Development of a quantification method of seizure susceptibility using brain-wide electrical spatiotemporal dynamics

• Project/Area Number: 19H03550
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Hokkaido University (2021-2022); Osaka City University (2020); Nagoya City University (2019)
• Principal Investigator: 竹内 雄一 北海道大学, 薬学研究院, 准教授 (70588384)
• Co-Investigator(Kenkyū-buntansha): 大澤 匡弘 名古屋市立大学, 医薬学総合研究院(薬学), 准教授 (80369173)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2022: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2021: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: てんかん / 脳波 / 発作感受性 / バイオマーカー / 機械学習 / けいれん準備性 / 局所電場電位 / クロススペクトル因子分析法

Outline of Research at the Start

てんかんは脳内にけいれん準備性が形成されて、発作を繰り返し起こすようになる病態である。てんかんを根治するためには、けいれん準備性を客観的に評価し、低減・消去する手法を開発する必要がある。しかしこれまでけいれん準備性の実態が不明で、その評価が困難であることが根治療法の研究開発を妨げてきた。そこで本研究では、まずてんかん動物モデルおよびてんかん患者の神経活動記録からけいれん準備性を説明するパターンを情報学的手法で抽出・同定し、その程度をスコアとして定量化する技術を確立する。次にその定量法と経頭蓋脳深部刺激法等を組み合わせ、けいれん準備性スコアを低減する手法を見いだすことを目的とする。

Outline of Annual Research Achievements

てんかんは何らかの原因で脳内に発作感受性/けいれん準備性（発作の起こしやすさ）が形成されて、発作を繰り返し生じる病態である。てんかん根治のためには、発作感受性を客観的に評価し、低減・消去する手法を開発する必要がある。しかしこれまで発作感受性の定量法の欠如が根治療法の研究開発を妨げてきた。そこで本研究では、大規模脳活動記録から発作感受性を説明する脳活動パターンを情報学的手法で抽出・同定して発作感受性の程度を定量化する技術を開発すること、および同定した脳活動パターンの解析とその定量法を用いて発作感受性を低減・消去する手法を創出することを目的とした。
令和３年度までに発作感受性脳活動パターンの抽出・モデル化に成功していた。当該成果を受け、令和４年度はさらに以下の項目を達成した。
1. 発作感受性を低減する脳深部刺激法の開発：発作感受性脳活動パターンが乏しい脳状態をトリガーにした報酬系脳領域刺激で発作感受性が低い脳状態を強化することで、発作感受性を低減するてんかん根治療法の開発を目指した。まず前年度までに見出した発作感受性を説明する脳活動パターンを実時間検出するアルゴリズムを確立した。次に報酬系脳領域に刺激電極を刺入し、条件付け場所嗜好性試験により、当該脳部位の電気刺激によるオペラント条件付けの成立を確認した。
2. 新しい経頭蓋脳刺激法の開発：経頭蓋集束超音波刺激法は経頭蓋集束電気刺激法に比べて空間解像度および深部到達性が高い。そこで自由行動ラットの頭蓋骨に慢性留置可能な小型超音波トランスデューサーを作製した。
3. 臨床研究：難治性てんかん患者を対象にした閉ループ経頭蓋集束電気刺激法の臨床研究をハンガリーにおいて実施した。検討を行った5人全ての患者において閉ループ経頭蓋集束電気刺激法による顕著な発作制御効果を認めた。重篤な有害事象は認められなかった。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] セゲド大学(ハンガリー)
• [Int'l Joint Research] ニューヨーク大学(米国)
• [Int'l Joint Research] セゲド大学(ハンガリー)
• [Int'l Joint Research] ニューヨーク大学/ハーバード大学(米国)
• [Int'l Joint Research] セゲド大学(ハンガリー)
• [Int'l Joint Research] ニューヨーク大学/デューク大学/ハーバード大学(米国)
• [Int'l Joint Research] シンガポール国立大学(シンガポール)
• [Int'l Joint Research] セゲド大学(ハンガリー)
• [Int'l Joint Research] ニューヨーク大学/ハーバード大学/デューク大学(米国)
• [Int'l Joint Research] シンガポール国立大学(シンガポール)
• [Journal Article] 1. Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression. (2023)
  • Author(s): Li, Q.*, Takeuchi, Y.*, Wang, J., Barcsai, L., Pedraza, L.K., Kozak, G., Nakai, S., Kato, S., Kobayashi, K., Ohsawa, M., Lorincz, M.L., Devinsky, O., Buzsaki, G. and Berenyi, A. * Equal contribution
  • Journal Title: Neuron Volume: In press Issue: 13 Pages: 1-11
  • DOI: 10.1016/j.neuron.2023.04.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Time-targeted stimulation of the bran rewarding system as a novel brain disorder treatment (2023)
  • Author(s): Hara K, Takeuchi Y
  • Journal Title: Medical Science Digest Volume: 49 Pages: 154-156
• [Journal Article] Editorial: Oscillotherapeutics - Toward real-time control of pathological oscillations in the brain (2022)
