Personalized high-intensity temporal interference stimulation decouples cerebellar networks to enhance implicit learning

Chronic visceral pain management remains challenging due to limitations in selective targeting of C-fiber nociceptors. This study investigates temporal interference stimulation (TIS) on dorsal root ganglia (DRG) as a novel approach for selective C-fiber transmission block. We employed (1) GCaMP6 recordings in mouse whole DRG using a flexible, transparent microelectrode array for visualizing L6 DRG neuron activation, (2) ex vivo single-fiber recordings to assess sinusoidal stimulation effects on peripheral nerve axons, (3) in vivo behavioral assessment measuring visceromotor responses (VMR) to colorectal distension in mice, including a TNBS-induced visceral hypersensitivity model, and (4) immunohistological analysis to evaluate immediate immune responses in DRG following TIS. We demonstrated that TIS (2000 Hz and 2020 Hz carrier frequencies) enabled tunable activation of L6 DRG neurons, with the focal region adjustable by altering stimulation amplitude ratios. Low-frequency (20-50 Hz) sinusoidal stimulation effectively blocked C-fiber and Aδ-fiber transmission while sparing fast-conducting A-fibers, with 20 Hz showing highest efficacy. TIS of L6 DRG reversibly suppressed VMR to colorectal distension in both control and TNBS-induced visceral hypersensitive mice. The blocking effect was fine-tunable by adjusting interfering stimulus signal amplitude ratios. No apparent immediate immune responses were observed in DRG following hours-long TIS. In conclusion, TIS on lumbosacral DRG demonstrates promise as a selective, tunable approach for managing chronic visceral pain by effectively blocking C-fiber transmission. This technique addresses limitations of current neuromodulation methods and offers potential for more targeted relief in chronic visceral pain conditions.

Temporal Interference Stimulation (TIS) is an emerging technique for noninvasive focally-controlled electrical stimulation of neural structures. Progress in TIS is predicated on understanding of stimulation amplitudes in tissues. To better optimize spatiotemporal patterns of stimulation, we suggest the use of simple benchtop phantom model experiments. We describe techniques to map temporal interference hotspots and extrapolate such findings to an insect model, Locusta migratoria. We discuss the importance of mapping the amplitudes of tonic and phasic stimulation present when applying TIS in vitro and in vivo, to effectively harness the unique spatiotemporal stimulation patterns inherent to TIS.Clinical Relevance- TIS is used clinically for stimulation of the central and peripheral nervous systems, the methods suggested here represent effective strategies to plan and model stimulation experiments to verify where stimulation foci will be, to understand on-target versus off-target stimulation.

Temporal interference stimulation (TIS) is a promising noninvasive method for neurostimulation, yet its mechanism remains debated. TIS is often described as delivering low-frequency stimulation via the amplitude modulation (beat frequency) of interfering kHz carriers. However, this view overlooks known biophysical responses to kHz stimuli. Here, we test modulated (TIS) and unmodulated kHz waveforms on peripheral nerves in Locusta migratoria and in human sensory and motor pathways. We find that stimulation thresholds and strength-frequency relationships are governed by the kHz carrier itself, with minimal dependence on amplitude modulation. Across 0.5–12.5 kHz in humans and up to 100 kHz in locusts, all waveforms show overlapping excitation behavior, indicating a shared underlying mechanism. Our results support the hypothesis that suprathreshold TIS acts through kHz rectification, rather than envelope-specific effects. We further explore modulation frequency resonance, tonic vs. phasic effects, and suggest that two-electrode premodulated kHz may offer advantages over multielectrode TIS approaches.

Temporal interference stimulation (TIS) is a new form of transcranial electrical stimulation (tES) that has been proposed as a method for targeted, noninvasive stimulation of deep brain structures. While TIS holds promise for a variety of clinical and nonclinical applications, little data is yet available regarding its effects in humans and its mechanisms of action. To inform the design and safe conduct of experiments involving TIS, researchers require quantitative guidance regarding safe exposure limits and other safety considerations. To this end, we undertook a two-part effort to determine frequency-dependent thresholds for applied currents below which TIS is unlikely to pose risk to humans in terms of heating or unwanted stimulation. In Part II of this effort, described here, we draw on a previously compiled list (see Part I) of adverse effects (AEs) reported for transcranial direct/alternating current stimulation (tDCS/ACS), deep brain stimulation (DBS), and TIS to determine biophysics-informed exposure metrics for assessing safety. Using an in silico approach, we conduct multiphysics simulations of various tACS, DBS, and TIS exposure scenarios in an anatomically detailed head and brain model. By matching the stimulation in terms of the identified exposure metrics, we infer frequency-dependent TIS parameters that produce exposure conditions equivalent to those known to be safe for tACS and DBS. Based on the results of our simulations and existing knowledge regarding tES and DBS safety, we propose frequency-dependent thresholds below which TIS voltages and currents are unlikely to pose a risk to humans. Safety-related data from ongoing and future human studies are required to verify and refine the thresholds proposed here.

