Nonlinearities and Timescales in Temporal Interference Stimulation

Abstract

Objective: In temporal interference (TI) deep brain stimulation (DBS), the neurons of mice react to two interfering sinusoids with a slightly different frequency. This is called a temporal interference (TI) signal. It was previously seen that for the same input intensity, the neurons do not react to a purely sinusoidal signal. This study aims to get a better understanding into the mechanism for this, which is largely unknown. Methods: This study makes use of single compartment models to computationally simulate the response of neurons to the sinusoidal and TI-waveform. This study also compares different neuron models to get insight in which models are able to model the experimental behavior. Results: It was found that integrate-and-fire models do not reflect the experimental behavior while the Hodgkin-Huxley and Frankenhaeuer-Huxley model do reflect this behavior. It was seen that changing the characteristics of the ion gates in the Frankenhaeuser-Huxley model alters the response to both sinusoidal and TI signal. It can even make sure that the firing threshold of the sinusoidal input becomes lower than that of the TI input. Conclusion: The results show that the ion-gates have a big influence on the behavior and their characteristics can define the way the neuron reacts to sinusoidal and TI inputs. Significance: This paper makes advances both in terms of biophysical insight of the neuron as well as the insight in computational modelling of TI-stimulation.

Safety Recommendations for Temporal Interference Stimulation in the Brain

“…Thus, they conclude that GHK nonlinearity is not a necessary driver of the neural response to TIS. Furthermore, by varying the time constants and steady-state values of the FH and HH ion channels, they demonstrate that the response to TIS exposure depends sensitively on nonlinearities in voltage-dependent ion channel gating dynamics 196 .…”

“…Hyperpolarizing potassium channels respond more slowly, leading to transient charge accumulation inside the cell, briefly depolarizing the membrane. Here, the key quantities responsible for sensitivity to TIS are ion channel time constants, in contrast to Mirzakhalili et al, who emphasize the intrinsic membrane time constant of axonal fibers 95 . In the same vein, Plovie et al simulate various single compartment neuron models to explore TI mechanisms 196 . To this end, they define a “TI zone” as the range of input currents over which an amplitude modulated TI signal induces firing at the difference frequency while an unmodulated carrier at the same frequency does not.…”

“…In the same vein, Plovie et al simulate various single compartment neuron models to explore TI mechanisms 196 . To this end, they define a “TI zone” as the range of input currents over which an amplitude modulated TI signal induces firing at the difference frequency while an unmodulated carrier at the same frequency does not.…”

Temporal interference stimulation disrupts spike timing in the primate brain

“…The mechanisms responsible for demodulation are not yet well-understood, but they likely involve a combination of cell-intrinsic and network properties. Within a single cell, asymmetries between inwardgoing sodium and outward-going potassium channels may be sufficient to generate susceptibility to AM electric fields 18,36 . This would be consistent with recent work showing that the presence of glia tends to dampen neuronal demodulation of TI stimuli 37 .…”

Temporal interference stimulation disrupts spike timing in the primate brain

“…The mechanisms responsible for demodulation are not yet well-understood, but they likely involve a combination of cell-intrinsic and network properties. Within a single cell, asymmetries between inward-going sodium and outward-going potassium channels may be sufficient to generate susceptibility to AM electric fields (Mirzakhalili et al, 2020; Plovie et al, 2023). Within larger networks, frequency-dependent adaptation of a circuit could also contribute to demodulation (Esmaeilpour et al, 2021).…”