Granger causality: Cortico-thalamic interdependencies during absence seizures in WAG/Rij rats

Abstract

Linear Granger causality was used to identify the coupling strength and directionality of information transport between frontal cortex and thalamus during spontaneous absence seizures in a genetic model, the WAG/Rij rats. Electroencephalograms were recorded at the cortical surface and from the specific thalamus. Granger coupling strength was measured before, during and after the occurrence of spike-wave discharges (SWD).

Before the onset of SWD, coupling strength was low, but associations from thalamus-to-cortex were stronger than vice versa. The onset of SWD was associated with a rapid and significant increase of coupling strength in both directions. There were no changes in Granger causalities before the onset of SWD. The strength of thalamus-to-cortex coupling remained constantly high during the seizures. The strength of cortex-to-thalamus coupling gradually diminished shortly after the onset of SWD and returned to the pre-SWD level when SWD stopped. In contrast, the strength of thalamus-to-cortex coupling remained elevated even after cessation of SWD.

The strong and sustained influence of thalamus-to-cortex may facilitate propagation and maintenance of seizure activity, while rapid reduction of cortex-to-thalamus coupling strength may prompt the cessation of SWD. However, the linear estimation of Granger coupling strength does not seem to be sufficient for predicting episodes with absence epilepsy.

Introduction

Over the years electroencephalography is widely used in clinical practice for the investigation, classification and diagnosis of epileptic disorders. The electroencephalogram (EEG) provides valuable information in patients with typical and atypical epileptic syndromes and offers also important prognostic information.

Absence epilepsy, previously known as petit mal, is classically considered as non-convulsive generalized epilepsy (classification of the International League Against Epilepsy, ILAE) of unknown etiology (refs. in Panayiotopoulos, 1997). Clinically, absence seizures occur abrupt, last several seconds up to a minute and are accompanied by a brief decrease of consciousness that interrupts normal behavior. Absences may either have or have no facial automatisms, e.g. minimal jerks and twitches of facial muscles, and eye blinks. In humans, EEGs during typical absence seizures are characterized by the occurrence of generalized 3–5 Hz spike-wave complexes which have an abrupt on- and offset (Bosnyakova et al., 2007; Panayiotopoulos, 1997). Similar EEG paroxysms, spike-and-wave discharges (SWD) appear in rat strains with a genetic predisposition to absence epilepsy, such as GAERS (Genetic Absence Epilepsy Rats from Strasbourg; Vergnes, 1987) and WAG/Rij (Wistar Albino Glaxo from Rijswijk, Coenen and van Luijtelaar, 2003; see also http://www.socsci.ru.nl/wagrij/info.0.html). The EEG waveform and duration (1–30 s, mean 5 s) of SWD in rats and in humans are comparable, but the frequency of SWD in rats is higher, 8–11 Hz (Midzianovskaia et al., 2001, Sitnikova and van Luijtelaar, 2007, van Luijtelaar and Coenen, 1986).

Several modern computational techniques and advanced methods of EEG analysis have been developed to extract “hidden” information from the EEG in order to localize the region of onset and to anticipate the onset of ‘absences’ as early as possible (in rats, Meeren et al., 2002; Refs. for human data in Mormann et al., 2007). Our experiments are carried out in WAG/Rij rats (van Luijtelaar and Coenen, 1986). Every subject of this strain has typical absence seizures that are accompanied with spontaneous SWD in the EEG. Previously we used EEG coherence to measure neuronal synchrony between populations of thalamic and cortical neurons (Sitnikova and van Luijtelaar, 2006). We found that the onset of SWD was characterized by area-specific increase of coherence and supports the idea that the cortico-thalamo-cortical circuitry is primarily involved in the initiation and propagation of SWD (Meeren et al., 2005, Steriade, 2005). Coherence is a traditional measure of linear correlations between two EEG channels in the frequency domain, but it does not assume directionality of inter-channel interactions and does not provide temporal (time-domain) information of the EEG signals (Challis and Kitney, 1991). Granger causality compensates for these limitations (Ancona et al., 2004, Feldmann and Bhattacharya, 2004, Granger, 1969, Hlavackova-Schindler et al., 2007, Pereda et al., 2005). Granger causality concept can be used to determine directional coupling characteristics between recording sites in intracranial EEG and to reveal active abnormal causal relationships in epileptogenic networks (Chávez et al., 2003, Kaminski et al., 2001). Usually, Granger causality estimations are performed in long time intervals that include a dozen or even more, basic periods. The pairwise analysis is based on the construction of vector autoregressive (AR) models from bivariate data that estimates how well the current measure of one process can improve the prediction of the future of another process (Granger, 1969). Here we apply Granger causality to measure the strength of bidirectional functional interactions between neuronal assembles in thalamus and frontal cortex.

The present work aims to measure bidirectional (feedforward and feedback) network interdependences between local field potentials recorded simultaneously from the specific thalamus and the frontal cortex. Granger causality concept will be used to characterize the strength of functional connectivity between the cortical and thalamic EEGs for both directions before, during, and after SWD in rats.