Temporal Interference Stimulation Research Articles

Electric field temporal interference stimulation of neurons in vitro.

Electrical stimulation (ES) techniques, such as deep brain and transcranial electrical stimulation, have shown promise in alleviating the symptoms of depression and other neurological disorders in vivo. A new noninvasive ES method called temporal interference stimulation (TIS), possesses great potential as it can be used to steer the stimulation and possibly selectively modulate different brain regions. To study TIS in a controlled environment, we successfully established an in vitro 'TIS on a chip' setup using rat cortical neurons on microelectrode arrays (MEAs) in combination with a current stimulator. We validated the developed TIS system and demonstrated the spatial steerability of the stimulation by direct electric field measurements in the chip setup. We stimulated cultures of rat cortical neurons at 28 days in vitro (DIV) by two-channel stimulation delivering 1) TIS at 653 Hz and 643 Hz, resulting in a 10 Hz frequency envelope, 2) low-frequency stimulation (LFS) at 10 Hz and 3) high-frequency stimulation (HFS) at 653 Hz. Unstimulated cultures were used as control/sham. We observed the differences in the electric field strengths during TIS, HFS, and LFS. Moreover, HFS and LFS had the smallest effects on neuronal activity. Instead, TIS elicited neuronal electrophysiological responses, especially 24 hours after stimulation. Our 'TIS on a chip' approach eludicates the applicability of TIS as a method to modulate neuronal electrophysiological activity. The TIS on a chip approach provides spatially steerable stimuli while mitigating the effects of high stimulus fields near the stimulation electrodes. Thus, the approach opens new avenues for stimulation on a chip applications, allowing the study of neuronal responses to gain insights into the potential clinical applications of TIS in treating various brain disorders.

Target engagement of the subgenual anterior cingulate cortex with transcranial temporal interference stimulation in major depressive disorder: a protocol for a randomized sham-controlled trial.

Transcranial temporal interference stimulation (tTIS) is a new, emerging neurostimulation technology that utilizes two or more electric fields at specific frequencies to modulate the oscillations of neurons at a desired spatial location in the brain. The physics of tTIS offers the advantage of modulating deep brain structures in a non-invasive fashion and with minimal stimulation of the overlying cortex outside of a selected target. As such, tTIS can be effectively employed in the context of therapeutics for the psychiatric disease of disrupted brain connectivity, such as major depressive disorder (MDD). The subgenual anterior cingulate cortex (sgACC), a key brain center that regulates human emotions and influences negative emotional states, is a plausible target for tTIS in MDD based on reports of its successful neuromodulation with invasive deep brain stimulation. This pilot, single-site, double-blind, randomized, sham-controlled interventional clinical trial will be conducted at St. Michael's Hospital - Unity Health Toronto in Toronto, ON, Canada. The primary objective is to demonstrate target engagement of the sgACC with 130 Hz tTIS using resting-state magnetic resonance imaging (MRI) techniques. The secondary objective is to estimate the therapeutic potential of tTIS for MDD by evaluating the change in clinical characteristics of participants and electrophysiological outcomes and providing feasibility and tolerability estimates for a large-scale efficacy trial. Thirty participants (18-65 years) with unipolar, non-psychotic MDD will be recruited and randomized to receive 10 sessions of 130 Hz tTIS or sham stimulation (n = 15 per arm). The trial includes a pre- vs. post-treatment 3T MRI scan of the brain, clinical evaluation, and electroencephalography (EEG) acquisition at rest and during the auditory mismatch negativity (MMN) paradigm. This study is one of the first-ever clinical trials among patients with psychiatric disorders examining the therapeutic potential of repetitive tTIS and its neurobiological mechanisms. Data obtained from this trial will be used to optimize the tTIS approach and design a large-scale efficacy trial. Research in this area has the potential to provide a novel treatment option for individuals with MDD and circuitry-related disorders and may contribute to the process of obtaining regulatory approval for therapeutic applications of tTIS. ClinicalTrials.gov, identifier NCT05295888.

Fascicle-Selective Ultrasound-Powered Bidirectional Wireless Peripheral Nerve Interface IC.

