Neural excitatory rebound induced by valproic acid may predict its inadequate control of seizures

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).