Phase-Amplitude Coupling between Infraslow and High-Frequency Activities is a Potential Biomarker for Seizure Prediction
Authors: Hashimoto Hiroaki , Khoo Hui Ming , Yanagisawa Takufumi , Tani Naoki , Oshino Satoru , Kishima Haruhiko , Hirata Masayuki 
Published: November 2020

IMPORTANCEThis research describes a method to accurately predict the onset of epileptic seizures; this will help treat patients timely, prevent future seizures, and improve outcomes.OBJECTIVEWe aimed to assess whether the phase-amplitude coupling (PAC) between infraslow activities (ISA) and high-frequency activities (HFA) increases before seizure onset.DESIGN AND SETTINGThis retrospective, single-center case series included patients admitted to the neurosurgery department at Osaka University Hospital in Suita, Osaka, from July 2018 to July 2019.PARTICIPANTSWe enrolled seven patients with drug-resistant focal epilepsy who underwent intracranial electrode placement as part of a presurgical invasive electroencephalography study.MAIN OUTCOMES AND MEASURESWe comparatively analyzed the ISA, HFA, and ISA-HFA PAC in the seizure onset zone (SOZ) or non-SOZ (nSOZ) in the interictal, preictal, and ictal states.RESULTSWe recorded 15 seizures in seven patients [1 female (14%); mean (SD) age = 26 (12) years; age range, 15-47 years]. HFA and ISA were larger in the ictal states than in the interictal and preictal states. During seizures, the HFA and ISA of the SOZ were larger and earlier than those of nSOZ. In the preictal states, the ISA-HFA PAC was larger than that of the interictal states, and it began increasing at 93 seconds before the seizure onset (95% confidence interval: −116 – −71 s). There were no differences in the values and time of ISA-HFA PAC between both zones. Our phase-based analysis revealed differences between the SOZ- and nSOZ-PAC. In SOZ, the HFA amplitudes were tuned at the trough of the ISA oscillations, and in nSOZ, the HFA amplitudes were tuned at the peak of these oscillations. The receiver-operating characteristic curve showed that the ISA-HFA PAC of the SOZ showed the highest discrimination performance in the preictal and interictal states, with an area under the curve (AUC) of 0.926. However, ISA-HFA PAC was not suitable to differentiate between SOZ and nSOZ (interictal AUC = 0.555, preictal AUC = 0.691, and ictal AUC = 0.646).CONCLUSION AND RELEVANCEThis study demonstrated the novel insight that ISA-HFA PAC increases before the onset of seizures, regardless of the seizure onset zone. Our findings indicate that ISA-HFA PAC is a potential biomarker for predicting the onset of seizures and may be valuable to physicians who routinely treat epileptic patients.Key PointsQuestionIs phase-amplitude coupling (PAC) between infraslow activities (ISA) and high-frequency activities (HFA) a useful biomarker for seizure prediction?FindingsIn this case series study on 15 focal-onset seizures in seven epileptic patients who underwent intracranial electrode placement, we found that a PAC of the ISA phase and HFA amplitude achieved significantly higher values in preictal states than in the interictal states, and ISA-HFA PAC of the seizure onset zone (SOZ) began increasing at 93 seconds before seizure onset (SO), while both HFA and ISA increased after SO. The receiver-operating characteristic curve showed that the ISA-HFA PAC of the SOZ showed the highest discrimination performance in the preictal and interictal states, with an area under the curve of 0.926.MeaningThis study demonstrates that ISA-HFA PAC can differentiate between the preictal and interictal states of a seizure, indicating that it is a potential marker for seizure prediction.