This paper presents an innovative, minimally invasive, battery-free, wireless, peripheral nervous system (PNS) neural interface, which seamlessly integrates a millimeter-scale, fascicle-selective integrated circuit (IC) with extraneural recording and stimulating channels. The system also incorporates a wearable interrogator equipped with integrated machine-learning capabilities. This PNS interface is specifically tailored for adaptive neuromodulation therapy, targeting individuals with paralysis, amputation, or chronic medical conditions. By employing a neural pathway classifier and temporal interference stimulation, the proposed interface achieves precise deep fascicle selectivity for recording and stimulation without the need for nerve penetration or compression. Ultrasonic energy harvesters facilitate wireless power harvesting and data reception, enhancing the usability of the system. Key circuit performance metrics encompass a 2.2 μVrms input-referred noise, 14-bit ENOB, and a 173 dB Schreier figure of merit (FOM) for the neural analog-to-digital converter (ADC). Additionally, the ultra-low-power radio-frequency (RF) transmitter boasts a remarkable 1.38 pJ/bit energy efficiency. In vivo experiments conducted on rat sciatic nerves provide compelling evidence of the interface's ability to selectively stimulate and record neural fascicles. The proposed PNS neural interface offers alternative treatment options for diagnosing and treating neurological disorders, as well as restoring or repairing neural functions, improving the quality of life for patients with neurological and sensory deficits.

Visualizing interferential stimulation of human brains.

Transcranial electrical stimulation (TES) is limited in focally stimulating deep-brain regions, even with optimized stimulation montages. Recently, interferential stimulation (IFS), also known as transcranial temporal interference stimulation (TI, TIS, or tTIS), has drawn much attention in the TES community as both computational and experimental studies show that IFS can reach deep-brain areas. However, the underlying electrodynamics of IFS is complicated and difficult to visualize. Existing literature only shows static visualization of the interfered electric field induced by IFS. These could result in a simplified understanding that there is always one static focal spot between the two pairs of stimulation electrodes. This static visualization can be frequently found in the IFS literature. Here, we aimed to systematically visualize the entire dynamics of IFS. Following the previous study, the lead field was solved for the MNI-152 head, and optimal montages using either two pairs of electrodes or two arrays of electrodes were found to stimulate a deep-brain region close to the left striatum with the highest possible focality. We then visualized the two stimulating electrical currents injected with similar frequencies. We animated the instant electric field vector at the target and one exemplary off-target location both in 3D space and as a 2D Lissajous curve. We finally visualized the distribution of the interfered electric field and the amplitude modulation envelope at an axial slice going through the target location. These two quantities were visualized in two directions: radial-in and posterior-anterior. We hope that with intuitive visualization, this study can contribute as an educational resource to the community's understanding of IFS as a powerful modality for non-invasive focal deep-brain stimulation.

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

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here we show successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, functional magnetic resonance imaging studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as an exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional role. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.

A mini-review: recent advancements in temporal interference stimulation in modulating brain function and behavior.

Numerous studies have assessed the effect of Temporal Interference (TI) on human performance. However, a comprehensive literature review has not yet been conducted. Therefore, this review aimed to search PubMed and Web of Science databases for TI-related literature and analyze the findings. We analyzed studies involving preclinical, human, and computer simulations, and then discussed the mechanism and safety of TI. Finally, we identified the gaps and outlined potential future directions. We believe that TI is a promising technology for the treatment of neurological movement disorders, due to its superior focality, steerability, and tolerability compared to traditional electrical stimulation. However, human experiments have yielded fewer and inconsistent results, thus animal and simulation experiments are still required to perfect stimulation protocols for human trials.

Brain Response to Interferential Current Compared with Alternating Current Stimulation.

