Acute and persistent changes in neural oscillatory activity predict development of epilepsy following acute organophosphate intoxication in adult rats

Abstract

Objective

Acute organophosphate (OP) intoxication affects a significant number of individuals worldwide. Those who survive OP-induced cholinergic crisis, which includes status epilepticus, often develop neurological morbidities. Here, we provide a rigorous characterization of the acute and delayed electrophysiological responses to OP intoxication with the goal of identifying early electrophysiological changes that predict later brain changes, including spontaneous recurrent seizures (SRS).

Methods

Male and female rats were implanted with electroencephalographic (EEG) and intracranial EEG electrodes prior to acute intoxication with diisopropylfluorophosphate (DFP). All animals received standard of care therapeutics and were recorded continuously for 70 min post-DFP, then again for 5 min at 180 min post-DFP, 1 day postexposure (DPE), 3 DPE, and 7 DPE. Between 7 and 14 DPE, animals were recorded continuously.

Results

In both sexes, acute DFP intoxication produced rapid and robust elevations in broadband power that were reduced but not terminated by midazolam (MDZ). Theta–delta ratio (TDR) was reduced immediately following DFP exposure and was further depressed by MDZ intervention. In the days that followed, broadband power and TDR recovered toward baseline. From 7 to 14 DPE, electrographic spiking was observed in all animals, and 80% developed SRS. Increased broadband power during status epilepticus was positively correlated with spike rate and SRS frequency. Slower recovery of broadband power to baseline in the days following exposure also correlated with increased SRS burden. Finally, a higher acute TDR correlated with increased spike rates at 3 and 7 DPE.

Significance

The data presented in this study provide a rigorous characterization of post-DFP electrographic sequelae that significantly extends the field's current understanding of electrophysiological shifts caused by acute OP intoxication. Critically, we identified potential EEG-based biomarkers that may identify at-risk patients in a clinical setting.