  • Author(s): Takeuchi Y, Li Q, Kawano T, Nagai J, Mima T
  • Journal Title: Front Behav Neurosci Volume: 16 Pages: 1021616-1021616
  • DOI: 10.3389/fnbeh.2022.1021616
  • Open Access / Int'l Joint Research
• [Journal Article] Closed-loop brain stimulation to reduce pathologic fear (2022)
  • Author(s): Sierra RO, Pedraza LK, Barcsai L, Peijin A, Kozak G, Takeuchi Y, Lorincz ML, Devinsky O, Buzsaki G, Berenyi A
  • Journal Title: bioRxiv Volume: - Pages: 501314-501314
  • DOI: 10.1101/2022.07.24.501314
  • Open Access / Int'l Joint Research
• [Journal Article] 超音波ニューロモデュレーション (2022)
  • Author(s): 竹内雄一、関和彦
  • Journal Title: Clinical Neuroscience Volume: 40 Pages: 249-253
• [Journal Article] Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression (2022)
  • Author(s): Li Q, Takeuchi Y, Wang J, Barcsai L, Pedraza L, Kozak G, Nakai S, Kato S, Kobayashi K, Ohsawa M, Lorincz ML, Devinsky O, Buzsaki G, Berenyi A
  • Journal Title: bioRxiv Volume: 2022.02.01 Pages: 478683-478683
  • DOI: 10.1101/2022.02.01.478683
  • Open Access / Int'l Joint Research
• [Journal Article] Reduced MC4R signaling alters nociceptive thresholds associated with red hair (2021)
  • Author(s): Robinson KC, Kemeny LV, Fell GL, Hermann AL, Allouche J, Ding W, Yekkirala A, Hsiao JJ, Su MY, Theodosakis N, Kozak G, Takeuchi Y, Shen S, Berenyi A, Mao J, Woolf CJ, Fisher DE
  • Journal Title: Sci Adv Volume: 7 Issue: 14
  • DOI: 10.1126/sciadv.abd1310
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies (2021)
  • Author(s): Takeuchi Yuichi、Nagy Anett J.、Barcsai Livia、Li Qun、Ohsawa Masahiro、Mizuseki Kenji、Berenyi Antal
  • Journal Title: Frontiers in Neural Circuits Volume: 15 Pages: 701080-701080
  • DOI: 10.3389/fncir.2021.701080
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] オシレーション治療 (2021)
  • Author(s): 竹内雄一
  • Journal Title: Clinical Neuroscience Volume: 39 Pages: 847-851
• [Journal Article] Closed-loop stimulation of the medial septum terminates epileptic seizures (2021)
  • Author(s): Takeuchi Y, Harangozo M, Pedraza L, Foldi T, Kozak G, Li Q, Berenyi A
  • Journal Title: Brain Volume: 114 Issue: 3 Pages: 885-908
  • DOI: 10.1093/brain/awaa450
  • NAID: 130008001593
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a neural probe integrated with high-efficiency MicroLEDs for in vivo application (2020)
  • Author(s): Yasunaga H, Takagi T, Shinko D, Nakayama Y, Takeuchi Y, Nishikawa A, Loesing A, Ohsawa M, Sekiguchi H
  • Journal Title: Jpn J Appl Phys Volume: 60 Issue: 1 Pages: 16503-16503
  • DOI: 10.35848/1347-4065/abcffa
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oscillotherapeutics - Time-targeted interventions in epilepsy and beyond (2020)
  • Author(s): Takeuchi Y, Berenyi A
  • Journal Title: Neurosci Res Volume: 152 Pages: 87-107
  • DOI: 10.1016/j.neures.2020.01.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Closed-loop stimulation of the medial septum terminates epileptic seizures (2020)
