Abstract
Brain function depends on complex circuit interactions between excitatory and inhibitory neurons embedded in local and long-range networks. Systemic GABAA-receptor or NMDA-receptor modulation alters the excitatory/inhibitory balance (EIB), measurable with electroencephalography (EEG). However, EEG signatures are complex in localization and spectral composition. We developed and applied analytical tools to investigate the effects of two EIB modulators, MK801 (NMDAR-antagonist) and diazepam (GABAAR-modulator), on periodic and aperiodic EEG features in freely-moving male Sprague-Dawley rats. We investigated how, across three brain regions, EEG features are correlated with EIB modulation. We found that the periodic component was composed of seven frequency bands that presented region- and compound-dependent changes. The aperiodic component was also different between compounds and brain regions. Importantly, the parametrization into periodic and aperiodic components unveiled correlations between quantitative EEG and plasma concentrations of pharmacological compounds. MK-801 exposures were positively correlated with the slope of the aperiodic component. Concerning the periodic component, MK-801 exposures correlated negatively with the peak frequency of low-gamma oscillations but positively with those of high-gamma and high-frequency oscillations. As for the power, theta and low-gamma oscillations correlated negatively with MK-801, whereas mid-gamma correlated positively. Diazepam correlated negatively with the knee of the aperiodic component, positively to beta and negatively to low-gamma oscillatory power, and positively to the modal frequency of theta, low-, mid-, and high-gamma. In conclusion, correlations between exposures and pharmacodynamic effects can be better-understood thanks to the parametrization of EEG into periodic and aperiodic components. Such parametrization could be key in functional biomarker discovery.
SIGNIFICANCE STATEMENT
Excitatory-inhibitory balance (EIB) is compromised in neurological disorders. Our study demonstrates that pharmacologically-induced effects on EIB can be quantified by decomposing the qEEG PS signal into the oscillatory periodic and the 1/f aperiodic components. MK-801 and diazepam showed distinct signatures across brain regions and EEG components. Specific features of these components are sensitive to relatively small changes in measured exposure. This methodological approach and the features identified as sensitive to EIB modulation could be key for the development of new therapies and functional biomarkers in disorders with excitatory-inhibitory imbalance.
Footnotes
The authors declare no competing financial interests.
This research was supported by F. Hoffman-La Roche Ltd, partly as an M.Sc. internship to Irene Gonzalez-Burgos. This work was partially funded by Gobierno de Navarra in the form of predoctoral fellowships to Irene Gonzalez-Burgos and José A. Ochoa-Martinez.
These authors jointly supervised this work: Miguel Valencia and Roger Redondo.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
