EEG biomarkers of reduced inhibition in human cortical microcircuits in depression

Abstract

Major depressive disorder (depression) is a complex condition that involves multiple physiological mechanisms, spanning a range of spatial scales. Altered cortical inhibition is associated with treatment-resistant depression, and reduced dendritic inhibition by somatostatin-expressing (SST) interneurons has been strongly implicated in this aspect of the pathology. However, whether the effects of reduced SST inhibition on microcircuit activity have signatures detectible in electroencephalography (EEG) signals remains unknown. We used detailed models of human cortical layer 2/3 microcircuits with normal or reduced SST inhibition to simulate resting-state activity together with EEG signals in health and depression. We first show that the healthy microcircuit models exhibit emergent key features of resting-state EEG. We then simulated EEG from depression microcircuits and found a significant power increase in theta, alpha and low beta frequencies (4 - 15 Hz). Following spectral decomposition, we show that the power increase involved a combination of aperiodic broadband component, and a periodic theta and low beta components. Neuronal spiking showed a spike preference for the phase preceding the EEG trough, which did not differ between conditions. Our study thus used detailed computational models to identify EEG biomarkers of reduced SST inhibition in human cortical microcircuits in depression, which may serve to improve the diagnosis and stratification of depression subtypes, and in monitoring the effects of pharmacological modulation of inhibition for treating depression.

In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

“…Our results demonstrated that α5-PAM could directly recover function and resting state EEG features associated with a loss of SST-mediated inhibition in depression (Mazza et al 2022;Yao et al 2022), despite only boosting SST→Pyr synapses and not SST→PV and SST→VIP synapses, which were also reduced in our depression models. This is likely because the loss of SST interneuron inhibition in depression has a direct and thus much larger impact on Pyr neurons than the indirect disinhibitory effect of reduced SST interneuron inhibition onto interneurons.…”

“…As in previous studies, we used models of human cortical L2/3 microcircuits to study effects on cortical microcircuit function (Yao et al 2022) and EEG signal (Mazza et al 2022).…”

“…Simulated microcircuit EEG and power spectral analyses. We simulated dipole moments and corresponding EEG time series data generated by our microcircuit models (25s duration per simulation) using the same methodologies as in previous work (Hagen et al 2018;Mazza et al 2022). Specifically, we used a four-sphere volume conductor model (representing grey matter, cerebrospinal fluid, skull, and scalp with radii of 79 mm, 80 mm, 85 mm, and 90 mm, respectively) that assumed homogeneous, isotropic, and linear (frequency-independent) conductivity.…”

Increased aperiodic neural activity during sleep in major depressive disorder

“…Indeed, it has been suggested that GABAergic deficit may play a central role in the etiology of MDD, especially in melancholic (17) and treatment-resistant types of depression (18).…”

“…Recently, however, it has been shown that the slope of the aperiodic component reflects the ratio between excitatory and inhibitory currents in the brain (12). Given the crucial role of the proper balance between neural excitation and inhibition (E/I) for healthy cognition, behavior (13) and sleep, aperiodic activity seems to be a promising tool for investigating MDD with its cholinergic, monoaminergic (14,15), glutamatergic (16) and GABAergic imbalance (17,18). In MDD, the E/I ratio could be further affected by prescribed antidepressants.…”