Abstracts

Rationale: Cortical excitability, defined as the variable response to a given cortical stimulation, is widely studied in neuroscience and epilepsy research, from slice experiments and in silico modeling work to clinical pharmacology in humans, but its relationship to seizure occurrences remains to be understood.

Defining and quantifying the boundaries between physiological and pathological cortical dynamics is an active field of research, which has recently included the formalism of dynamical systems theory to characterize ictal transitions. Recent modeling and experimental work suggested that such transitions occur by the alignment of small stochastic perturbations and of a slower decrease in cortical resilience, also called the slow permittivity variable. However, this work mostly relied on measurements of excitability and resilience in in-vitro models of epilepsy, and in-vivo validation of these concepts and their broader applicability to the non-epileptic brain are currently lacking.

Methods: In this study, we used in-vivo optogenetic stimulation in awake, freely-moving mice to assess whether changes in cortical excitability quantified as evoked response to small perturbation corresponded to changes in resilience to larger perturbations leading to seizures.

We quantified cortical excitability as the line-length of local field potentials responses to both single and paired pulses of varying intensity and temporal intervals.

We also used train of optogenetic stimulation to induce hippocampal seizures and measured cortical resilience as the time of stimulation needed to elicit a seizure (time-to-seizure).

We then explored how these markers varied in the presence of GABAergic agonist (Diazepam (DZ)) and antagonist (Pentylenetetrazol (PTZ) and Picrotoxin (PTX)).

Results: We found that evoked cortical response to single opto-pulse was reduced by 29.3%, 95%CI [27.6-31.2] in presence of DZ and increased with GABAergic antagonist (5.1% [3.0-7.1] for PTZ and 9.3% [7.1-11.3] for PTX). GABAergic drugs also modulated cortical resilience with a 78.1% [54.5-113.0] increase in time-to-seizure in presence of Diazepam and a respectively 19.6% [3.0-10.8] and 10.6% [-4.0-18.5] decrease with PTZ and PTX, corroborating the changes observed in cortical excitability.

Conclusions: In this study, using minute perturbations of ongoing activity, we probed and quantified varying degrees of cortical excitability, modulated bidirectionally by GABAergic drugs. We provide strong in vivo experimental evidence for a direct relevance of these markers of cortical excitability to assess resilience to perturbations and susceptibility to seizures, confirming previous in vitro and in silico work.

From a translational perspective, the ability to gauge cortical excitability over time with minimal perturbations may open the way to refined diagnostic and therapeutic approaches in chronic dynamical brain disorders such as epilepsy.

Funding: Please list any funding that was received in support of this abstract.: Dr Baud is supported by an Ambizione grant (PZ00P3_179929) from the Swiss National Science Foundation and by a grant from the Velux Stiftung (1232).