Interictal high frequency oscillations in an animal model of infantile spasms
James D Frost1, Chong L Lee, John T Le
1Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Insights
This study investigated infantile spasms in rats, revealing that high-frequency oscillations (HFOs) are prominent in specific brain regions, suggesting widespread neocortical hyperexcitability as a key mechanism in this epilepsy.
Area of Science:
- Neuroscience
- Epilepsy Research
- Developmental Neuroscience
Background:
- Infantile spasms represent a common, devastating epilepsy in infants and children.
- The underlying mechanisms of infantile spasms remain poorly understood.
- High-frequency oscillations (HFOs) are implicated in focal epilepsy seizure generation.
Purpose of the Study:
- To investigate the occurrence and localization of HFOs in a rat model of infantile spasms.
- To analyze the basic mechanisms underlying HFO generation in this epilepsy model.
- To explore the relationship between interictal HFOs and seizure onset activity.
Main Methods:
- Induction of spasms in rats via chronic tetrodotoxin (TTX) infusion into the neocortex.
- Electrophysiological recordings, including multiunit activity and EEG, to detect HFOs.
- Analysis of HFOs during hypsarrhythmia, NREM sleep, and at seizure onset.
Main Results:
- HFOs were observed most frequently during hypsarrhythmia and NREM sleep.
- HFOs were most prominent in cortical regions contralateral and anterior to the TTX infusion site.
- Neuronal unit firing increased abruptly with HFO generation and seizure onset, indicating hyperexcitability.
Conclusions:
- Neocortical networks exhibit abnormal hyperexcitability in this infantile spasms model.
- This hyperexcitability is particularly pronounced in contralateral cortical regions and is not spatially restricted.
- HFOs and increased neuronal firing are consistent with a neocortical hyperexcitability hypothesis for infantile spasms.
Abstract:
While infantile spasms is the most common catastrophic epilepsy of infancy and early-childhood, very little is known about the basic mechanisms responsible for this devastating disorder. In experiments reported here, spasms were induced in rats by the chronic infusion of TTX into the neocortex beginning on postnatal days 10-12. Studies of focal epilepsy suggest that high frequency EEG oscillations (HFOs) occur interictally at sites that are most likely responsible for seizure generation. Thus, our goal was to determine if HFOs occurred and where they occurred in cortex in the TTX model. We also undertook multiunit recordings to begin to analyze the basic mechanisms responsible for HFOs. Our results show that HFOs occur most frequently during hypsarrhythmia and NREM sleep and are most prominent contralateral to the TTX infusion site in the homotopic cortex and anterior to this region in frontal cortex. While HFOs were largest and most frequent in these contralateral regions, they were also commonly recorded synchronously across multiple and widely-spaced recordings sites. The amplitude and spatial distribution of interictal HFOs were found to be very similar to the high frequency bursts seen at seizure onset. However, the latter differed from the interictal events in that the high frequency activity was more intense at seizure onset. Microwire recordings showed that neuronal unit firing increased abruptly with the generation of HFOs. A similar increase in neuronal firing occurred at the onset of the ictal events. Taken together, results suggest that neocortical networks are abnormally excitable, particularly contralateral to TTX infusion, and that these abnormalities are not restricted to small areas of cortex. Multiunit firing coincident with HFOs is fully consistent with a neocortical hyperexcitability hypothesis particularly since they both occur at seizure onset.
