Disrupted Energetic and Entropic Landscape in Individuals With Mild Cognitive Impairment: Insights From Network Control Theory.

The energetic and entropic organization of the brain's functional activity in mild cognitive impairment (MCI) has yet to be fully characterized. Network Control Theory (NCT) is a multi-modal approach that captures alterations in the brain's energetic landscape by combining the brain's functional activity and the structural connectome. Entropy is another complementary metric that can quantify the complexity and predictability in a neural time series, offering insights into the brain's dynamic functional activity. Our study aims to explore the differences in the brain's energetic and entropic landscape between people with MCI and healthy controls (HC). Four hundred ninety-nine HC and 55 MCI patients were included. First, k-means clustering was applied to functional MRI (fMRI) time series to identify commonly recurring brain activity states. Second, NCT was used to calculate the minimum energy required to transition between these brain activity states, otherwise known as transition energy (TE). The entropy of the fMRI time series as well as PET-derived amyloid beta (Aβ) and tau deposition were measured for each brain region. The TE and entropy were compared between MCI and HC at the network, regional, and global levels using linear models where age, sex, and intracranial volume were added as covariates. The association of TE and entropy with Aβ and tau deposition was investigated in MCI patients using linear models where age, sex, and intracranial volume were controlled. Commonly recurring brain activity states included those with high (+) and low (-) amplitude activity in visual (+/-), default mode (+/-), and dorsal attention (+/-) networks. Compared to HC, MCI patients required lower transition energy in the limbic network (adjusted p = 0.028). Decreased global entropy was observed in MCI patients compared to HC (p = 7.29e-7). There was a positive association between TE and entropy in the frontoparietal network (p = 7.03e-3). Increased global Aβ was associated with higher global entropy in MCI patients (ρ = 0.632, p = 0.041). Lower TE in the limbic network in MCI patients may indicate either neurodegeneration-related neural loss and atrophy or a potential functional upregulation mechanism in this early stage of cognitive impairment. Future studies that include people with Alzheimer's Disease (AD) are needed to better characterize the changes in the energetic landscape in the later stages of cognitive impairment.