Hemodynamic surrogates for excitatory membrane potential change during interictal epileptiform events in rat...

Hemodynamic changes in the brain are often used as surrogates for epileptic neuronal activity in both the laboratory and the clinic (e.g., intrinsic signal, functional magnetic resonance imaging and single-photon emission computed tomography) in spite of the fact that perfusion-based signals have been shown to overestimate the population of spiking neurons. In addition, mechanisms of neurovascular coupling that apply during normal cortical processing may not be relevant in pathological circumstances such as epilepsy. For these reasons, we investigated the spatiotemporal dynamics of epileptic neurovascular coupling using voltage-sensitive dyes (VSDs) to generate spatial maps of excitatory membrane activity and intrinsic optical spectroscopy (IOS) to measure deoxy-hemoglobin and total hemoglobin, i.e., cerebral blood volume (CBV), in vivo during interictal spikes in rat neocortex to examine their spatiotemporal correlations. We hypothesized that the IOS signal would correlate spatially with subthreshold excitatory activity, which involves a larger area of cortex than suprathreshold neuronal spiking. However, we found that both perfusion and oximetric signals spatially overshot the extent of the excitatory VSD signal by approximately 2x. Nevertheless, a high correlation could be found at specific time points in the evolution and dissolution of the hemodynamic signals. The increase in deoxy-hemoglobin reached the highest correlation with the excitatory VSD signal earlier than CBV signals although CBV signals correlated equally well at certain time points. The amplitude of the hemodynamic signals had a linear correlation with the amplitude of the VSD signals except for small nonlinearities in the very center of the focus and in the periphery of the surround, indicating a tight spatial coupling. Our data suggest that hemodynamic signals can accurately define the spatial extent of excitatory interictal epileptiform subthreshold membrane activity at specific time points in their evolution.