Realistic modeling of mesoscopic ephaptic coupling in the human brain

Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and proposed as a substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to model mesoscopic ephaptic activity in the human brain and explore its trajectory during aging by characterizing the electric field generated by cortical dipoles using realistic finite element modeling. Extrapolating from electrophysiological measurements, we first observe that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant self-generated fields and to those produced by noninvasive transcranial brain stimulation, and therefore possibly able to modulate neuronal activity. Then, to evaluate the role of these fields in the human cortex in large MRI databases, we adapt an interaction approximation that considers the relative orientation of neuron and field to estimate the membrane potential perturbation in pyramidal cells. We use this approximation to 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 healthy subjects aged 16–83. Results reveal that ephaptic coupling, in the simplified mesoscopic modeling approach used here, significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. This study suggests that by providing the means for fast and direct interaction between neurons, ephaptic modulation may contribute to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology.Author summary: We study the potential role of a less understood type of communication between neurons in the brain. While the principal mechanism for neuron communication is synaptic, active neurons generate electric fields. Whether this is physiologically relevant at the systems level or merely an epiphenomenon is uncertain because these fields are rather weak at the mesoscopic scale (i.e., between single neuron and entire brain scales). We first review converging evidence from in-vitro and in-vivo studies that suggest the former, and then, using realistic finite element modeling, we show that the electric fields generated by transcranial electrical current stimulation are of the same magnitude as endogenous ones in this scale. We then develop a method to estimate the amount of potential ephaptic or electric-field interaction in an individual brain using finite element modeling and show its decrease with age in a large cohort of 401 subjects. Ephaptic interaction may be important for complex processing in biological neural networks, because it travels at very fast speeds and provides a potential communication link across distant neurons in the cortex. Assessing the physiological relevance of this mechanism may be key in understanding some brain disorders and to design improved tES protocols.