) [PDF] [Link]
- Wu YJ, Lin CC, Yeh CM, Chien ME, Tsao MC, Tseng P, Huang CW, Hsu KS. Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats. Brain Stimulation 2017;10(6):1079-1087. (IF 8.955, Clinical Neurology 13/208, 93.99%; Neurosciences 19/273, 93.22%) [PDF] [Link]
- Wu YJ, Tseng P, Huang HW, Hu JF, Juan CH, Hsu KS, Lin CC. The facilitative effect of transcranial direct current stimulation on visuospatial working memory in patients with diabetic polyneuropathy: a pre-post sham-controlled study. Frontiers in Human Neuroscience 2016;10:479-489. (IF 3.169, Psychology 27/77, 65.58%) [PDF] [Link]
- Wu YJ, Tseng P, Chang CF, Pai MC, Hsu KS, Lin CC, Juan CH. Modulating the interference effect on spatial working memory by applying transcranial direct current stimulation over the right dorsolateral prefrontal cortex. Brain and Cognition 2014;91:87-94. (IF 2.310, Psychology, Experimental 51/91, 44.51%) [PDF] [Link]
Theme 2: Seizure and Epilepsy, Clinical and Basic Studies
- YT Fang, TL Lee, YH Tu, SH Lin, ME Chien, CW Huang, KS Hsu, YJ Wu*. Factors associated with mortality in patients with super-refractory status epilepticus. Scientific Reports 2022;12(1): 9670. (IF 4.38, Multidisciplinary Sciences 17/72, 77.08%) [PDF] [Link]
- Lai MC, Hung TY, Lin KM, Sung PS, Wu SJ, Yang CS, Wu YJ, Tsai JJ, Wu SN†, Huang CW*. Sodium Metabisulfite: Effects on Ionic Currents and Excitotoxicity. Neurotoxicity Research 2018;34(1):1-15.
- Lai MC, Lin KM, Tsai JJ, Wu YJ, Huang CW. Dupuytren’s contracture: subacute onset after long-term antiepileptic drug use. Neuropsychiatry 2016;6(6): 366-368.
- Chow JC, Huang CW, Fang CW, Wu YJ, Tsai JJ. Lamotrigine-induced hypersensitivity syndrome in a Han Chinese patient with the HLA-B*5801 genotype. Neurological Sciences 2013;34(1):117-119.
- Wu YJ, Lin CC. Cold-induced eyelid myotonia. Neurology 2013;80(8):e81-e81. (IF 8.166) [PDF]
- Wu YJ, Pai MC. Two gloves and one sock syndrome after a pontine hemorrhage. Neurologist 2012;18(4):196-198. [PDF]
- Wu YJ, Tsai TT, Huang CW. Conjugate eye deviation shifting in hemispheric stroke indicates an emerging mass effect. Journal of Clinical Neuroscience 2011; 18(9):1276-1278. [PDF]
- Hsieh CY, Chiou NJ, Wu YJ, Tsai JJ, Huang CW. Somatosensory rub evoked reflex epilepsy of a temporal lobe origin. Neurological Sciences 2011;32(2):297-299.
- Huang CW, Wu YJ, Wu SN. Modification of activation kinetics of delayed rectifier K+ currents and neuronal excitability by methyl-β-cyclodextrin. Neuroscience 2011;176:431-41.
