Cortico-cortical evoked potentials: Analytical techniques and emerging paradigms for epileptogenic zone localization

Cortico-cortical evoked potentials (CCEPs) are an active electrophysiological technique used during intracranial electroencephalography to evaluate the effective connectivity and influence of therapeutic stimulation between distinct cortical regions and pinpoint epileptogenic zones (EZs) in patients with epilepsy. Various methodologies have been implemented to analyze CCEPs and characterize the epileptogenic networks for EZ localization. Despite its promise, their interpretation remains challenging due to the large volumes of spatially and temporally complex data generated. Early studies focused largely on qualitative descriptors and predefined, semi-quantitative features such as waveform morphology and peak latencies. However, these methods are limited by the significant heterogeneity in CCEP waveform conformations across patients and cortical regions. The specific technique used for extraction of features, such as the spectral band power and root mean squared values, remains open to empirical refinement, as does choice of appropriate latency windows, with no consensus reached regarding the optimal approach. Graph theoretical metrics such as degree centrality, betweenness centrality, and clustering coefficients can provide a rich representation of epileptogenic network connectivity. However, these metrics are often abstract and difficult to interpret in a clinical setting or to the non-expert, and their neuroscientific substrates remains poorly understood. The lack of standardization in stimulation protocol and data-processing pipelines has further contributed to inconsistency in reported findings. Emerging machine learning approaches have been increasingly applied to CCEP data, offering a more data-driven and potentially generalizable way to identify electrophysiological biomarkers of the epileptogenic effective connectivity. In this article, we discuss qualitative, quantitative, and spectral features; network-analytical metrics; and more recently, data driven methodologies aimed at improving the interpretability and clinical utility of CCEP data.