  • Author(s): Takeuchi Y, Harangozo M, Pedraza L, Foldi T, Kozak G, Berenyi A
  • Journal Title: bioRxiv Volume: 3
  • DOI: 10.1101/2020.03.09.982827
  • NAID: 130008001593
  • Open Access / Int'l Joint Research
• [Journal Article] Tonic GABAergic inhibition is essential for nerve injury-induced afferent remodeling in the somatosensory thalamus and associated ectopic sensations (2020)
  • Author(s): Nagumo Y, Ueta Y, Nakayama H, Osaki H, Takeuchi Y, Uesaka N, Kano M, Miyata M
  • Journal Title: Cell Rep Volume: 31 Issue: 12 Pages: 107797-107797
  • DOI: 10.1016/j.celrep.2020.107797
  • Peer Reviewed / Open Access
• [Journal Article] The metabotropic glutamate receptor subtype 1 regulates development and maintenance of lemniscal synaptic connectivity in the somatosensory thalamus (2019)
  • Author(s): Narushima M, Yagasaki Y, Takeuchi Y, Aiba A, Miyata M
  • Journal Title: PLoS ONE Volume: 14 Issue: 12 Pages: 820-820
  • DOI: 10.1371/journal.pone.0226820
  • Peer Reviewed / Open Access
• [Journal Article] A collagen-coated PGA conduit for interpositional-jump graft with end-to-side neurorrhaphy for treating facial nerve paralysis in rat (2018)
  • Author(s): Niimi Yosuke、Matsumine Hajime、Takeuchi Yuichi、Osaki Hironobu、Tsunoda Satoshi、Miyata Mariko、Yamato Masayuki、Sakurai Hiroyuki
  • Journal Title: Microsurgery Volume: Epub ahead of print Issue: 1 Pages: 70-80
  • DOI: 10.1002/micr.30291
  • Peer Reviewed / Open Access
• [Presentation] Bidirectional GABAergic and cholinergic modulation of delta-band activities in a hippocampal-like circuit in silico (2023)
  • Author(s): Itagaki K, Minami M, Takeuchi Y
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Transcranial sonoporation technology for non-invasive gene transfection to neurons in the cerebral cortex (2023)
  • Author(s): Mimura T, Chan M, Minami M, Takeuchi Y
  • Organizer: The 143rd Annual Meeting of the Pharmaceutical Society of Japan
• [Presentation] Controlling pathologic fear expression through closed-loop brain stimulation (2022)
  • Author(s): Sierra RO, Pedraza LK, Barcsai L, Peijin A, Kozak G, Takeuchi Y, Lorincz M, Berenyi A
  • Organizer: The 52nd SfN Annual Meeting
  • Int'l Joint Research
• [Presentation] Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents (2022)
  • Author(s): Li Q, Takeuchi Y, Wang J, Barcsai L, Pedraza KL, Kozak G, Nakai S, Kato S, Kobayashi K, Ohsawa M, Lorincz ML, Devinsky O, Buzsaki G, Berenyi A
  • Organizer: The 52nd SfN Annual Meeting
  • Int'l Joint Research
• [Presentation] A neural basis of decision-making under conflicting predictions of reward and punishment (2022)
  • Author(s): Yoshida K, Chan M, Li Q, Pedraza L, Sierra R, Minami M, Berenyi A, Takeuchi Y
  • Organizer: The 52nd SfN Annual Meeting
  • Int'l Joint Research
• [Presentation] Initial evidence, safety and feasibility of Intersectional Short Pulse stimulation, a novel spatio-temporally focused closed-loop neuromodulation for drug resistant focal epilepsy (2022)
  • Author(s): Chadaide Z, Fabo D, Barcsai L, Pejin A, Foldi T, Furuglyas K, Somogyvari Z, Gyurkovics T, Nadasdi M, Rafi P, Kamondi A, Buzsaki G, Devinsky O, Eross LG, Berenyi A
