An early disruption of neuronal excitation–inhibition (E–I) balance in preclinical animal models of Alzheimer’s disease (AD) has been frequently reported, but is difficult to measure directly and non-invasively in humans. Here, we examined known and novel neurophysiological measures sensitive to E–I in patients across the AD continuum. Resting-state magnetoencephalography (MEG) data of 86 amyloid-biomarker-confirmed subjects across the AD continuum (17 patients diagnosed with subjective cognitive decline, 18 with mild cognitive impairment (MCI) and 51 with dementia due to probable AD (AD dementia)), 46 healthy elderly and 20 young control subjects were reconstructed to source-space. E–I balance was investigated by detrended fluctuation analysis (DFA), a functional E/I (fE/I) algorithm, and the aperiodic exponent of the power spectrum. We found a disrupted E–I ratio in AD dementia patients specifically, by a lower DFA, and a shift towards higher excitation, by a higher fE/I and a lower aperiodic exponent. Healthy subjects showed lower fE/I ratios (< 1.0) than reported in previous literature, not explained by age or choice of an arbitrary threshold parameter, which warrants caution in interpretation of fE/I results. Correlation analyses showed that a lower DFA (E–I imbalance) and a lower aperiodic exponent (more excitation) was associated with a worse cognitive score in AD dementia patients. In contrast, a higher DFA in the hippocampi of MCI patients was associated with a worse cognitive score. This MEG-study showed E–I imbalance, likely due to increased excitation, in AD dementia, but not in early stage AD patients. To accurately determine the direction of shift in E–I balance, validations of the currently used markers and additional in vivo markers of E–I are required.

A body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. A growing number of studies have investigated the association between the gut microbiota and brain connectivity in humans. Linking brain connectivity measures to the gut microbiota can provide important mechanistic insights into the bi-directional gut-brain communication. In this systematic review, we therefore synthesized the available literature assessing this association, evaluating the degree of consistency in microbiota-connectivity associations. Following the PRISMA guidelines, a PubMed search was conducted, including studies published up to September 1, 2022. We identified 16 studies that met the inclusion criteria. Several bacterial genera, including Prevotella, Bacteroides, Ruminococcus and Blautia were most consistently reported in association with brain connectivity. Additionally, the salience (specifically the insula and anterior cingulate cortex), default mode and frontoparietal networks were most frequently associated with the gut microbiota, both in terms of microbial diversity and composition. Altogether, based on our synthesis, there is evidence for an association between the gut microbiota and brain connectivity. However, the specificity of the signal is yet unclear as most findings were poorly replicated across studies. The current studies show substantial inter-study heterogeneity in methodology and reporting, limiting the robustness and reproducibility of the findings and emphasizing the need to harmonize methodological approaches. To enhance comparability and replicability, future research should focus on further standardizing processing pipelines and employ data-driven multivariate analysis strategy.

A body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. Linking measures of brain connectivity to the gut microbiota can provide important mechanistic insights into the bi-directional gut-brain communication. In this systematic review, we therefore synthesized the available literature assessing this association, evaluating the degree of consistency in microbiota-connectivity associations. Following the PRISMA guidelines, a PubMed search was conducted, including studies published up to September 1, 2022. We identified 16 studies that met the inclusion criteria. Several bacterial genera, including Prevotella, Bacteroides, Ruminococcus, Blautia, and Collinsella were most frequently reported in association with brain connectivity. Additionally, connectivity of the salience (specifically the insula and anterior cingulate cortex), default mode, and frontoparietal networks were most frequently associated with the gut microbiota, both in terms of microbial diversity and composition. There was no discernible pattern in the association between microbiota and brain connectivity. Altogether, based on our synthesis, there is evidence for an association between the gut microbiota and brain connectivity. However, many findings were poorly replicated across studies, and the specificity of the association is yet unclear. The current studies show substantial inter-study heterogeneity in methodology and reporting, limiting the robustness and reproducibility of the findings and emphasizing the need to harmonize methodological approaches. To enhance comparability and replicability, future research should focus on further standardizing processing pipelines and employing data-driven multivariate analysis strategies.