Endogenous and exogenous electric fields as modifiers of brain activity: rational design of noninvasive brain stimulation with transcranial alternating current stimulation

Abstract

Synchronized neuronal activity in the cortex generates weak electric fields that are routinely measured in humans and animal models by electroencephalography and local field potential recordings. Traditionally, these endogenous electric fields have been considered to be an epiphenomenon of brain activity. Recent work has demonstrated that active cortical networks are surprisingly susceptible to weak perturbations of the membrane voltage of a large number of neurons by electric fields. Simultaneously, noninvasive brain stimulation with weak, exogenous electric fields (transcranial current stimulation, TCS) has undergone a renaissance due to the broad scope of its possible applications in modulating brain activity for cognitive enhancement and treatment of brain disorders. This review aims to interface the recent developments in the study of both endogenous and exogenous electric fields, with a particular focus on rhythmic stimulation for the modulation of cortical oscillations. The main goal is to provide a starting point for the use of rational design for the development of novel mechanism-based TCS therapeutics based on transcranial alternating current stimulation, for the treatment of psychiatric illnesses.

Keywords: feedback electric field; magnetic resonance imaging; neuronal network; transcranial alternating current stimulation.

Figure 1.. Vertical integration of spatial scales from molecules (nanometer scale) all the way to the whole brain (centimeter scale). Integration of findings from the study of the brain at these different levels may represent the most promising approach to understand how neural activity gives rise to behavior and how impaired neural activity causes disease. This review focuses on the network level (at the mesoscopic scale) that is sandwiched between the microscopic and the macroscopic levels.

Figure 2.. Schematic representation of feedforward and feedback control of complex systems. Feedforward input is predetermined and independent of the response of the system to the input. Examples of feedforward signals in the context of this review are exogenous electric fields that are applied to animal preparations or humans in the form of TCS. Feedback is defined as input that depends of the state or output of the system to be controlled. Endogenous electric fields fall in this category since the neuronal activity of a network generates an electric field that in turn targets again the same neurons that generate the activity in the first place. EEG, electroencephalogram; LFP, local field potential; TCS, transcranial current stimulation

Figure 3.. Illustration of how sparse, nonsynchronized activity does not generate a pronounced electric field and therefore is likely unaltered by the proposed feedback between neuronal activity and electric fields. Synchronized activity generates a more pronounced electric field and is therefore able to use the resulting endogenous electric field to further sustain and amplify the ongoing synchronized activity. EEG, electroencephalogram; EF, electric field

Figure 4.. Arnold's tongues. Effects of periodic perturbations are limited to stimulation frequencies close to the intrinsic (fundamental) frequency and its harmonics. Inverted triangles (“tongues”) delimit areas where for increasing stimulation amplitude, a broader range of stimulation frequencies are effective. f, frequency