  • Organizer: The 52nd SfN Annual Meeting
  • Int'l Joint Research
• [Presentation] A neural basis of decision-making under conflicting predictions of reward and punishment (2022)
  • Author(s): Yoshida K, Chan M, Li Q, Pedraza L, Sierra R, Berenyi A, Minami M, Takeuchi Y
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Decoding and quantification of seizure susceptibility with cross-regional oscillatory brain activity patterns in a rat model of temporal lobe epilepsy (2022)
  • Author(s): Takeuchi Y, Li Q, Berenyi A, Minami M
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Reduced operant task engagement and altered neural oscillations in a triple-hit rat model of schizophrenia (2022)
  • Author(s): Chan M, Li Q, Horvath G, Berenyi A, Minami M, Takeuchi Y
  • Organizer: The 45th Annual Meeting of the Japan Neuroscience Society
• [Presentation] Closed-loop control of neurological and psychiatric disorders (2022)
  • Author(s): Takeuchi Y
  • Organizer: BPCNPNPPP4
  • Invited
• [Presentation] Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression (2022)
  • Author(s): Li Q, Takeuchi Y, Wang J, Barcsai L, Pedraza KL, Kozak G, Nakai S, Kato S, Kobayashi K, Ohsawa M, Lorincz ML, Berenyi A
  • Organizer: IBRO Workshop 2022
  • Int'l Joint Research
• [Presentation] Controlling pathological fear expression through closed-loop brain stimulation (2022)
  • Author(s): Barcsai L, Sierra R, Pedraza L, Lakos B, Pejin A, Kozak G, Takeuchi Y, Foldi T, Lorincz M, Berenyi A
  • Organizer: IBRO Workshop 2022
  • Int'l Joint Research
• [Presentation] Closed-loop stimulation of the medial septum terminates epileptic seizures (2021)
  • Author(s): Takeuchi Y
  • Organizer: The 44th Annual Meeting of the Japan Neuroscience Society
  • Invited
• [Presentation] Closed-loop brain stimulation for controlling epileptic seizures (2021)
  • Author(s): Takeuchi Y
  • Organizer: The 51st Annual Meeting of the Japanese Society of Clinical Neurophysiology
  • Invited
• [Presentation] Closed-loop stimulation of the medial septum terminates epileptic seizures (2021)
  • Author(s): Takeuchi Y
  • Organizer: The 94th Annual Meeting of the Japan Pharmacological Society
• [Presentation] Closed-loop brain stimulation for epileptic seizures and beyond (2021)
  • Author(s): Takeuchi Y
  • Organizer: The 98th Annual Meeting of the Physiological Society of Japan
• [Presentation] The metabotropic glutamate receptor subtype 1 regulates development and maintenance of lemniscal synaptic connectivity through cortical activity in the somatosensory thalamus (2020)
  • Author(s): Narushima M, Yagasaki Y, Takeuchi Y, Aiba A, Miyata M
  • Organizer: FENS Meeting 2020
  • Int'l Joint Research
• [Presentation] Controlling fear expression through closed-loop intervention: Sharp-waves ripples triggering medial forebrain bundle stimulation enhance extinction and induce long-lasting fear attenuation (2020)
