Nonlinear hemodynamic responses in human epilepsy: a multimodal analysis with fNIRS-EEG and fMRI-EEG

Functional magnetic resonance imaging (fMRI) combined with electroencephalography (fMRI-EEG) is a neuroimaging technique based on the blood oxygenation level dependent (BOLD) signal which has been shown to be useful in the study of epilepsy for the localization of the epileptogenic focus. Functional near-infrared spectroscopy (fNIRS) combined with EEG (fNIRS-EEG) is another imaging technique based on the measurement of oxygenated and deoxygenated hemoglobin with complementary clinical potential in epilepsy, for continuous patient monitoring, language lateralization, and focus localization. In this work fMRI-EEG and fNIRS-EEG are used to quantify nonlinear hemodynamic responses in three cases of human refractory focal epilepsy, by using the Volterra kernel expansion up to second order. Prior to analyzing real data, extensive simulations are carried out to show that nonlinearities are estimable. The Volterra methodology is then applied to multimodal data recorded from 3 epileptic patients selected for their frequent spiking activity. Care is taken to account for variability of hemodynamic responses due to other causes than Volterra nonlinearities. Statistically significant nonlinearities are observed for all patients and all modalities. Good concordance between fNIRS and fMRI is found for both the amplitude of the Volterra responses, and, with limitations, in the localization of the epileptic focus and regions of inverted responses (negative BOLD signals). In one patient, Volterra nonlinearities allowed epileptic focus identification with fMRI, while analyses without nonlinearities failed to see it. In simulations when nonlinearities were included, analysis without Volterra nonlinearities performed poorly. These two observations suggest routinely checking for nonlinearities in functional imaging of patients presenting with frequent spikes.