Personalized whole-brain neural mass models reveal combined Aß and tau hyperexcitable influences in Alzheimer's disease.

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-ß (Aß) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aß and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aß-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

Revealing the combined roles of Aß and tau in Alzheimer's disease via a pathophysiological activity decoder.

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-ß (Aß) and tau-PET from AD-related participants (N=132). Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aß and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aß-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

Detecting brain network communities: Considering the role of information flow and its different temporal scales.

The identification of community structure in graphs continues to attract great interest in several fields. Network neuroscience is particularly concerned with this problem considering the key roles communities play in brain processes and functionality. Most methods used for community detection in brain graphs are based on the maximization of a parameter-dependent modularity function that often obscures the physical meaning and hierarchical organization of the partitions of network nodes. In this work, we present a new method able to detect communities at different scales in a natural, unrestricted way. First, to obtain an estimation of the information flow in the network we release random walkers to freely move over it. The activity of the walkers is separated into oscillatory modes by using empirical mode decomposition. After grouping nodes by their co-occurrence at each time scale, k-modes clustering returns the desired partitions. Our algorithm was first tested on benchmark graphs with favorable performance. Next, it was applied to real and simulated anatomical and/or functional connectomes in the macaque and human brains. We found a clear hierarchical repertoire of community structures in both the anatomical and the functional networks. The observed partitions range from the evident division in two hemispheres -in which all processes are managed globally- to specialized communities seemingly shaped by physical proximity and shared function. Additionally, the spatial scales of a network's community structure (characterized by a measure we term within-communities path length) appear inversely proportional to the oscillatory modes' average frequencies. The proportionality constant may constitute a network-specific propagation velocity for the information flow. Our results stimulate the research of hierarchical community organization in terms of temporal scales of information flow in the brain network.

Estimation of global and local complexities of brain networks: A random walks approach.

The complexity of brain activity has been observed at many spatial scales and has been proposed to differentiate between mental states and disorders. Here we introduced a new measure of (global) network complexity, constructed as the sum of the complexities of its nodes (i.e., local complexity). The complexity of each node is obtained by comparing the sample entropy of the time series generated by the movement of a random walker on the network resulting from removing the node and its connections, with the sample entropy of the time series obtained from a regular lattice (ordered state) and a random network (disordered state). We studied the complexity of fMRI-based resting-state networks. We found that positively correlated (pos) networks comprising only the positive functional connections have higher complexity than anticorrelation (neg) networks (comprising the negative connections) and the network consisting of the absolute value of all connections (abs). We also observed a significant correlation between complexity and the strength of functional connectivity in the pos network. Our results suggest that the pos network is related to the information processing in the brain and that functional connectivity studies should analyze pos and neg networks separately instead of the abs network, as is commonly done.

Design of optimal nonlinear network controllers for Alzheimer's disease.

Brain stimulation can modulate the activity of neural circuits impaired by Alzheimer's disease (AD), having promising clinical benefit. However, all individuals with the same condition currently receive identical brain stimulation, with limited theoretical basis for this generic approach. In this study, we introduce a control theory framework for obtaining exogenous signals that revert pathological electroencephalographic activity in AD at a minimal energetic cost, while reflecting patients' biological variability. We used anatomical networks obtained from diffusion magnetic resonance images acquired by the Alzheimer's Disease Neuroimaging Initiative (ADNI) as mediators for the interaction between Duffing oscillators. The nonlinear nature of the brain dynamics is preserved, given that we extend the so-called state-dependent Riccati equation control to reflect the stimulation objective in the high-dimensional neural system. By considering nonlinearities in our model, we identified regions for which control inputs fail to correct abnormal activity. There are changes to the way stimulated regions are ranked in terms of the energetic cost of controlling the entire network, from a linear to a nonlinear approach. We also found that limbic system and basal ganglia structures constitute the top target locations for stimulation in AD. Patients with highly integrated anatomical networks-namely, networks having low average shortest path length, high global efficiency-are the most suitable candidates for the propagation of stimuli and consequent success on the control task. Other diseases associated with alterations in brain dynamics and the self-control mechanisms of the brain can be addressed through our framework.

Permutation entropy analysis of heart rate variability for the assessment of cardiovascular autonomic neuropathy in type 1 diabetes mellitus.

Heart rate variability (HRV) analysis is a relevant tool for the diagnosis of cardiovascular autonomic neuropathy (CAN). To our knowledge, no previous investigation on CAN has assessed the complexity of HRV from an ordinal perspective. Therefore, the aim of this work is to explore the potential of permutation entropy (PE) analysis of HRV complexity for the assessment of CAN. For this purpose, we performed a short-term PE analysis of HRV in healthy subjects and type 1 diabetes mellitus patients, including patients with CAN. Standard HRV indicators were also calculated in the control group. A discriminant analysis was used to select the variables combination with best discriminative power between control and CAN patients groups, as well as for classifying cases. We found that for some specific temporal scales, PE indicators were significantly lower in CAN patients than those calculated for controls. In such cases, there were ordinal patterns with high probabilities of occurrence, while others were hardly found. We posit this behavior occurs due to a decrease of HRV complexity in the diseased system. Discriminant functions based on PE measures or probabilities of occurrence of ordinal patterns provided an average of 75% and 96% classification accuracy. Correlations of PE and HRV measures showed to depend only on temporal scale, regardless of pattern length. PE analysis at some specific temporal scales, seem to provide additional information to that obtained with traditional HRV methods. We concluded that PE analysis of HRV is a promising method for the assessment of CAN.