Less efficacy of valproic acid monotherapy may be caused by neural excitatory rebound in focal seizures

Valproic acid (VPA) represents one of the most efficient antiepileptic drugs (AEDs) with either general or focal seizures, but a certain percentage of patients are not recovered or even worse, the mechanism under this phenomenon remains unclear. Here, we retrospectively reviewed 16 patients who received awake craniotomy surgery. Intro-operative high density electrocorticogram (ECoG) was used to record the local field potential (LFP) response to VPA treatment. We found the less efficacy of VPA monotherapy was associated with ECoG spectrum power shift from higher to lower frequency after VPA injection, together with increased synchronization of the LFP. Furthermore, we established the computational model to testify the hypothesis that the ineffectivity of VPA may be caused by excitatory dynamic rebound during the inhibitory power increasing. In addition to test the hypothesis, we employed the mice with Kanic Acid (KA)-induced epileptic model to confirm that it would be inhibited by VPA on behavior and neural activity. Also, the neural activity shows significant rebound on spike firing. Then we discovered that the LFP would increase the power spectral density in multiple wave bands after the VPA delivers. These findings suggest that less efficacy of valproic acid monotherapy in focal seizures may be caused by neural excitatory rebound which mediated by elevated inhibitory power. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Chinese National Natural Science Foundation of China (Grant numbers 6212780073, 81970418, 31570921), Xinglin Scholar of Shanghai University of Traditional Chinese Medicine (Grant No. A1-U1820501040222), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZJLab; Science and Technology Commission of Shanghai Municipality (Grant No. 18JC1410403); MOE Frontiers Center for Brain Science. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of Huashan Hospital, Fudan University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. * AEDs : Antiepileptic Drugs KA : Kanic Acid VPA : sodium Valproate LFP : Local Field Potential i.p. : intraperitoneal ECoG : electrocorticography PSD : Power Spectral Density DEX : dexmedetomidine TCI : Target-Controlled Infusion OAA/S : Observer’s Assessment of Alertness/Sedation Scale IEDs : Interictal Epileptiform Discharges PSI : Phase Synchronization Index PLV : Phase Locking Value