However, if the intrinsic oscillator prefers certain frequencies, the rational design of tACS paradigms is more complex (and interesting). The selective preference of certain stimulation frequencies is called resonance, a well-known phenomenon that can be observed in many physical and biological systems. Technically, either resonance can be easily determined by application of periodic stimulation with identical amplitude, but different frequencies. Any Inhibitors,research,lifescience,medical measure of oscillatory structures will reveal the degree to which the system prefers a given

frequency. In fact, one can look for two fundamental properties that delineate the resonance properties of the system: (i) the presence of so-called

“Arnold tongues”; and (ii) the presence of harmonics. Arnold tongues delineate the areas of entrainment for parameter pairs of stimulation amplitude and frequency. The tongueshaped areas derive from the fact Inhibitors,research,lifescience,medical that the stronger the amplitude of the periodic stimulation, the broader the range of frequencies to which an intrinsic oscillator can be entrained (Figure 4.) This corresponds to the intuitive concept Inhibitors,research,lifescience,medical that weak forces can only amplify the intrinsically present dynamics whereas stronger forces can—to a certain extent—override/modulate the frequency of the intrinsic oscillator. Harmonic frequencies refer to the phenomenon that stimulation Inhibitors,research,lifescience,medical at multiples of the intrinsic frequencies has a privileged effect on the amplitude of the ongoing oscillation. Computational simulations of large-scale cortical networks demonstrated that such resonance

effects indeed mediate the modulatory effects of tACS19; yet detailed experimental demonstration of resonance at the network level has remained elusive. Likely, the discovery of such a phenomenon will build on the well-documented intrinsic resonance of individual neurons,67,68 especially layer V pyramidal cells that are interestingly very sensitive to electric fields due to their Inhibitors,research,lifescience,medical elongated somatodendritic axis.69 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 Batimastat stimulation … Feedback stimulation: the future? In this review, I have discussed the recent evidence for: (i) a modulatory effect of endogenous electric fields that likely provide a synchronizing network signal by feedback; and (ii) network resonance as the putative mechanistic principle by which rhythmically active neuronal networks are sensitive to periodic perturbations by both endogenous and exogenous electric fields. Together, these recent discoveries provide fertile grounds for the development of novel noninvasive brain stimulation paradigms.