Temporal interference (TI) stimulation, which utilizes multiple external electric fields with amplitude modulation for neural modulation, has emerged as a potential noninvasive brain stimulation methodology. However, the clinical application of TI stimulation is inhibited by its uncertain fundamental mechanisms, and research has previously been restricted to numerical simulations and immunohistology without considering the acute in vivo response of the neural circuit. To address the characterization and understanding of the mechanisms underlying the approach, we investigated instantaneous brainwide activation patterns in response to invasive interferential current (IFC) stimulation compared with low-frequency alternative current stimulation (ACS). Results demonstrated that IFC stimulation is capable of inducing regional neural responses and modulating brain networks; however, the activation threshold for significantly recruiting a neural response using IFC was higher (at least twofold) than stimulation via alternating current, and the spatial distribution of the activation signal was restricted. A distinct blood oxygenation level-dependent (BOLD) response pattern was observed, which could be accounted for by the activation of distinct types of cells, such as inhibitory cells, by IFC. These results suggest that IFC stimulation might not be as efficient as conventional brain modulation methods, especially when considering TI stimulation as a potential alternative for stimulating subcortical brain areas. Therefore, we argue that a future transcranial application of TI on human subjects should take these implications into account and consider other stimulation effects using this technique.

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.

Obstructive sleep apnea improves with non-invasive hypoglossal nerve stimulation using temporal interference

BackgroundPeripheral nerve stimulation is used in both clinical and fundamental research for therapy and exploration. At present, non-invasive peripheral nerve stimulation still lacks the penetration depth to reach deep nerve targets and the stimulation focality to offer selectivity. It is therefore rarely employed as the primary selected nerve stimulation method. We have previously demonstrated that a new stimulation technique, temporal interference stimulation, can overcome depth and focality issues.MethodsHere, we implement a novel form of temporal interference, bilateral temporal interference stimulation, for bilateral hypoglossal nerve stimulation in rodents and humans. Pairs of electrodes are placed alongside both hypoglossal nerves to stimulate them synchronously and thus decrease the stimulation amplitude required to activate hypoglossal-nerve-controlled tongue movement.ResultsComparing bilateral temporal interference stimulation with unilateral temporal interference stimulation, we show that it can elicit the same behavioral and electrophysiological responses at a reduced stimulation amplitude. Traditional transcutaneous stimulation evokes no response with equivalent amplitudes of stimulation.ConclusionsDuring first-in-man studies, temporal interference stimulation was found to be well-tolerated, and to clinically reduce apnea-hypopnea events in a subgroup of female patients with obstructive sleep apnea. These results suggest a high clinical potential for the use of temporal interference in the treatment of obstructive sleep apnea and other diseases as a safe, effective, and patient-friendly approach. Trial registrationThe protocol was conducted with the agreement of the International Conference on Harmonisation Good Clinical Practice (ICH GCP), applicable United States Code of Federal Regulations (CFR) and followed the approved BRANY IRB File # 22-02-636-1279.

A voltage-controlled current source for temporal interference stimulation: Analysis, design, and study.

The temporal interference stimulation is a new technique to modulate brain activity by applying multiple channels of voltage-controlled current source (VCCS) simultaneously to the receptor surface. In this paper, the envelopes of the overlapped current waves at several areas of the receptor were analyzed and discussed with different circuit structures of VCCS. A complementary differential current source (CDCS) was designed to fit the best circuit topology based on the analysis of the enhanced Howland current source structure. Experiments were conducted by injecting current to a swine tissue using the CDCS and conventional VCCS and acquiring the voltage waveform data from different parts of the tissue. The waveforms were compared and analyzed, revealing that the conventional VCCS may generate an interference envelope in unexpected regions, while the CDCS did not. The CDCS design approach in this paper provides a new solution for temporal interference stimulation VCCS.

Why Temporal Inference Stimulation May Fail in the Human Brain: A Pilot Research Study.

Temporal interference stimulation (TIS) aims at targeting deep brain areas during transcranial electrical alternating current stimulation (tACS) by generating interference fields at depth. Although its modulatory effects have been demonstrated in animal and human models and stimulation studies, direct experimental evidence is lacking for its utility in humans (in vivo). Herein, we directly test and compare three different structures: firstly, we perform peripheral nerve and muscle stimulation quantifying muscle twitches as readout, secondly, we stimulate peri-orbitally with phosphene perception as a surrogate marker, and thirdly, we attempt to modulate the mean power of alpha oscillations in the occipital area as measured with electroencephalography (EEG). We found strong evidence for stimulation efficacy on the modulated frequency in the PNS, but we found no evidence for its utility in the CNS. Possible reasons for failing to activate CNS targets could be comparatively higher activation thresholds here or inhibitory stimulation components to the carrier frequency interfering with the effects of the modulated signal.

