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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported in part by the United States National Institutes of Health (NIH) through grants EB008374, MH125479, and EB006733. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at Alzheimer′s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.