- Wu YJ, Lai ML, Huang CW. Reversible postvaccination paraneoplastic encephalomyelitis in a patient with lung adenocarcinoma. International Journal of Neuroscience 2010;120(12):792-795. [PDF]
- Wu YJ, Tsai JJ, Huang CW. Nonketotic hyperglycemia-related reflex epileptic seizures induced by Mah-Jong playing. Epilepsy & Behavior 2010;19(3):533-535. [PDF]
Theme 3: Neuromodulation & Neurosciences
- Chen CH, Tsai TC, Wu YJ, Hsu KS*.Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice. JCI insight 2023 May 18;e161874.(IF 9.496, Medicine, Research & Experimental 19/139, 86.69%) [Link]
Book Chapter
- 黃英儒,莊雯莉,呂明桂等人.非侵入性腦刺激術-基礎、臨床與研究.民國111年9月初版.合記. 吳怡真,第11章,經顱直流電刺激的電生理與細胞分子機轉. [Book]
研究成果
(1)經顱直流電刺激用於促進認知功能的效應與機轉研究 陽極經顱直流電刺激雖廣泛被用於認知與學習的神經心理學實驗,而其神經生理尚未完全清楚。基於對認知功能的興趣一開始實驗室利用經顱直流電刺激施予背外側前額葉於一般正常受試者,測試其對視知覺空間工作記憶的影響,並搭配動作干擾的實驗設計,研究證實陽極經顱直流電刺可促進前額葉的空間工作記憶功能,尤其是在有干擾的狀況下直流電刺激的效應更加顯著(2014 Brain and Cognition)。此研究的進行奠定了研究團隊在認知神經科學上的基礎,也幫助將這方面的研究帶進臨床運用在病人身上。吳醫師在日常的神經科病患診視中發現糖尿病患者在神經方面的表現不僅只有周邊神經病變,也有認知功能的缺損,透過認知評估發現這群病人合併有輕度認知功能障礙(mild cognitive impairment, MCI),其空間工作記憶也有缺損,透過右背外側前額葉施予陽極經顱直流電刺激可以提升這群病人的空間工作記憶缺失,此一研究開啟了運用非侵襲性微量電流改善疾病相關的認知功能障礙的可能性(2016 Frontiers in Human Neuroscience)。為了解陽極經顱直流電刺激對糖尿病認知功能提升的神經生理機制,研究團隊利用糖尿病疾病動物模式證實此由顱外提供的非侵襲性弱電流刺激可以藉由改善疾病動物中受損的神經可塑性,促進調節神經可塑性相關的神經傳遞物質與神經滋養因子的表現,並增加樹突棘數目,穿顱直流電刺激除了活化電導極下方的神經元活性,也活化了其旁鄰區域與功能性連結的遠方區域。上述研究發現都是此領域重要而尚未清楚的議題,也提供未來臨床運用於神經精神疾患重要的基礎依據(2017 Brain Stimulation,2020 Neuropharmacology)。
(2)癲癇重積症的臨床研究 癲癇是腦部神經元異常興奮放電的表現,癲癇重積症是癲癇持續發作無法自行停止的神經科急重症,病人在持續嚴重的癲癇發作之下往往需要呼吸道插管使用呼吸器、使用抗癲癇藥與麻醉鎮定藥物合併多種治療,往往伴隨高死亡率與併發症,而死亡相關的原因多重複雜尚未被清楚了解。我們回顧成大醫院13年期間收治的超級難治型癲癇重積症患者,剖析致病原因、病程進展、治療與反應、抗癲癇與麻醉鎮定藥物的使用、及併發症等各種與死亡相關的因素,並提出可能減少死亡率的治療建議,提供第一線治療難治型癲癇重積症具體實際的幫助(2022 Scientific Reports)。
(3)經顱直流電刺激用於治療癲癇重積症的效應與機轉研究 為了解決上述藥物難治型癲癇重積症此一重要臨床問題,實驗室運用陰極經顱直流電刺激(transcranial direct current stimulation, tDCS)於嚴重持續發作的急性癲癇重積症動物模式。為了進行相關研究,實驗室在科技部研究計畫經費的支持下建立癲癇動物模式,並建置活體清醒動物配合行為同步腦部電生理記錄的軟硬體設施,以及活體經顱直流電刺激合併同時腦部電生理活動記錄的技術。我們的研究發現經顱直流電刺激可以減少嚴重癲癇的發作、亦可調節癲癇腦波頻譜共振、並減少其神經後遺症(2020 Experimental Neurology)。在後續系列研究中則以慢性自發性癲癇動物模式探討機制,驗證經顱直流電刺激可以藉由增強腦內自生性的低頻腦波共振作為抑制癲癇興奮性的神經生理機制,此研究結果揭示非侵襲性微量陰極直流電對癲癇興奮性調節的病態生理機制,獲刊登於領域代表期刊(2021 Brain Stimulation, IF 8.955, 6.01% in Clinical Neurology, 6.78% in Neuroscience)。神經調節術因為科技的進步,未來將有越來越多的機會被運用到疾病的治療,因此神經調節的效應與機制更顯重要,此兩篇研究對非侵襲性腦刺激術調節癲癇提供重要的轉譯研究證據,也為目前最具挑戰的難治型癲癇的臨床困境提供新的治療契機,並提供學理上的神經生理機制作為後續臨床試驗的基礎。