Biophysical investigation of temporal interference neuromodulation

Abstract

Temporal Interference (TI) stimulation is a non-invasive deep brain stimulation technique that has promise for treating brain diseases caused by aberrant neural activity. During TI, two high frequency electric fields are applied to the brain. These fields differ in frequency by a small amount termed the difference frequency. Neurons are stimulated at the difference frequency, however, it has not been determined how this occurs. The mechanism of action of TI is currently unknown, and elucidation of this is pivotal for development of the technique. In this thesis, I present work that probes the mechanisms of TI stimulation, and the nonlinear processes underlying it. Additionally, I investigate whether these processes are present in endogenous neural activity. I investigated the mechanism and parameter space of TI stimulation. I found that a neural frequency conversion process that originates at the single neuron membrane, is occurring during stimulation, resulting in subthreshold polarisation at the difference frequency. This nonlinear frequency conversion occurs at a wide range of applied frequencies, suggesting that it is being mediated by Frequency Mixing (FM). The strength of this nonlinear process and thus the strength of TI stimulation, is dependent on the applied frequency, but not on the difference frequency. Additionally, I found that the strength of TI stimulation is dependent on the summed amplitude of the applied currents. These findings aid in the elucidation of the mechanisms by which TI exerts its effects, which may help development of the technique, and have implications for the focality of the stimulation. Additionally, I investigated the presence of FM in endogenous neural activity by testing a new methodology for detection of FM via a three-way phase relationship between the signals involved. I found evidence for this nonlinear process in human cortical activity. I suggest that it may be disturbed in Traumatic Brain Injury (TBI), where large-scale functional networks are disrupted. Lastly, I validated a novel technique for non invasive deep brain stimulation called Pulse-Width Modulated-Temporal Interference (PWM-TI). I found that PWM-TI can effectively stimulate neurons at the difference frequency, with comparable efficiency to traditional TI.