Cortical low‐frequency power correlates with behavioral impairment in animal model of focal limbic seizures

Abstract

Objective Impairment in consciousness is a debilitating symptom during and after seizures; however, its mechanism remains unclear. Limbic seizures have been shown to spread to arousal circuitry to result in a "network inhibition" phenomenon. However, prior animal model studies did not relate physiological network changes to behavioral responses during or following seizures. Methods Focal onset limbic seizures were induced while rats were performing an operant conditioned behavioral task requiring response to an auditory stimulus to quantify how and when impairment of behavioral response occurs. Correct responses were rewarded with sucrose. Cortical and hippocampal electrophysiology measured by local field potential recordings was analyzed for changes in low‐ and high‐frequency power in relation to behavioral responsiveness during seizures. Results As seen in patients with seizures, ictal (p < .0001) and postictal (p = .0015) responsiveness was variably impaired. Analysis of cortical and hippocampal electrophysiology revealed that ictal (p = .002) and postictal (p = .009) frontal cortical low‐frequency 3–6‐Hz power was associated with poor behavioral performance. In contrast, the hippocampus showed increased power over a wide frequency range during seizures, and suppression postictally, neither of which were related to behavioral impairment. Significance These findings support prior human studies of temporal lobe epilepsy as well as anesthetized animal models suggesting that focal limbic seizures depress consciousness through remote network effects on the cortex, rather than through local hippocampal involvement. By identifying the cortical physiological changes associated with impaired arousal and responsiveness in focal seizures, these results may help guide future therapies to restore ictal and postictal consciousness, improving quality of life for people with epilepsy.

Arousal and Consciousness in Focal Seizures

“…13 Focal hippocampal seizures in rats and mice induced by brief 2s, 60 Hz hippocampal stimulation also exhibit behavioral arrest and cortical slow waves resembling human temporal lobe seizures. [13][14][15][16][17][18] These findings established the validity of the rodent models for investigating impaired behavior and physiology in focal limbic seizures.…”

“…Rodent model studies have verified that cortical physiology during focal limbic seizures closely resembles states of decreased arousal such as deep anesthesia or sleep. Like in human limbic seizures, the cortex in rodent models shows slow waves, decreased CBF, and hypometabolism [13][14][15][16][17][18][19] (Figure 2). Cortical neuronal recordings showed Up and Down states of action potential firing and membrane potential oscillations mimicking the physiology of deep sleep and anesthesia.…”

“…24,35,36 The mechanisms of impairment in the postictal period are still under investigation, but both human and animal model studies of focal limbic seizures show persistent cortical slow-wave activity and decreased cortical CBF and metabolism in the postictal period. 6,7,9,13,19,37 In addition, during the postictal period, cholinergic neurotransmission remains depressed, fMRI signals in the central thalamus and upper brainstem tegmentum are reduced, firing of thalamic intralaminar neurons and of subcortical cholinergic and serotonergic neurons is reduced, and behavioral responsiveness is impaired in association with cortical slow-wave activity. 19,[22][23][24]37 These findings suggest that persistently depressed arousal in subcortical and cortical networks may play an important role in postictal impaired consciousness following focal limbic seizures.…”

Understanding Focal Seizures in Adults: A Comprehensive Review

“…Studies using rodent models have confirmed that the cortical physiology experienced throughout focal limbic seizures is nearly similar to low-arousal states such as deep anesthesia or sleep [5]. The brain of the mouse model exhibits steady waves, hypometabolism, and decreased cerebral blood flow, identical to human limbic seizures [6][7][8][9][10][11]. Membrane potential oscillations and action potential firing patterns in cortical neurons were recorded in up and down states, simulating anesthesia and deep sleep physiology [5][6][7][8]11,12].…”