Patent Granted: Our invention, " A method for detection of high-density epileptic spikes", was granted approval for a Taiwan Patent. (I876981, 2025/3/11-2044/5/5)
我們的發明"高密度癲癇棘波檢測方法"獲得經濟部智慧財產局核准台灣專利. (發明第 I876981號, 專利權期間2025/3/11-2044/5/5)
Book Chapter
Publications
Theme 1: Transcranial Direct Current Stimulation, Clinical and Basic Research
We have been working on the transcranial direct current stimulation (tDCS) application to healthy people and patients with neurological disorders, and investigating the neurophysiological mechanism in the disease animal model. 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.
Chiang CC, Chien ME, Huang YC, Lin JT, Liang SF, Hsu KS, Durand DM, Wu YJ*. Cathodal weak direct current decreases epileptic excitability with reduced neuronal activity and enhanced delta oscillations. Journal of Physiology 2025;603(9):2763-2782. (IF 4.4, 89.1% in Physiology) [PDF] [Link]
Chiang CC, Chien ME, Huang YC, Liang SF, Hsu KS, Durand DM, Wu YJ* (18 Jun 2024). Noninvasive subthreshold current decreases seizure excitability by reducing neuronal activity and enhancing spike-delta wave coupling. 10th Annual BRAIN Initiative Conference, Rockville, MD, USA.
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) [PDF] [Link]
Wu YJ*, Chiang CC, Chien ME, Huang YC, Liang SF, Hsu KS, Durand DM (14 Nov 2023). Cathodal transcranial direct current stimulation decreases the epileptic excitability: From neuronal firings to local field potential oscillations. 2023 Neuroscience, Society of Neuroscience, Washington DC, USA.
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 Neurosciences, *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, 2019 Neuroscience, 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: Clinical Studies: Seizure, Epilepsy and General Neurology
PY Lin, CT Hsiao, HW Huang, YJ Wu, SJ Fu, YC Lee*. Intrafamilial Phenotypic Variation in Taiwanese Patients with Hereditary Spastic Paraplegia and Charcot-Marie-Tooth Disease Due to KIF5A Mutations: A Cross-Sectional Observational Study. Acta Neurol Taiwan 2025 Jun 11. Online ahead of print. [Link]
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: Vagus Nerve: Neuromodulation & Neuroscience
Yu-Chieh Hung, Yi-Jen Wu, Miao-Er Chien, Yu-Ting Lin, Cheng-Fang Tsai, Kuei-Sen Hsu*. Loss of oxytocin receptors in hilar mossy cells impairs social discrimination. Neurobiology of Disease 2023;187:106311. [PDF] [Link]. (IF 6.1, Neurosciences 84.7% )
Fang YT† , Lin YT† , Tseng WL, Tseng P, Hua GL, Chao YJ, Wu YJ*. Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications. Frontiers in Aging Neuroscience 2023;15:1173987. [PDF] [Link]. (IF 5.702, Neurosciences 75.82%)
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;8(22):e161874.(IF 9.496, Medicine, Research & Experimental 19/139, 86.69%) [PDF] [Link]
Theme 4: Focus Ultrasound in Epilepsy
Pei-Hsuan Wu, Miao-Er Chien, Yi-Jen Wu*, Ching-Hsiang Fan*. Focused ultrasound combined with drug-loaded microbubbles suppresses ictal spikes in kainic acid-induced epileptic animals. Ultrasonics Sonochemistry 2025 September, 120:107518. [PDF] [Link] (IF 9.7, Acoustics 98.8% )
Patent
Title of Invention: A method for detection of high-density epileptic spikes 高密度癲癇棘波檢測方法
Inventor: Yi-Jen Wu*, Sheng-Fu Liang, Jyun-Ting Lin
Application filed by National Cheng Kung University on May 6, 2024.
Application No: I876981.
Application Country: Taiwan.
Patent Period: 2025/3/11-2044/5/5
Research Findings
經顱直流電刺激用於促進認知功能的效應與機轉研究
實驗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)。
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)。
經顱直流電刺激用於治療癲癇的效應與機轉研究
為了解決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)。我們在海馬迴CA1記錄到透過經顱微弱電流刺激產生的對應電場,這個誘發電場大小高度正對應於顱外電刺激的強度。陰極弱直流電刺激顯著降低了這些癲癇興奮神經元的放電頻率,而陽極刺激則呈現相反效果,展示出極性特異性與電流強度依賴性的神經元放電反應。從細胞層次至群體層次的神經電生理研究,我們發現了陰極弱直流電刺激減少了LFP中癲癇尖峰數量與幅度、增加delta震盪頻譜強度,並透過抑制興奮性神經元活動、降低其放電頻率,藉由強化神經元放電與δ波的耦合來entrain局部電位頻譜往delta低頻增強,同時伴隨抑制性突觸可塑性的變化,藉此減輕癲癇的神經興奮性(2025 Journal of Physiology)。
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,此系列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,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,也可做為弱直流電運用於以過度興奮性為病生理的神經精神疾病之潛在應用基礎,並提供病生理機制作為後續臨床試驗的基礎。
高密度癲癇棘波檢測方法的開發
臨床腦波的判讀我們以pattern and evolution來判斷epileptiform discharge或electrographic seizure的消長,而在waveform上臨床腦波以寬度(spike width)定義尖波或棘波,較少以高度(spike amplitude)或頻譜輔以定義,其實這些方法都是可以運用在臨床上的。臨床上會遇到的挑戰是如何具體量化high-density polyspikes,即便在演算法上其高密度、高變異度、也是挑戰,尤其是在癲癇重積狀態(status epilepticus)的長時段發作腦波long recording ictal EEG。這是我們開發這個high-density epileptic spike detection algorithm的初衷之一,希望有一個方法對於高密度連續癲癇尖棘波可以讀得又快又準,幫病人也幫醫師,除了運用於癲癇訊號的判讀,也可以做為治療的標的或對治療的反應指標。當然,利用頻譜分析的方法可以追求相同的目標,但另一個很有趣的契機是在標示出癲癇尖棘波之後這些spike在區域或網絡上的神經生理意義是甚麼?對於病生理的理解與治療,我們希望因此可以做更深入的研究與想像。因此在漫長的跨域合作努力之後誕生了這個方法,一個從我眼睛看出去然後比我看得更快更準更具體的spike detection algorithm。也希望這個方法能幫助臨床診斷、與癲癇電生理的研究,延伸更多的可能!