Authors: Giulio Ruffini, Ricardo Salvador, Ehsan Tadayon, Roser Sanchez-Todo, Alvaro Pascual-Leone, Emiliano Santarnecchi – Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and recently proposed as substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to map ephaptic activity in the human brain and explore its trajectory during aging by characterizing the macroscopic electric field generated by cortical dipoles using realistic finite element modeling. We find that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant endogenous fields and to those generated by noninvasive transcranial brain stimulation, therefore possibly able to modulate neuronal activity. Then, to evaluate the role of self-generated ephaptic fields in the human cortex, we adapt an interaction approximation that considers the relative orientation of neuron and field to derive the membrane potential perturbation in pyramidal cells. Building on this, we define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from subjects aged 16-83. Results reveal that ephaptic modulation follows gyrification patterns in the human brain, and significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. By providing the means for fast and direct interaction between neurons, ephaptic modulation likely contributes to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology.

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