ID: 221898 MRI Compatible Device for Synchronized Synthesis of Multiple Carriers for Temporal Interference Stimulation

Temporal interference stimulation (TIS) [1] is considered a promising approach for non-invasive targeted modulation of deep brain region activity as it strongly reduces stimulation of overlaying structures and is more customizable than other transcranial electric stimulation methods. TIS is based on the beat frequency envelope of high frequency carriers. When the number of carriers and the complexity of the signal exceeds two, solutions based on signal generators and standalone current sources become increasingly difficult to synchronize to ensure coherent, phase-controlled modulation envelopes. The bandwidth and output impedance limitations of many available devices have prevented exploration of TIS beyond a few kHz. Magnetic resonance imaging (MRI) compatibility is also not fully provided with conventional solutions. Here, we sought to develop a highly flexible and safe device.

ID: 212051 EM Exposure During Non-Invasive Brain Stimulation Applications: Impact of Uncertainties on Treatment Relevant Metrics

Performance and safety of non-invasive brain stimulation (NIBS) techniques (e.g., transcranial electric stimulation (tES) or temporal interference stimulation (TIS)) rely on the precise delivery of stimulation dose (typically electric (E-)field related quantities) to targets. The assessment of uncertainty associated with electromagnetic (EM) dose calculated by finite-element method (FEM) simulations using detailed anatomical human head models to optimize stimulation parameters (e.g., electrode positions, current intensities) and predict safety and performance metrics is therefore essential. We systematically investigated the impact of experimental and modelling sources of uncertainty/variability on tES exposure and exposure-derived quantities (maximum amplitude modulation for TIS, focality of stimulation, etc.).

0494 Early Feasibility Study on Use of Noninvasive Temporal Interference Stimulation of the Hypoglossal Nerve in the Treatment of OSA

Abstract Introduction Hypoglossal nerve stimulation has proven effective as an alternative to Positive Airway Pressure (PAP) machines in treating obstructive sleep apnea (OSA). The only currently FDA-approved hypoglossal nerve stimulator requires surgical implantation. Somnial Inc. is developing a noninvasive nerve stimulator based on temporal interference (TI), such that multiple supra-kHz-modulating electrical fields overlap to create a hyper-localized field modulating at a lower, nerve-stimulating frequency equal to the offset between the original fields. Bilateral stimulation reduces lateral movement of the tongue and requires less energy applied to the individual nerves. In early studies, transcutaneous, bilateral TI stimulation showed strong forward and central tongue movement with long-term tolerability. Methods To determine the clinical impact of TI on the treatment of OSA, 11 patients recently diagnosed with moderate to severe OSA (AHI 15-50/hour) based on in-lab polysomnography (PSG) and BMI < 35 were subjected to bilateral TI stimulation of the hypoglossal nerves during another PSG. Two pairs of electrodes were placed on either side, medial to the inferior aspect of the mandible overlying the genioglossus muscle. The frequencies were modulated in a 4-second-on, 2-second-off pattern. Initial power settings were determined as sufficient to move the tongue without discomfort and were increased throughout the night in an approach similar to a CPAP titration study. Results 5 of the 11 patients analyzed in the study, including 4 out of 4 women, responded to the therapy (AHI reduction from baseline by >50% and an AHI of < 20/hour). Patient questionnaires indicate the treatment was well tolerated throughout the night. Conclusion These promising proof of concept results after a single night indicate the potential for the use of TI in the treatment of OSA. Transcutaneous application of stimulation energy via TI energy could be used to determine the efficacious does required to reduce AHI events in the at-home healthcare setting. This justifies future research in long-term, chronic-treatment studies with TI stimulation and the advancement of a home-based device. Support (if any)

