Temporal Interference Stimulation for Focused Stimulation of Deep Structures of Human Brain: A Computer-Based Feasibility Study

Abstract

Temporal interference (TI) stimulation was recently proposed that allows for the stimulation of deep brain structures while avoiding the stimulation of neocortical regions by injecting two alternating currents with different high frequencies via two electrode pairs attached on the scalp. This allows for the selective stimulation of deep brain regions with TI currents oscillating at the frequency equal to the difference of two high frequencies. Despite the effectiveness of TI stimulation proved through animal experiments, it is difficult to deliver TI currents to a specific deep brain region due to the complex structures of the human brain. Also, it is hard to send sufficient TI currents that can induce neural firing to deep brain regions of the human brain because the size of anatomical structures is much larger than that of small animal. In this dissertation, the author suggested three approaches to address abovementioned issues by using the computational simulation with finite element (FE) head models. Firstly, we optimized electrode configurations and injection currents that can deliver maximum TI stimulation currents to a specific deep brain region, the head of the right hippocampus, considering the real anatomical head structures of each individual. Three realistic FE head models were employed for the optimization. The distribution of the optimized TI currents was then compared with that of the unoptimized TI currents and the conventional single frequency AC stimulation. Optimization of TI stimulation parameters allows for the delivery of the desired amount of TI current to the target region while effectively reducing the TI currents delivered to cortical regions compared to the other stimulation approaches. Inconsistency of the optimal stimulation conditions suggest that customized stimulation, considering the individual anatomical differences, is necessary for more effective transcranial TI stimulation. Customized transcranial TI stimulation based on the numerical field analysis is expected to enhance the overall effectiveness of noninvasive stimulation of the human deep brain structures. Secondly, it is difficult to achieve a focal stimulation of deep brain structures in the human brain only using two electrode pairs due to the complex structures of the human brain. Given that multiple electrodes are generally used for more focal stimulation in the study of transcranial electrical stimulation (tES), the usage of multiple electrode pairs could allow for the focal delivery of temporal interference (TI) currents to the target. To do this, in the present study, we suggested multi-pair TIS, employing more than two electrode pairs, for more focal stimulation of the deep brain region (the head of the right hippocampus in this study). Three realistic finite element models were used to validate the feasibility of multi-pair TIS. Contrary to the conventional TIS using two electrode pairs, we sequentially added additional eight electrode pairs to the conventional two electrode pairs. Simultaneous to the addition of each electrode pair, the optimal electrode conditions of the added electrode pair were determined to maximize the delivery of TI currents to the target while avoiding the stimulation of neocortical regions. Our results demonstrated that the multi-pair TIS can lead to a more focal stimulation than the conventional two-pair TIS for all head models. This was achieved by either the increase in TI envelope amplitude at the target or the decrease in that over neocortical regions as the number of electrode pairs added. Lastly, it is difficult to deliver sufficient temporal interference (TI) currents to induce neural activities to deep brain regions in the human brain when electrodes are attached on the scalp transcranially because the size of the anatomical structures of the human is much bigger and their anatomical structures are more complex than the small animal. Injecting stronger currents might allow for the increase in TI currents; however, there is a limit on increasing the injection current regarding safety concerns for transcranial TIS (tTIS). Also, TI currents tend to spread over neocortical regions when employing tTIS, resulting in the decrease of an efficacy of TIS. To address these issues, we suggested a novel method, epidural temporal interference stimulation (eTIS), of which electrodes are attached on dura mater. Then, we validated the computational simulation for eTIS with phantom experiments. We firstly optimized the electrode conditions that can deliver maximum TI currents to each of the three different targets (anterior hippocampus, subthalamic nucleus, and ventral intermediate nucleus of the thalamus) using finite element head model. Our findings demonstrated that eTIS has the advantage on avoiding the delivery of TI currents over neocortical regions compared to tTIS for all targets. Also, our results indicated that a possibility of optimized eTIS that can induce neural activities at each target when injecting the same level of currents used in epidural cortical stimulation. Through the phantom experiments, we observed that electric fields were oscillating with the frequency (10 Hz) of the difference between two high frequency of 2 kHz and 2.01 kHz. Furthermore, we demonstrated that the difference between simulated and measured TI envelope amplitudes was similar. For the first time, we demonstrated the feasibility of eTIS that can achieve more focal stimulation of deep brain regions than tTIS with less invasive placement of electrodes compared to deep brain stimulation (DBS) and validated the computational simulation for eTIS using the realistic human brain-sized phantom model. Future studies will be required to validate the effectiveness of eTIS. In conclusion, the suggested approaches are expected to be used to enhance the effectiveness of TI stimulation for stimulating the human deep brain structures. In the future study, the efficacy of the approaches needs to be further validated via human trials.