Abstracts

Rationale:
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with refractory epilepsy. The exact etiology of SUDEP is unknown, but impairment of arousal is implicated. Many SUDEP victims are found in a prone position. Positional airway obstruction can increase risk of respiratory failure. Post-ictal generalized EEG suppression (PGES), a period of low amplitude EEG activity following some seizures, is a potential SUDEP risk factor and is associated with reduced arousability. Seizures with PGES exhibit longer post-ictal immobility, which may contribute to airway obstruction. The mechanisms underlying PGES are unknown. Serotonergic (5-HT) neurotransmission is implicated in SUDEP due to its role in sleep/wake regulation and arousal. Our data in mice indicate that pre-seizure application of a selective serotonin reuptake inhibitor shortens PGES duration. We hypothesize that increasing pre-seizure 5-HT levels may also reduce postictal immobility.
Method:
C57BL/6J mice (6 – 20 weeks old) were implanted with EEG/EMG electrodes and a bipolar stimulating/recording electrode in the right basolateral amygdala (AP: -1.3 mm; ML: -2.8 mm; DV: -4.7 mm). After recovery, afterdischarge threshold determination, and kindling, mice received pretreatment with saline or citalopram (20 mg/kg, i.p.) prior to induction of a seizure during wake/NREM sleep. Seizure and PGES duration were determined off-line. Post-ictal immobility was assessed via video by latency to the first twitch, paw movement, and body movement. Certain EEG frequency bands are associated with sleep/arousal, thus frequency characteristics (delta, 1 – 4 Hz; theta, 4 – 8 Hz; alpha, 8 – 12 Hz; beta, 12 – 30 Hz) were analyzed during recovery from PGES.
Results:
We observed immobility at the onset of PGES that sequentially recovered following seizures. Citalopram pretreatment decreased PGES duration and reduced latency to the first twitch and paw movement. Resumption of baseline EEG activity similarly occurred in a stepwise manner and was accelerated by citalopram pretreatment. PGES duration was correlated with the latency to body movement and latency of delta and theta to return to baseline. Likewise, a correlation between latency to body movement and recovery of delta and theta was observed.
Conclusion:
These data suggest that PGES duration may influence post-ictal immobility and suppression of low EEG frequencies. Recovery of delta and theta may be important to or indicative of resumption of body movement. Future experiments will be necessary to determine the circuitry and receptor subtypes underlying the effect of 5-HT on PGES. Furthermore, future investigations will examine whether arousability to potent and salient stimuli (CO2, touch, sound) is impaired during PGES.
Funding:
:Post-Comprehensive Exam Fellowship from UIowa Graduate College and Pre-Doctoral Fellowship from the American Epilepsy Society (with LivaNova, PLC) to A.N.P.; Iowa Center for Research by Undergraduates Research Fellows Program award to K.M.V.; NIH/NINDS R01 NS095842 and the Beth L. Tross Epilepsy Professorship to G.F.B.