Neural excitatory rebound induced by valproic acid may predict its inadequate control of seizures
Xiang Zou,
Zilu Zhu,
Yu Guo,
Hongmiao Zhang,
Yuchen Liu,
Zhengyu Cui,
Zunji Ke,
Shize Jiang,
Yusheng Tong,
Zehan Wu,
Ying Mao,
Liang Chen,
Deheng Wang
Affiliations
Xiang Zou
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
Zilu Zhu
School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Yu Guo
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Hongmiao Zhang
College of Mechanical and Electrical Engineering, Soochow University, Suzhou, 215000, China
Yuchen Liu
School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Zhengyu Cui
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Zunji Ke
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Shize Jiang
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
Yusheng Tong
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Zehan Wu
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
Ying Mao
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Tianqiao and Chrissy Chen International Institute for Brain Diseases, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200040, China; Corresponding authors at: Department of Neurosurgery, Huashan Hospital, Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China.
Liang Chen
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Tianqiao and Chrissy Chen International Institute for Brain Diseases, Shanghai 200040, China; Corresponding authors at: Department of Neurosurgery, Huashan Hospital, Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China.
Deheng Wang
School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Corresponding authors at: School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Rd, Shanghai 201203, China.
Summary: Background: Valproic acid (VPA) represents one of the most efficient antiseizure medications (ASMs) for both general and focal seizures, but some patients may have inadequate control by VPA monotherapy. In this study, we aimed to verify the hypothesis that excitatory dynamic rebound induced by inhibitory power may contribute to the ineffectiveness of VPA therapy and become a predictor of post-operative inadequate control of seizures. Methods: Awake craniotomy surgeries were performed in 16 patients with intro-operative high-density electrocorticogram (ECoG) recording. The relationship between seizure control and the excitatory rebound was further determined by diagnostic test and univariate analysis. Thereafter, kanic acid (KA)-induced epileptic mouse model was used to confirm that its behavior and neural activity would be controlled by VPA. Finally, a computational simulation model was established to verify the hypothesis. Findings: Inadequate control of seizures by VPA monotherapy and post-operative status epilepticus are closely related to a significant excitatory rebound after VPA injection (rebound electrodes≧5/64, p = 0.008), together with increased synchronization of the local field potential (LFP). In addition, the neural activity in the model mice showed a significant rebound on spike firing (53/77 units, 68.83%). The LFP increased the power spectral density in multiple wavebands after VPA injection in animal experiments (p < 0.001). Computational simulation experiments revealed that inhibitory power-induced excitatory rebound is an intrinsic feature in the neural network. Interpretation: Despite the limitations, we provide evidence that inadequate control of seizures by VPA monotherapy could be associated with neural excitatory rebounds, which were predicted by intraoperative ECoG analysis. Combined with the evidence from computational models and animal experiments, our findings suggested that ineffective ASMs may be because of the excitatory rebound, which is mediated by increased inhibitory power. Funding: This work was supported by National Natural Science Foundation of China (62127810, 81970418), Shanghai Municipal Science and Technology Major Project (2018SHZDZX03) and ZJLab; Science and Technology Commission of Shanghai Municipality (18JC1410403, 19411969000, 19ZR1477700, 20Z11900100); MOE Frontiers Center for Brain Science; Shanghai Key Laboratory of Health Identification and Assessment (21DZ2271000); Shanghai Shenkang (SHDC2020CR3073B).