  • Author(s): Pedraza L, Sierra R, Takeuchi Y, Kozak G, Peijin A, Berenyi A
  • Organizer: FENS Meeting 2020
  • Int'l Joint Research
• [Presentation] Controlling fear expression through closed-loop intervention: Sharp-waves ripples triggering medial forebrain bundle stimulation enhance extinction and induce long-lasting fear attenuation (2020)
  • Author(s): Pedraza L, Sierra R, Takeuchi Y, Kozak G, Peijin A, Berenyi A
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] On-demand interventions of epileptic seizures and beyond (2020)
  • Author(s): Takeuchi Y
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Closed-loop stimulation of the medial septum terminates epilepsy seizures in rats (2020)
  • Author(s): Takeuchi Y, Harangozo M, Pedraza L, Foldi T, Kozak G, Berenyi A
  • Organizer: The 93th Annual Meeting of the Japan Pharmacological Society
• [Presentation] 時空間特異的な脳活動介入によるてんかんの制御 (2020)
  • Author(s): 竹内雄一
  • Organizer: 第29回神経行動薬理学若手研究者の集い
• [Presentation] A closed-loop proxy-intervention of epileptic seizures (2020)
  • Author(s): Takeuchi Y, Harangozo; M, Pedraza L, Foldi T, Kozak G, Berenyi A
  • Organizer: IBRO Workshop 2020
  • Int'l Joint Research
• [Presentation] The functional role of altered olfactory network synchrony in the development of depression (2020)
  • Author(s): Li Q, Takeuchi Y, Kozak G, Ohsawa M, Harangozo M, Berenyi A
  • Organizer: IBRO Workshop 2020
  • Int'l Joint Research
• [Presentation] Closed-loop manipulation of hippocampal ripples reduce persistent fear expression in animal model of posttraumatic-stress disorder (2020)
  • Author(s): Pedraza L, Sierra R, Takeuchi Y, Kozak G, Peijin A, Barcsai L, Berenyi A
  • Organizer: IBRO Workshop 2020
  • Int'l Joint Research
• [Presentation] Coding of self-motion-induced and self-independent visual motion in the rat dorsomedial striatum (2020)
  • Author(s): Nagy A, Takeuchi Y, Berenyi A
  • Organizer: IBRO Workshop 2020
  • Int'l Joint Research
• [Book] Oscillotherapeutics - Toward Real-Time Control of Pathological Oscillations in the Brain (2022)
  • Author(s): Takeuchi Y, Kawano T, Li Q, Mima T, Nagai J
  • Total Pages: 109
  • Publisher: Lausanne: Frontiers Media SA.
  • ISBN: 9782889764587
• [Book] タウ・バイオロジー（細胞 2021.1） (2021)
  • Author(s): 竹内雄一（分担執筆）
  • Total Pages: 68
  • Publisher: 北隆館
• [Book] 神経難病の治療開発update（BIO Clinica 2020.8） (2020)
  • Author(s): 竹内雄一（分担執筆）
  • Total Pages: 106
  • Publisher: 北隆館
• [Book] てんかんの進歩（Medical Science Digest 2020.2） (2020)
  • Author(s): 竹内雄一（分担執筆）
  • Total Pages: 60
  • Publisher: 北隆館
• [Book] 神経精神疾患のイメージング（Medical Science Digest 2020.6） (2020)
  • Author(s): 竹内雄一（分担執筆）
  • Total Pages: 88
  • Publisher: 北隆館
• [Remarks] researchmap
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• [Remarks] 研究グループウェブサイト
  • URL: https://ytakelab.notion.site/Takeuchi-lab-e8b576adbca245e3b633705c65abce80
• [Remarks] 個人ホームページ
  • URL: https://ytake.org/
• [Funded Workshop] Symposium: Cutting-edge closed-loop and non-invasive brain stimulation technologies for neurological and psychiatric disorders (2020)