Responses of model cortical neurons to temporal interference stimulation and related transcranial alternating current stimulation modalities

Abstract

Objective. Temporal interference stimulation (TIS) was proposed for non-invasive, focal, and steerable deep brain stimulation. However, the mechanisms underlying experimentally-observed suprathreshold TIS effects are unknown, and prior simulation studies had limitations in the representations of the TIS electric field (E-field) and cerebral neurons. We examined the E-field and neural response characteristics for TIS and related transcranial alternating current stimulation modalities. Approach. Using uniform-field approximation, we simulated a range of stimulation parameters in biophysically-realistic model cortical neurons, including different orientations, frequencies, amplitude ratios, amplitude modulation, and phase difference of the E-fields, and obtained thresholds for both activation and conduction block. Results. For two E-fields with similar amplitudes (representative of E-field distributions at the target region), TIS generated an amplitude-modulated total E-field. Due to the phase difference of the individual E-fields, the total TIS E-field vector also exhibited rotation where the orientations of the two E-fields were not aligned (generally also at the target region). TIS activation thresholds (75–230 V/m) were similar to those of high-frequency stimulation with or without modulation and/or rotation. For E-field dominated by the high-frequency carrier and with minimal amplitude modulation and/or rotation (typically outside the target region), TIS was less effective at activation and more effective at block. Unlike amplitude-modulated high-frequency stimulation, TIS generated conduction block with some orientations and amplitude ratios of individual E-field at very high amplitudes of the total E-field (>1700 V/m). Significance. The complex 3D properties of the TIS E-fields should be accounted for in computational and experimental studies. The mechanisms of suprathreshold cortical TIS appear to involve neural activity block and periodic activation or onset response, consistent with computational studies of peripheral axons. These phenomena occur at E-field strengths too high to be delivered tolerably through scalp electrodes and may inhibit endogenous activity in off-target regions, suggesting limited significance of suprathreshold TIS.

Temporal interference current stimulation in peripheral nerves is not driven by envelope extraction

“…Further, our data suggest that the integration and thresholding properties of neuronal membranes are mostly linear processes which do not extract low frequency energy, and any nonlinear properties affect the firing threshold by approximately less than 6%. In addition to our exploration of the phasic on-target firing properties, our data support the conclusions of multiple modeling studies which predicted that interferential techniques will induce significant offtarget conduction block due to the source signals [3,10,12,20,21].…”

Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning

“…However, the fact that the peak of the stimulation field of such protocols cannot be focused on deep brain regions without strongly stimulating the overlying cortex, along with their characteristic of only achieving mild and inhibitory effects 41 , makes this possibility very unlikely. Fourth, multiple groups have now highlighted the possibility of high-intensity, suprathreshold tTIS to generate conduction blocks 58 , 69 . However, the field strengths reached in the current experiments employing subthreshold, low-intensity tTIS are several orders of magnitude lower than the one employed in the aforementioned works, rendering such effects unlikely.…”

Frequency-dependent membrane polarization across neocortical cell types and subcellular elements by transcranial alternating current stimulation

“…Therefore, neurons in the deep brain area respond to the low-frequency oscillating envelope rather than to the kHz stimulation. Particularly, computational studies [55,56] use the morphologically and biophysically realistic models to examine cell response to TI stimulation, and their results demonstrate that the resulting lowfrequency envelope with 10 Hz can affect both subthreshold and firing activity in cortical neurons. In this work, we use the same neuron models to examine the cellular and subcellular polarization to oscillating EFs at low frequencies (1-100 Hz), which includes the frequency range of the amplitude-modulated EF induced by TI stimulation.…”