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

Background. Electrical neuromodulation remains an effective therapy for multiple neurological disorders. One strategy to electrically stimulate nerves utilizes the interference of multiple high frequency waveforms. This technique, known as temporal interference stimulation or interferential current stimulation, has recently gained significant attention as a method to improve the state-of-the-art in neurostimulation in both animal studies and human clinical trials. Objective. Here we report our investigation into the fundamental properties of the neuronal response to these types of waveforms—the effects of carrier and envelope frequencies, thresholds, firing behavior, and phase and asymmetric interference patterns. Methods. We utilized a cuff electrode on the rat sciatic nerve to apply a variety of interferential signals. We recorded muscle activity in the plantar muscles and biceps femoris, which are proxies for activity on two of the major branches of the sciatic, which are spatially distinct in the target volume. We tested both fundamental recruitment properties as well as spatial techniques to selectively activate either muscle group. Results. Our data suggest, contrary to the currently accepted explanation, that neurons do not extract envelopes at all, and that the response to these signals is well explained by a resistor–capacitor (i.e. integrator) membrane with a fixed firing threshold. Basic interference techniques do not change recruitment far from electrodes. Techniques can produce regions of both phasic activation and tonic activation/conduction block. Conclusions. An integrator model suggests that interference techniques are less capable of minimally invasive stimulation for a subcortical brain target than previously thought. Human clinical trials using these techniques should reevaluate their methods. Interference stimulation allows significant target selectivity in a peripheral cuff electrode with targets near electrodes. These techniques can allow spatially distinct regions of phasic firing, tonic firing, conduction block, and no effect.

Investigating the direct effect of temporal interference (TI) stimulation on cortical activity with simultaneous EEG recording in humans

Investigating the direct effect of temporal interference (TI) stimulation on cortical activity with simultaneous EEG recording in humans

Establishing the non-human primate as an animal model for temporal interference stimulation. I. Simulations of electric fields

Establishing the non-human primate as an animal model for temporal interference stimulation. I. Simulations of electric fields

Establishing the non-human primate as an animal model for temporal interference stimulation. II. Application and neurophysiological recordings in a behaving preparation

Establishing the non-human primate as an animal model for temporal interference stimulation. II. Application and neurophysiological recordings in a behaving preparation

A Real-Time Non-Implantation Bi-Directional Brain-Computer Interface Solution without Stimulation Artifacts.

The non-implantation bi-directional brain-computer interface (BCI) is a neural interface technology that enables direct two-way communication between the brain and the external world by both "reading" neural signals and "writing" stimulation patterns to the brain. This technology has vast potential applications, such as improving the quality of life for individuals with neurological and mental illnesses and even expanding the boundaries of human capabilities. Nonetheless, non-implantation bi-directional BCIs face challenges in generating real-time feedback and achieving compatibility between stimulation and recording. These issues arise due to the considerable overlap between electrical stimulation frequencies and electrophysiological recording frequencies, as well as the impediment caused by the skull to the interaction of external and internal currents. To address those challenges, this work proposes a novel solution that combines the temporal interference stimulation paradigm and minimally invasive skull modification. A longitudinal animal experiment has preliminarily validated the feasibility of the proposed method. In signal recording experiments, the average impedance of our scheme decreased by 4.59 kΩ, about 67%, compared to the conventional technique at 18 points. The peak-to-peak value of the Somatosensory Evoked Potential increased by 8%. Meanwhile, the signal-to-noise ratio of Steady-State Visual Evoked Potential increased by 5.13 dB, and its classification accuracy increased by 44%. The maximum bandwidth of the resting state rose by 63%. In electrical stimulation experiments, the signal-to-noise ratio of the low-frequency response evoked by our scheme rose by 8.04 dB, and no stimulation artifacts were generated. The experimental results show that signal quality in acquisition has significantly improved, and frequency-band isolation eliminates stimulation artifacts at the source. The acquisition and stimulation pathways are real-time compatible in this non-implantation bi-directional BCI solution, which can provide technical support and theoretical guidance for creating closed-loop adaptive systems coupled with particular application scenarios in the future.

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

Objective. Temporal interference stimulation (TIS) was proposed as a non-invasive, focal, and steerable deep brain stimulation method. 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 the 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. Main results. For two E-fields with similar amplitudes (representative of E-field distributions at the target region), TIS generated an amplitude-modulated (AM) 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−1) 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 AM high-frequency stimulation, TIS generated conduction block with some orientations and amplitude ratios of individual E-fields at very high amplitudes of the total E-field (>1700 V m−1). 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.