Excitation-inhibition imbalance in Alzheimer’s disease using multiscale neural model inversion of resting-state fMRI

Abstract

Alzheimer′s disease (AD) is a serious neurodegenerative disorder without a clear understanding of the etiology and pathophysiology. Recent experimental data has suggested excitation-inhibition (E-I) imbalance as an essential element and critical regulator of AD pathology, but E-I imbalance has not been systematically mapped out in both local and large-scale neuronal circuits in AD. Using a multiscale neural model inversion framework, we identified disrupted E-I balance as well as impaired excitatory and inhibitory connections in a large network during AD progression based on resting-state functional MRI data from the Alzheimer′s Disease Neuroimaging Initiative (ADNI) database. We observed that E-I balance is progressively disrupted from mild cognitive impairment (MCI) to AD and alteration of E-I balance is bidirectional varying from region to region. Also, we found that inhibitory connections are more significantly impaired than excitatory connections and the strength of the majority of excitatory and inhibitory connections reduces in MCI and AD, leading to gradual decoupling of neural populations. Moreover, we revealed a core AD network comprising mainly of limbic and cingulate regions including the hippocampus, pallidum, putamen, nucleus accumbens, inferior temporal cortex and caudal anterior cingulate cortex. These brain regions exhibit consistent and stable E-I alteration across MCI and AD, which may represent a stable AD biomarker and an important therapeutic target. Overall, our study constitutes the first attempt to delineate E-I imbalance in large-scale neuronal circuits during AD progression, which facilitates the development of new treatment paradigms to restore pathological E-I balance in AD.

A comprehensive investigation of intracortical and corticothalamic models of alpha rhythms

“…While our analyses suggest that mesoscopic scale empirical data such as human scalp EEG signals may be insufficient to advance one alpha theory over another one, our investigation helps to clarify the role of the E-I loop in each model, how the synaptic gains influence the represented dynamics, and the implications of these in various alpha mechanisms. These factors are valuable in studies of how an imbalance in E-I can lead to altered dynamics, such as different oscillatory patterns or reduced alpha magnitude, which are associated with various neural pathologies and disorders (Eichler and Meier, 2008; Li et al, 2022).…”

Rodents’ visual gamma as a biomarker of pathological neural conditions

“…the one induced by visual stimuli of higher contrasts) is known to originate cortically, from the interaction between inhibitory and excitatory neurons (Meneghetti et al, 2020. Its degradation is, once again, the probe for an altered I/E balance which was reported in numerous studies involving the tau and AD pathophysiology (Shimojo et al, 2020;Maestú et al, 2021;Ranasinghe et al, 2022;Li et al, 2022), together with cortical atrophy and cell death (SantaCruz et al, 2005), pyramidal dendritic atrophy (Crimins et al, 2011) and pyramidal axonal boutons loss (Jackson et al, 2017).…”