Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures

Abstract

Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40–60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.

How Absence Seizures Impair Sensory Perception: Insights from Awake fMRI and Simulation Studies in Rats

“…Moreover, other studies utilizing optical flowmetry in GAERS have noticed decreased cerebral blood flow in cortical capillaries during an absence seizure, with preserved P O2 , P CO2 , and arterial blood pressure (Neblig et al, 1996) suggesting decreased cortical brain activity. However, the mechanism for the observed subcortical fMRI increases in this study and a previous study (McCafferty et al, 2023) illustrating the disagreement between electrophysiological and fMRI signals, are yet to explained and demand further studies.…”

“…Our findings of negative HRFs in the cortical regions (Figure 5) are in line with this hypothesis, suggesting reduced neuronal activity. Supporting evidence was found in a recent neuroimaging study conducted with GAERS showing that during an absence seizure, a larger group of neural populations in the frontoparietal cortex had a decreased firing rate, while a smaller portion of neuronal populations had an increased firing rate, leading to reduced fMRI cortical activity (McCafferty et al, 2023). Moreover, other studies utilizing optical flowmetry in GAERS have noticed decreased cerebral blood flow in cortical capillaries during an absence seizure, with preserved P O2 , P CO2 , and arterial blood pressure (Neblig et al, 1996) suggesting decreased cortical brain activity.…”

“…Notably, thalamic subnetwork is believed to play a role in coordinating and spacing of SWDs via feedforward inhibition together with burst firing patterns. This leads to the rhythms of neuronal silence and activation periods that are detected in SWD waves and spikes (Huguenard, 2019; McCafferty et al, 2023).…”

“…Although SWDs are initially triggered by hyperactive somatosensory cortical neurons, neuronal firing rates, especially in majority of frontoparietal cortical and thalamocortical relay neurons, are decreased rather than increased during SWD, resulting in an overall decrease in activity in these neuronal populations (McCafferty et al, 2023). Previous fMRI studies have demonstrated blood volume or BOLD signal decreases in several cortical regions including parietal and occipital cortex, but also, quite surprisingly, increases in subcortical regions such as thalamus, medulla and pons (David et al, 2008; McCafferty et al, 2023). In line with these findings, graph-based analyses have shown an increased segregation of cortical networks from the rest of the brain (Wachsmuth et al, 2021).…”

Neuronal Physiology of Generalized Seizures: The 4 Horsemen of Absence Epilepsy

“…In this paper, McCafferty et al advanced our understanding of absence seizure physiology by testing their effects on consciousness, functional magnetic resonance imaging (fMRI) signaling, and cortical/thalamic single neuron firing rates during absence seizures in genetic absence epilepsy rats from Strasbourg (GAERS). 2 For decades, absence epilepsy researchers studied inbred strains of rats and mice and, more recently, gene-targeted knockin mice that express human epilepsy mutations. 3 These rodent absence epilepsy models exhibit locomotor arrest during SWDs, but it was uncertain if this behavior cessation reflected altered consciousness.…”