To describe high frequency (HF) electrographic activity accompanying ictal discharges in the tetrodotoxin (TTX) model of infantile spasms. Previous studies of HF oscillations in humans and animals suggest that they arise at sites of seizure onset. We compared HF oscillations at several cortical sites to determine regional differences. Methods: TTX was infused for 4 weeks into the neocortex of rats beginning on postnatal days 11 or 12. Electroencephalography (EEG) electrodes were implanted 2 weeks later and video-EEG recordings were analyzed between postnatal days 31 and 47. EEG recordings were digitally sampled at 2,048 Hz. HF EEG activity (20-900 Hz) was quantified using compressed spectral arrays and band-pass filtering.
Multiple seizures were analyzed in 10 rats. Ictal onset was associated with multiple bands of rhythmic HF activity that could extend to 700 Hz. The earliest and most intense discharging typically occurred contralaterally to where TTX was infused. HF activity continued to occur throughout the seizure (even during the electrodecrement that is recorded with more traditional filter settings), although there was a gradual decrease of the intensity of the highest frequency components as the amplitude of lower frequency oscillations increased. Higher frequencies sometimes reappeared in association with spike/sharp-waves at seizure termination.
The findings show that HF EEG activity accompanies ictal events in the TTX model. Results also suggest that the seizures in this model do not originate from the TTX infusion site. Instead HF discharges are usually most intense and occur earliest contralaterally, suggesting that these homologous regions may be involved in seizure generation.
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"The existing models of epilepsy provide good tools to study the basic mechanisms by which seizures are generated, and the model of temporal lobe epilepsy (TLE) induced by pilocarpine or kainic acid (KA) simulates most of the characteristics of this pathology [2– 4]. In this TLE model, high frequency oscillations known as fast ripples (FRs, 250–600 Hz) have been observed, as in tetrodotoxin and tetanus toxin models of epilepsy567, in computational models in silico [8, 9] and in patients with TLE [2, 10, 11]. FRs can be evoked by electrical stimulation of the same brain areas where they occur spontaneously and they reflect bursts of population spikes from synchronously firing principal cells in relatively small areas of the hippocampus (HIP, 1 mm 3 )121314. "
[Show abstract][Hide abstract]ABSTRACT: Background:
In models of temporal lobe epilepsy and in patients with this pathology, high frequency oscillations called fast ripples (FRs, 250-600 Hz) can be observed. FRs are considered potential biomarkers for epilepsy and, in the light of many in vitro and in silico studies, we thought that electrical synapses mediated by gap junctions might possibly modulate FRs in vivo.
Animals with spontaneous recurrent seizures induced by pilocarpine administration were implanted with movable microelectrodes in the right anterior and posterior hippocampus to evaluate the effects of gap junction blockers administered in the entorhinal cortex. The effects of carbenoxolone (50 nmoles) and quinine (35 pmoles) on the mean number of spontaneous FR events (occurrence of FRs), as well as on the mean number of oscillation cycles per FR event and their frequency, were assessed using a specific algorithm to analyze FRs in intracranial EEG recordings.
We found that these gap junction blockers decreased the mean number of FRs and the mean number of oscillation cycles per FR event in the hippocampus, both during and at different times after carbenoxolone and quinine administration.
These data suggest that FRs may be modulated by gap junctions, although additional experiments in vivo will be necessary to determine the precise role of gap junctions in this pathological activity associated with epileptogenesis.
Full-text · Article · Sep 2014 · BioMed Research International
"Another model that has provided significant insights is the model produced via intracerebral chronic infusions of tetrodotoxin (TTX) for several weeks starting from the 10th day of life in rat pups. This leads to the development of spontaneous recurrent brief spasm-like seizures in adulthood (Frost et al., 2011. The seizures are characterized by brief extensor or flexor spasms; the ictal EEG pattern consists of an initial generalized, high amplitude, slow wave followed by an electrodecrement with superimposed fast activity. "
[Show abstract][Hide abstract]ABSTRACT: The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.
"In contrast to the observations that ictal HFOs associated with focal seizures frequently evolved into another form such as repetitive spike-wave discharges, ictal HFOs associated with spasms frequently terminated without evolving into another form (Nariai et al., 2011). A study of a rat model of epileptic spasms with ECoG also showed that ictal events began with increase of HFOs below 200 Hz, which was followed within 100 ms by increase of activity above 200 Hz and ictal HFOs subsequently slowed down in frequency to below 100 Hz (Frost et al., 2011). These observations are consistent with the hypotheses that spasms are of cortical and not of brainstem origin and that the cortical sites showing initial increase of HFOs during ictal events may be located close to the region responsible for seizure generation. "
[Show abstract][Hide abstract]ABSTRACT: Epilepsy is one of the most frequent neurological diseases. In focal medically refractory epilepsies, successful surgical treatment largely depends on the identification of epileptogenic zone. High-frequency oscillations (HFOs) between 80 and 500Hz, which can be recorded with EEG, may be novel markers of the epileptogenic zone. This review discusses the clinical importance of HFOs as markers of epileptogenicity and their application in different types of epilepsies. HFOs are clearly linked to the seizure onset zone, and the surgical removal of regions generating them correlates with a seizure free post-surgical outcome. Moreover, HFOs reflect the seizure-generating capability of the underlying tissue, since they are more frequent after the reduction of antiepileptic drugs. They can be successfully used in pediatric epilepsies such as epileptic spasms and help to understand the generation of this specific type of seizures. While mostly recorded on intracranial EEGs, new studies suggest that identification of HFOs on scalp EEG or magnetoencephalography (MEG) is possible as well. Thus not only patients with refractory epilepsies and invasive recordings but all patients might profit from the analysis of HFOs. Despite these promising results, the analysis of HFOs is not a routine clinical procedure; most results are derived from relatively small cohorts of patients and many aspects are not yet fully understood. Thus the review concludes that even if HFOs are promising biomarkers of epileptic tissue, there are still uncertainties about mechanisms of generation, methods of analysis, and clinical applicability. Large multicenter prospective studies are needed prior to widespread clinical application.
Full-text · Article · Apr 2012 · Progress in Neurobiology