Realistic modeling of mesoscopic ephaptic coupling in the human brain

Abstract

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.

A personalizable autonomous neural mass model of epileptic seizures

“…Moreover, since extrasynaptic NMDA receptor activation induced by glutamate spillover is susceptible to activate the calcium-sensitive calpain that leads to KCC2 cleavage and downregulation (23), every seizure is susceptible to aggravate chloride homeostasis through the alteration of KCC2 expression in the membrane. Severe dowregulation of chloride transporter may lead to constant constitutive depolarizing GABA (11) whereas mild dowregulation could be associated with activity dependent overload of chloride in case of intense activity of GABAergic interneurons (3). Both of these can be represented by the model through the α KCC2 parameter.…”

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sub-class of GABAergic interneurons, somatostatin-positive 23 (SST) cells, triggered epileptiform activity (6).

24Mechanistically, the dysregulation of chloride homeostasis 25 observed in epileptic tissues appears to play a major role in the 26 depolarizing effect of GABA A neurotransmitters during epilep-27 tic seizures (7), and there is evidence for the accumulation of 28 chloride in pyramidal cells at seizure onset (8). Changes in the 29 expression level of chloride cotransporters, such as KCC2 (K-30 Cl cotransporter type 2) and NKCC1 (Na-K-2Cl cotransporter 31 type 1) have been identified as the main causes for pathological 32 chloride accumulation in the epileptic tissue (3,(9)(10)(11)(12).

33Recently, a computational model including activity-34 dependent GABA depolarization was used to reproduce epilep-35 tic discharges in Dravet syndrome patients (13). In the model, 36 GABA depolarization was mediated by PV-cells and was rep-37 resented by a parameter that was gradually increased to gen-38 fast-onset seizure initiation, ictal-like activity and seizure-like 40 activity termination.

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“…Mechanistically, the dysregulation of chloride homeostasis 25 observed in epileptic tissues appears to play a major role in the 26 depolarizing effect of GABA A neurotransmitters during epilep-27 tic seizures (7), and there is evidence for the accumulation of 28 chloride in pyramidal cells at seizure onset (8). Changes in the 29 expression level of chloride cotransporters, such as KCC2 (K-30 Cl cotransporter type 2) and NKCC1 (Na-K-2Cl cotransporter 31 type 1) have been identified as the main causes for pathological 32 chloride accumulation in the epileptic tissue (3,(9)(10)(11)(12).…”

Analysis and extension of exact mean-field theory with dynamic synaptic currents

“…Such modulation of the effective coupling provides a long-sought mechanism for the surprising sensitivity of networks to weak electric fields generated by brain stimulation or by neural tissue itself, a phenomenon known as ephaptic interaction (31). It may also explain why stronger electrics fields are needed to induce measurable effects in in-vitro (low, disrupted connectivity) or small animal studies as compared with humans.…”

The Electromagnetic Will

“…The researchers concluded that, "Endogenous brain activity can causally affect neural function through field effects under physiological conditions", and that the resulting synchronization "may have a substantial effect on neural information processing and plasticity". These pioneering papers were followed by several additional studies [62,[69][70][71][72][73][74] that extended the demonstration of ephaptic/field interactions into several other systems. One of the most impressive is a recent study from Wade G. Regehr's laboratory at Harvard Medical School who used a combination of in vivo multielectrode recordings to measure both intracellular and extracellular voltages with dynamic clamping and optogenetics in live rodents and rodent brain slices [72].…”