fMRI of Brain Activation in a Genetic Rat Model of Absence Seizures

Abstract

Summary:Purpose: EEG-triggered functional magnetic resonance imaging (fMRI) was used to identify areas of brain activation during spontaneous spike-and-wave discharges (SWDs) in an epileptic rat strain under awake conditions.Methods: Spontaneous absence seizures from 10 WAG/Rij rats were imaged by using T 2 * -weighted echo planar imaging at 4.7Tesla. fMRI of the blood-oxygenation-level-dependent (BOLD) signal was triggered based on EEG recordings during imaging. Images obtained during spontaneous SWDs were compared with baseline images.Results: Significant positive BOLD signal changes were apparent in several areas of the cortex and several important nuclei of the thalamus. In addition, no negative BOLD signal was found in any brain area.Conclusions: We have shown that EEG-triggered BOLD fMRI can be used to detect cortical and thalamic activation related to the spontaneous SWDs that characterize absence seizures in awake WAG/Rij rats. These results draw an anatomic correlation between areas in which increased BOLD signal is found and those in which SWDs have been recorded. In addition, no negative BOLD signal was found to be associated with these spontaneous SWDs. We also demonstrated the technical feasibility of using EEG-triggered fMRI in a genetic rat model of absence seizure. Key Words: Absence seizure-fMRIEpilepsy-WAG/Rij-Imaging.Typical absence seizures consist of multiple, brief (≤20 s) impairments of consciousness with characteristic bilaterally synchronous 3-Hz spike-and-wave discharges (SWDs) on electroencephalography (EEG). A typical absence seizure is manifested behaviorally as a "staring spell" and can be accompanied by atonic postures such as drooping of the head and/or automatisms such as lip smacking (1).Genetic rat models of absence epilepsy have been studied for many years and are thought to mimic more accurately the spontaneous seizures of human epilepsy than do drug-induced animal models. The strain of rats named WAG/Rij (Wistar Albino Glaxo strain bred in Rijswijk, the Netherlands) have been inbred for absence-like characteristics for >100 generations, which implies that they are homozygous (2,3). This strain exhibits spontaneous SWDs that have a frequency of 7 to 11 Hz, duration of 1 to 45 s, and an amplitude of 200 to 1,000 µV (4). As in the human condition, EEG changes are accompanied by immobile behavior and staring. Age-related changes Accepted February 18, 2004. Address correspondence and reprint requests to Dr. J.R. Tenney at University of Massachusetts Medical School, CCNI Building, 55 Lake Avenue North, Worcester, MA 01655, U.S.A. E-mail: jeffrey.tenney@umassmed.edu in the number of SWDs have been found. At an age of 75 days, only 17% of rats experience a single SWD in a 4-h period, compared with 140 and 245 days, at which SWDs affected 83% and 100% of rats, respectively (5).Electrophysiology recordings of the WAG/Rij model have been used to uncover the neural structures responsible for the generation and propagation of SWDs. Many of these studies have implicated the coupling of ...

The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies

“…Our data are in agreement with other studies that used fMRI to further characterize the neural circuits involved in the generation of absence seizures in the WAG/Rij (Tenney et al, 2004) (Nersesyan et al, 2004) and in human patients with absence epilepsy (Aghakhani, 2004) (Bai et al, 2010). Our study was the first electrophysiological validation of fMRI connectivity analyses based on Granger causality and Dynamic Causal Modelling using a well characterized animal model of functional coupling.…”

On the Origin and Suddenness of Absences in Genetic Absence Models

“…It was revealed that the BOLD signal was increased in several cortical and thalamic zones including the RTN, mediodorsal nucleus (MD), ventral posteromedial/posterolateral nuclei (VPM/VPL), and posterior thalamic nuclei (Po) during spontaneous absence seizures in awake rats compared with baseline images. 80 Quantitative data are presented in Figure 2.…”

Temporal Dependence in Uncoupling of Blood Volume and Oxygenation during Interictal Epileptiform Events in Rat Neocortex

“…However, investigations into the initial dip have all been done after peripheral activation of visual and somatosensory cortex using ORIS or fMRI, and no data exists on the initial dip after epileptiform events. Indeed, previous fMRI studies of epilepsy have generally found an increase in BOLD signal, implying that CBF oversupplies the epileptic focus with HBO 2 (Krakow et al, 2001;Lemieux et al, 2001a,b;Benar et al, 2002;Nersesyan et al, 2004;Tenney et al, 2004). Epilepsy is a pathological condition, and the metabolic demands associated with the IIS are "supranormal."…”

“…Although an increase in perfusion is universally demonstrated, some studies find that perfusion oversupplies metabolism (Lemieux et al, 2001a,b;Benar et al, 2002;Nersesyan et al, 2004;Tenney et al, 2004), whereas others demonstrate the opposite, namely inadequate perfusion to meet metabolic demand (Ingvar and Siesjo, 1983;Tanaka et al, 1990;Kreisman et al, 1991;Pereira de Vasconcelos et al, 2002). We chose to investigate the relationship between perfusion, hemoglobin oxygenation, and epileptiform activity using optical recording of intrinsic signals (ORIS), which offers the highest combined spatial and temporal resolution of any technique .…”