Neuromodulation effect of temporal interference stimulation based on network computational model.

Deep brain stimulation (DBS) has long been the conventional method for targeting deep brain structures, but noninvasive alternatives like transcranial Temporal Interference Stimulation (tTIS) are gaining traction. Research has shown that alternating current influences brain oscillations through neural modulation. Understanding how neurons respond to the stimulus envelope, particularly considering tTIS's high-frequency carrier, is vital for elucidating its mechanism of neuronal engagement. This study aims to explore the focal effects of tTIS across varying amplitudes and modulation depths in different brain regions. An excitatory-inhibitory network using the Izhikevich neuron model was employed to investigate responses to tTIS and compare them with transcranial Alternating Current Stimulation (tACS). We utilized a multi-scale model that integrates brain tissue modeling and network computational modeling to gain insights into the neuromodulatory effects of tTIS on the human brain. By analyzing the parametric space, we delved into phase, amplitude, and frequency entrainment to elucidate how tTIS modulates endogenous alpha oscillations. Our findings highlight a significant difference in current intensity requirements between tTIS and tACS, with tTIS requiring notably higher intensity. We observed distinct network entrainment patterns, primarily due to tTIS's high-frequency component, whereas tACS exhibited harmonic entrainment that tTIS lacked. Spatial resolution analysis of tTIS, conducted via computational modeling and brain field distribution at a 13 Hz stimulation frequency, revealed modulation in deep brain areas, with minimal effects on the surface. Notably, we observed increased power within intrinsic and stimulation bands beneath the electrodes, attributed to the high stimulus signal amplitude. Additionally, Phase Locking Value (PLV) showed slight increments in non-deep areas. Our analysis indicates focal stimulation using tTIS, prompting further investigation into the necessity of high amplitudes to significantly affect deep brain regions, which warrants validation through clinical experiments.

Pilot study of using transcranial temporal interfering theta-burst stimulation for modulating motor excitability in rat.

Transcranial temporal interference stimulation (tTIS) is a promising brain stimulation method that can target deep brain regions by delivering an interfering current from surface electrodes. Most instances of tTIS stimulate the brain with a single-frequency sinusoidal waveform generated by wave interference. Theta burst stimulation is an effective stimulation scheme that can modulate neuroplasticity by generating long-term potentiation- or depression-like effects. To broaden tTIS application, we developed a theta burst protocol using tTIS technique to modulate neuroplasticity in rats. Two cannula electrodes were unilaterally implanted into the intact skull over the primary motor cortex. Electrical field of temporal interference envelopes generated by tTIS through cannula electrodes were recorded from primary motor cortex. Theta burst schemes were characterized, and motor activation induced by the stimulation was also evaluated simultaneously by observing electromyographic signals from the corresponding brachioradialis muscle. After validating the stimulation scheme, we further tested the modulatory effects of theta burst stimulation delivered by tTIS and by conventional transcranial electrical stimulation on primary motor cortex excitability. Changes in the amplitude of motor evoked potentials, elicited when the primary motor cortex was activated by electrical pulses, were measured before and after theta burst stimulation by both techniques. Significant potentiation and suppression were found at 15 to 30 min after the intermittent and continuous theta burst stimulation delivered using tTIS, respectively. However, comparing to theta burst stimulations delivered using conventional form of transcranial electrical stimulation, using tTIS expressed no significant difference in modulating motor evoked potential amplitudes. Sham treatment from both methods had no effect on changing the motor evoked potential amplitude. The present study demonstrated the feasibility of using tTIS to achieve a theta burst stimulation scheme for motor cortical neuromodulation. These findings also indicated the future potential of using tTIS to carry out theta burst stimulation protocols in deep-brain networks for modulating neuroplasticity.

Population-level insights into temporal interference for focused deep brain neuromodulation.

The ability to stimulate deep brain regions in a focal manner brings new opportunities for treating brain disorders. Temporal interference (TI) stimulation has been suggested as a method to achieve focused stimulation in deep brain targets. Individual-level knowledge of the interferential currents has permitted personalizing TI montage via subject-specific digital human head models, facilitating the estimation of interferential electric currents in the brain. While this individual approach offers a high degree of personalization, the significant intra-and inter-individual variability among specific head models poses challenges when comparing electric-field doses. Furthermore, MRI acquisition to develop a personalized head model, followed by precise methods for placing the optimized electrode positions, is complex and not always available in various clinical settings. Instead, the registration of individual electric fields into brain templates has offered insights into population-level effects and enabled montage optimization using common scalp landmarks. However, population-level knowledge of the interferential currents remains scarce. This work aimed to investigate the effectiveness of targeting deep brain areas using TI in different populations. The results showed a trade-off between deep stimulation and unwanted cortical neuromodulation, which is target-dependent at the group level. A consistent modulated electric field appeared in the deep brain target when the same montage was applied in different populations. However, the performance in terms of focality and variability varied when the same montage was used among populations. Also, group-level TI exhibited greater focality than tACS, reducing unwanted neuromodulation volume in the cortical part by at least 1.5 times, albeit with higher variability. These results provide valuable population-level insights when considering TI montage selection.

