From mechanisms to markers: novel noninvasive EEG proxy markers of the neural excitation and inhibition system in humans

Abstract

Brain function is a product of the balance between excitatory and inhibitory (E/I) brain activity. Variation in the regulation of this activity is thought to give rise to normal variation in human traits, and disruptions are thought to potentially underlie a spectrum of neuropsychiatric conditions (e.g., Autism, Schizophrenia, Downs’ Syndrome, intellectual disability). Hypotheses related to E/I dysfunction have the potential to provide cross-diagnostic explanations and to combine genetic and neurological evidence that exists within and between psychiatric conditions. However, the hypothesis has been difficult to test because: (1) it lacks specificity—an E/I dysfunction could pertain to any level in the neural system- neurotransmitters, single neurons/receptors, local networks of neurons, or global brain balance - most researchers do not define the level at which they are examining E/I function; (2) We lack validated methods for assessing E/I function at any of these neural levels in humans. As a result, it has not been possible to reliably or robustly test the E/I hypothesis of psychiatric disorders in a large cohort or longitudinal patient studies. Currently available, in vivo markers of E/I in humans either carry significant risks (e.g., deep brain electrode recordings or using Positron Emission Tomography (PET) with radioactive tracers) and/or are highly restrictive (e.g., limited spatial extent for Transcranial Magnetic Stimulation (TMS) and Magnetic Resonance Spectroscopy (MRS). More recently, a range of novel Electroencephalography (EEG) features has been described, which could serve as proxy markers for E/I at a given level of inference. Thus, in this perspective review, we survey the theories and experimental evidence underlying 6 novel EEG markers and their biological underpinnings at a specific neural level. These cheap-to-record and scalable proxy markers may offer clinical utility for identifying subgroups within and between diagnostic categories, thus directing more tailored sub-grouping and, therefore, treatment strategies. However, we argue that studies in clinical populations are premature. To maximize the potential of prospective EEG markers, we first need to understand the link between underlying E/I mechanisms and measurement techniques.

Combining Aperiodic 1/f Slopes and Brain Simulation: An EEG/MEG Proxy Marker of Excitation/Inhibition Imbalance in Alzheimer’s Disease

“…We have described a new method for inferring alteration in the E/I balance of neuronal circuits in Alzheimer’s disease using EEG and MEG measures. It is based on a recent neuroimaging biomarker, the 1/f slope, which has been proposed as a robust proxy marker for noninvasive real-time interrogation of E/I imbalance in many neuropsychiatric conditions (Ahmad et al 2022). We used a regression model to map empirical 1/f slopes onto E/I estimations obtained from computational simulations of a recurrent cortical microcircuit model of spiking neurons that has shown to capture the main properties of simulated and real field potentials (P. Martínez-Cañada et al 2021; Trakoshis et al 2020; Mazzoni et al 2015).…”

“…Recently, a range of novel E/I biomarkers has been described that are noninvasive and applicable in humans and which can be deployed on a large scale. (Ahmad et al 2022). These markers represent a key translational link across species and recording scales and can be applied in resting-state experiments and tasks that do not require extensive cognitive processing.…”

“…For these reasons, current MRS approaches have limited utility for tracking variations of E/I across cortical regions or behavioural states. Recently, a range of novel features derived from electroencephalography (EEG) and magnetoencephalography (MEG) recordings have been described as robust proxy makers for noninvasive real-time measurements of changes in E/I balance (Ahmad et al 2022; Manyukhina et al 2022; Pablo Martínez-Cañada, Noei, and Panzeri 2021; Molina et al 2020; Gao, Peterson, and Voytek 2017). One of the most promising candidate E/I biomarkers is the exponent of the 1/f spectral power law, often referred to in the literature as the ‘1/f slope’.…”

Human Neuronal Excitation/Inhibition Balance Explains and Predicts Neurostimulation Induced Learning Benefits

“…Previous human and animal studies have indicated the importance of the ratio of neuronal excitation to inhibition (E/I) for learning, i.e., skill acquisition (Ahmad et al, 2022; Dorrn et al, 2010; Nishiyama et al, 2010; Shibata et al, 2017). Previous magnetic resonance spectroscopy (MRS) studies highlighted the neurotransmitters glutamate and gammaa-minobutyric acid (GABA) as the underlying building blocks of E/I, and suggested their important role in memory and learning, including predicting educational levels later in life (Barron et al, 2016; Shibata et al, 2017; Wijtenburg et al, 2017; Zacharopoulos et al, 2021a; Zacharopoulos et al, 2021b).…”

“…Recently, the interest in electrophysiology has been expanded from this oscillatory (i.e., periodic or spectral power) perspective to include an aperiodic perspective, e.g., aperiodic activity (Ahmad et al, 2022; Donoghue et al, 2020). Aperiodic activity is shown in the EEG spectrum as a 1/ f -like structure and is dominant in the spectrum even when there is no periodic or oscillatory activity.…”