A Sheep Model for the Study of Focal Epilepsy with Concurrent Intracranial EEG and Functional MRI

Abstract

Summary: Purpose:We describe a sheep model of penicillininduced seizure activity using electroencephalography (EEG) and functional MRI (fMRI).Methods: Ten adult sheep were used. Spikes and seizures were generated by instillation of 8,000-10,000 IU of penicillin into the right prefrontal cortex via a specially designed port. Bilateral intracranial EEG was acquired by using carbon fiber electrodes. Animals had behavioral characterization of their seizures and were then anesthetized for fMRI studies. Functional MRI was performed at 1.5 and 3 Tesla by measuring blood oxygen level-dependent (BOLD) weighted signal intensity at different times during the evolution of seizures.Results: Behavioral seizures were associated with electrographic seizures. Intracranial EEG obtained in the MR scanner was of high quality. Focal spiking and seizures were seen in all animals and developed 11.3 ± 11.2 s and 17.3 ± 12.1 min after penicillin administration, respectively. An average of 13 ± 4.8 seizures were seen per animal, each lasting 27.3 ± 12.3 s. Functional MR images with little parenchymal artefact were obtained. Regional BOLD signal-intensity changes were observed during seizures at the seizure focus and ipsilateral amygdala.Conclusions: We have developed an animal model of partial epilepsy in which seizures can be reliably elicited with concurrent fMRI and intracranial EEG. During unilateral electrographic seizures, focal BOLD signal changes occurred at the seizure focus and ipsilateral amygdala, suggesting the presence of a cortico-subcortical loop. This observation illustrates the potential of the model for understanding seizure generation, spread, and possibly the consequences of repeated seizures on the brain. Key Words: EEG-Epilepsy-Functional MRIMagnetic resonance-Seizure models-Sheep.Seizures are associated with electrical discharges measured on the electroencephalogram (EEG) together with increased blood flow and oxygenation at the site of the epileptic focus (1-3). Functional magnetic resonance imaging (fMRI) shows increased signal intensity in areas of high blood flow due to a decrease in deoxyhemoglobin concentration, as detected by blood oxygen leveldependent (BOLD) contrast techniques (4). Sequential images can be rapidly obtained, giving fMRI the unique ability to provide good temporal and excellent spatial information. The response predictably follows neuronal activation, typically beginning after 3 s and peaking after ∼6 s (5-8). During seizures, however, the temporal relation between blood-flow changes, electrical discharges, and behavioral seizures is not understood. Indeed, BOLD signals may even precede the onset of electrographic seizures (9,10).Some attempts have been made to study seizures in humans with fMRI, but these reports are few and anecdotal, and none correlates EEG with the BOLD response (10,11). As seizures are not predictable and difficult to study in the MR system, imaging of interictal activity by EEG spike-triggered fMRI techniques has been developed (12-16). None of these studies, however...

The pig model in brain imaging and neurosurgery

“…For example, the sheep has been successfully used to develop a model for PD using MPTP poisoning (Beale et al, 1989;Baskin et al, 1994). It has been involved in brain microdialysis studies (Westerink, 1995) or intracranial electroencephalography (Opdam et al, 2002). However, neuroscience studies using mature sheep remain infrequent primarily because of the ruminant-related differences in physiology.…”

MRI Techniques and New Animal Models for Imaging the Brain

“…This method is used to make inferences about the effects of the stimuli by decomposing data into effects and errors, and computes statistical maps related to the effects of the stimuli (see Monti 2011 for principles). This kind of study is widely used in human and non-human primates, but due to a required subjects's involvement, typical fMRI activation paradigms have only been used in a few studies in large animals such as pigs or sheep (Fang et al 2005b, Fang et al 2005c, Fang et al 2006, Opdam et al 2002. Due to the constraints mentioned above (see 2.1), this kind of experimental paradigm will not be discussed further in this chapter.…”

“…MRI methods have also been used with large animal models in studies on epilepsy (sheep: Opdam et al 2002), to develop new chemotherapeutic strategies such as local injection in the fourth ventricle (pig, Sandberg et al 2008), and to test the toxicity of chemotherapeutic treatment on normal brain tissue close to the injection site (Makiranta et al 2002). In sheep, MRI has validated in vivo ultra-sound transcranial brain surgery (Pernot et al 2007).…”

Magnetic Resonance Imaging in Experimental Models of Brain Disorders

“…Furthermore, fMRI can be used to assess epileptic activity. In a sheep model of penicillin-induced partial epilepsy, BOLD fMRI was performed in combination with electroencephalography (Opdam et al, 2002).…”