Multi-objective optimization via evolutionary algorithm (MOVEA) for high-definition transcranial electrical stimulation of the human brain.

Designing a transcranial electrical stimulation (tES) strategy requires considering multiple objectives, such as intensity in the target area, focality, stimulation depth, and avoidance zone. These objectives are often mutually exclusive. In this paper, we propose a general framework, called multi-objective optimization via evolutionary algorithm (MOVEA), which solves the non-convex optimization problem in designing tES strategies without a predefined direction. MOVEA enables simultaneous optimization of multiple targets through Pareto optimization, generating a Pareto front after a single run without manual weight adjustment and allowing easy expansion to more targets. This Pareto front consists of optimal solutions that meet various requirements while respecting trade-off relationships between conflicting objectives such as intensity and focality. MOVEA is versatile and suitable for both transcranial alternating current stimulation (tACS) and transcranial temporal interference stimulation (tTIS) based on high definition (HD) and two-pair systems. We comprehensively compared tACS and tTIS in terms of intensity, focality, and steerability for targets at different depths. Our findings reveal that tTIS enhances focality by reducing activated volume outside the target by 60%. HD-tTIS and HD-tDCS can achieve equivalent maximum intensities, surpassing those of two-pair tTIS, such as 0.51 V/m under HD-tACS/HD-tTIS and 0.42 V/m under two-pair tTIS for the motor area as a target. Analysis of variance in eight subjects highlights individual differences in both optimal stimulation policies and outcomes for tACS and tTIS, emphasizing the need for personalized stimulation protocols. These findings provide guidance for designing appropriate stimulation strategies for tACS and tTIS. MOVEA facilitates the optimization of tES based on specific objectives and constraints, advancing tTIS and tACS-based neuromodulation in understanding the causal relationship between brain regions and cognitive functions and treating diseases. The code for MOVEA is available at https://github.com/ncclabsustech/MOVEA.

A computational study on the optimization of transcranial temporal interfering stimulation with high-definition electrodes using unsupervised neural networks.

Transcranial temporal interfering stimulation (tTIS) can focally stimulate deep parts of the brain related to specific functions using beats at two high frequencies that do not individually affect the human brain. However, the complexity and nonlinearity of the simulation limit it in terms of calculation time and optimization precision. We propose a method to quickly optimize the interfering current value of high-definition electrodes, which can finely stimulate the deep part of the brain, using an unsupervised neural network (USNN) for tTIS. We linked a network that generates the values of electrode currents to another network, which is constructed to compute the interference exposure, for optimization by comparing the generated stimulus with the target stimulus. Further, a computational study was conducted using 16 realistic head models. We also compared tTIS with transcranial alternating current stimulation (tACS), in terms of performance and characteristics. The proposed method generated the strongest stimulation at the target, even when targeting deep areas or performing multi-target stimulation. The high-definition tTISl was less affected than tACS by target depth, and mis-stimulation was reduced compared with the case of using two-pair inferential stimulation in deep region. The optimization of the electrode currents for the target stimulus could be performed in 3 min. Using the proposed USNN for tTIS, we demonstrated that the electrode currents of tTIS can be optimized quickly and accurately. Moreover, we confirmed the possibility of precisely stimulating the deep parts of the brain via transcranial electrical stimulation.

Multiscale Computational Model Reveals Nerve Response in a Mouse Model for Temporal Interference Brain Stimulation.

There has been a growing interest in the non-invasive stimulation of specific brain tissues, while reducing unintended stimulation in surrounding regions, for the medical treatment of brain disorders. Traditional methods for non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), can stimulate brain regions, but they also simultaneously stimulate the brain and non-brain regions that lie between the target and the stimulation site of the source. Temporal interference (TI) stimulation has been suggested to selectively stimulate brain regions by superposing two alternating currents with slightly different frequencies injected through electrodes attached to the scalp. Previous studies have reported promising results for TI applied to the motor area in mice, but the mechanisms are yet to be clarified. As computational techniques can help reveal different aspects of TI, in this study, we computationally investigated TI stimulation using a multiscale model that computes the generated interference current pattern effects in a neural cortical model of a mouse head. The results indicated that the threshold increased with the carrier frequency and that the beat frequency did not influence the threshold. It was also found that the intensity ratio between the alternating currents changed the location of the responding nerve, which is in agreement with previous experiments. Moreover, particular characteristics of the envelope were investigated to predict the stimulation region intuitively. It was found that regions with high modulation depth (| maximum| - | minimum| values of the envelope) and low minimum envelope (near zero) corresponded with the activation region obtained via neural computation.