Optimal stimulation sites are not the most affected: personalised models of resting-state fMRI in Alzheimer's disease

Resting-state functional connectivity (FC) is altered in Alzheimer's disease (AD), widely regarded as a distributed network process; whether its signature reduces to a few focal sites has not been tested causally, a question central to targeted neuromodulation. We fit subject-specific, cross-subject-identifiable models whose free-running dynamics reproduce those of each individual patient. The fitted model parameters classify AD from controls at modest accuracy, below that of structural atrophy; we build on the functional model nonetheless, because dynamics, not tissue loss, are what stimulation can act on. Changing a virtual patient's model connectivity toward the control template reverts its AD classification, establishing in silico that the disease signature is correctable, yet the required correction is intrinsically distributed: a coordinated, multi-site change of the model connectivity that no single-node edit reproduces. Where, then, should a physically realisable focal drive act? A single-site drive at the node whose connectivity is most altered fails to revert the classification even at supra-physiological amplitudes, whereas selecting each patient's site by its effect on the disease discriminant achieves complete, individualised reclassification from one site, and a real-time closed-loop controller reaches comparable efficacy at lower dose using only causally available information. Optimal targets are cortical and heterogeneous: the site to stimulate is not where connectivity is most altered but where the network is most therapeutically responsive.