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.

Understanding and treating heterogeneous brain disorders requires specialized techniques spanning genetics, proteomics, and neuroimaging. Designed to meet this need, NeuroPM-box is a user-friendly, open-access, multi-tool cross-platform software capable of characterizing multiscale and multifactorial neuropathological mechanisms. Using advanced analytical modeling for molecular, histopathological, brain-imaging and/or clinical evaluations, this framework has multiple applications, validated here with synthetic (N > 2900), in-vivo (N = 911) and post-mortem (N = 736) neurodegenerative data, and including the ability to characterize: (i) the series of sequential states (genetic, histopathological, imaging or clinical alterations) covering decades of disease progression, (ii) concurrent intra-brain spreading of pathological factors (e.g., amyloid, tau and alpha-synuclein proteins), (iii) synergistic interactions between multiple biological factors (e.g., toxic tau effects on brain atrophy), and (iv) biologically-defined patient stratification based on disease heterogeneity and/or therapeutic needs. This freely available toolbox (neuropm-lab.com/neuropm-box.html) could contribute significantly to a better understanding of complex brain processes and accelerating the implementation of Precision Medicine in Neurology.

There is a critical need for a better multiscale and multifactorial understanding of neurological disorders, covering from genes to neuroimaging to clinical factors and treatments effects. Here we present NeuroPM-box, a cross-platform, user-friendly and open-access software for characterizing multiscale and multifactorial brain pathological mechanisms and identifying individual therapeutic needs. The implemented methods have been extensively tested and validated in the neurodegenerative context, but there is not restriction in the kind of disorders that can be analyzed. By using advanced analytic modeling of molecular, neuroimaging and/or cognitive/behavioral data, this framework allows multiple applications, including characterization of: (i) the series of sequential states (e.g. transcriptomic, imaging or clinical alterations) covering decades of disease progression, (ii) intra-brain spreading of pathological factors (e.g. amyloid and tau misfolded proteins), (iii) synergistic interactions between multiple brain biological factors (e.g. direct tau effects on vascular and structural properties), and (iv) biologically-defined patients stratification based on therapeutic needs (i.e. optimum treatments for each patient). All models outputs are biologically interpretable. A 4D-viewer allows visualization of spatiotemporal brain (dis)organization. Originally implemented in MATLAB, NeuroPM-box is compiled as standalone application for Windows, Linux and Mac environments: neuropm-lab.com/software. In a regular workstation, it can analyze over 150 subjects per day, reducing the need for using clusters or High-Performance Computing (HPC) for large-scale datasets. This open-access tool for academic researchers may significantly contribute to a better understanding of complex brain processes and to accelerating the implementation of Precision Medicine (PM) in neurology.

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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 develop and validate a personalized brain activity model that incorporates functional MRI, amyloid-beta (Abeta) and tau-PET from AD-related participants (N=132). By simulating electrophysiological activity mediated by toxic protein deposition, this integrative approach uncovers key patho-mechanistic interactions, including synergistic Abeta 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 Abeta-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.