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

Alzheimers disease (AD) is a serious neurodegenerative disorder without a clear understanding of the etiology and pathophysiology. Recent experimental data has suggested neuronal 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 for either local or large-scale neuronal circuits in AD. By applying a Multiscale Neural Model Inversion (MNMI) framework to the resting-state functional MRI (rs-fMRI) data from the Alzheimers Disease Neuroimaging Initiative (ADNI), we identified brain regions with disrupted E-I balance based on impaired mesoscale excitatory and inhibitory connection strengths in a large network during AD progression. We observed that both intra-regional and inter-regional E-I balance is progressively disrupted from cognitively normal individuals, to mild cognitive impairment (MCI) and to AD, and E-I difference (or ratio) can be abnormally increased or decreased, depending on specific region. Also, we found that (local) inhibitory connections are more significantly impaired than excitatory ones and the strengths of the majority of connections are reduced in MCI and AD, leading to gradual decoupling of neural populations. Moreover, we revealed a core AD network comprised mainly of limbic and cingulate regions including the hippocampus, pallidum, putamen, nucleus accumbens, inferior temporal cortex and caudal anterior cingulate cortex (cACC). These brain regions exhibit consistent and stable E-I alterations across MCI and AD, and thus may represent early AD biomarkers and important therapeutic targets. Lastly, the E-I difference (or ratio) of multiple brain regions (precuneus, posterior cingulate cortex, pallium, cACC, putamen and hippocampus) was found to be significantly correlated with the Mini-Mental State Examination (MMSE) score, indicating that the degree of E-I impairment is behaviorally related to MCI/AD cognitive performance. Overall, our study constitutes the first attempt to delineate E-I imbalance in large-scale neuronal circuits during AD progression, which may facilitate the development of new treatment paradigms to restore pathological E-I balance in AD.