Temporal interference (TI) stimulation is a promising non-invasive neuromodulation strategy that uses two high-frequency electric fields to generate a low-frequency amplitude-modulated envelope at their intersection, enabling targeting of deep brain regions. However, in vivo safety concerns remain regarding the impact of the low-frequency envelope applied to the brain. Therefore, the objective of this study was to systematically evaluate the acute thermal and cellular safety profile of TI using an invasive in vivo mouse model, and to compare its thermal effects with those of direct low-frequency stimulation using an in vitro egg-white model. In the egg-white model, no protein coagulation was observed with TI stimulation (10 mA at 1,000 Hz and 1,005 Hz for 20 min), which generated a 5 Hz envelope. In contrast, conventional 5 Hz alternating current stimulation (tACS) at 10 mA induced localized coagulation. In the mouse model, intracranial TI stimulation (2 mA at 1,000 Hz and 1,005 Hz for 20 min) targeting the hippocampus resulted in a mild and stable temperature increase of ∼0.7 °C. Histological analysis revealed a localized increase in astrocyte activation (GFAP) in the stratum lacunosum-moleculare (SLM) compared to other hippocampal subfields. No significant expression difference was observed in the hippocampus for the heat stress marker (HSP70) or the inflammatory marker (iNOS). These findings suggest that TI has a favorable short-term safety profile, with minimal thermal effects and no widespread inflammatory response.

tVNS affects and depends on autonomous and central nervous system states

Temporal Interference (TI) stimulation has emerged as a novel, non-invasive technique for selectively modulating deep brain regions while minimizing stimulation of superficial cortical layers, addressing key limitations of traditional transcranial electrical stimulation (tES) methods. This review systematically examines advancements in TI research from June 2017 to December 2024, encompassing safety evaluations, computational modeling (including Finite Element Method simulations), and stimulation–parameter optimisation. The paper synthesizes 63 publications on the efficacy of TI in deep brain neuromodulation, its optimisation strategies, and emerging methodologies aimed at improving stimulation precision and reducing off-target effects. Furthermore, the review explores the clinical applications of TI, particularly its potential in treating neurological disorders such as epilepsy, Parkinson's disease, and cognitive impairments. Despite its promise, challenges remain, including variability in stimulation outcomes, the need for individualized treatment protocols, and gaps in understanding the long-term effects of TI. By consolidating current knowledge and identifying future research priorities, this review provides a comprehensive perspective on the transformative potential of TI stimulation in neuroscience and clinical neurotherapeutics.

IntroductionTranscranial alternating current stimulation (tACS) and temporal interference stimulation (TIS) as electrical neuromodulation therapy have shown promising applications in cognitive impairments. Meanwhile, the TIS technique is more novel, with deep and non-invasive brain stimulation. At present, the therapeutic or neuromodulation differences between TIS and tACS on post-stroke cognitive dysfunction(PSCI) are still unclear. Here, we aim to compare and analyze the neuromodulation model and clinical performances of TIS and tACS.Methods and analysisThe prospective, single-blind and randomized controlled trial will be conducted over a 2-week period. Through precise statistical sample size calculation,thirty-six eligible participants with mild PSCI will be recruited and randomly allocated to either the tACS or the TIS group. Participants in the TIS group will receive stimulation at frequencies of 2005 Hz and 2010 Hz targeting the hippocampal region. Those in the tACS group will undergo 5 Hz stimulation of the dorsolateral prefrontal cortex (DLPFC). The intervention will last for 2 weeks, with each participant receiving 25-min stimulation sessions once a day, five times per week. The primary outcome measure will be the Montreal Cognitive Assessment (MoCA), while secondary outcomes will include performance on the N-back task, digital span test (DST), shape trails test (STT) and functional near-infrared spectroscopy (fNIRS). All clinical assessments will be collected at two time points: pre-intervention (T1) and post-intervention (T2).Trial registrationThe trial protocol is registered with www.chictr.org.cn under protocol registration number ChiCTR2400081207. Registered on February 26, 2024.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09001-7.

ObjectiveThis study investigates the effects of temporal interference stimulation (TI) with different envelope frequencies on the cortical excitability of the primary motor cortex (M1).MethodsIn this randomized, double-blind, crossover study, 26 participants completed four separate study visits. During these visits, they received 20 min of three types of TI (10, 20, and 40 Hz envelope frequency) and sham stimulation applied over M1 in a randomized order. Transcranial magnetic stimulation (TMS) was employed to assess motor-evoked potentials (MEP) and resting motor threshold (RMT) over the left M1 (ipsilateral area) and right M1 (contralateral area) before, immediately after, and 30 and 60 min after stimulation.ResultsThe blinding efficacy was excellent, and no severe side effects were reported. TI stimulation with varying envelope frequencies affected MEP differently; 20 Hz TI stimulation enhanced the MEP of the ipsilateral M1 with after-effects appearing at 60 min, and no significant differences were observed between the 10 or 20 Hz TI stimulation with sham groups. However, no significant changes in RMT were observed under any of the TI conditions.Conclusion20 Hz TI stimulation increased the cortical excitability of the ipsilateral M1, highlighting that frequency is an important factor in the modulatory effect of TI.

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.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

Transorbital electrical stimulation (TES) has emerged as a promising approach for eliciting visual percepts, or phosphenes, in both sighted and visually impaired individuals. However, the utility of these approaches is limited owing to cumbersome setups consisting of wired gel electrodes and the difficulty in optimizing stimulation paradigms. Overall, optimizing transorbital stimulation paradigms, remains a huge challenge, particularly regarding electrode type and waveform characteristics. In this study, we investigated whether the type of electrode (i.e. wet versus dry) affects the psychometric curve for phosphene detection. Our findings indicate that both electrode types yield comparable detection thresholds, suggesting that dry electrodes could offer a viable, practical alternative for TES without compromising efficacy, while dramatically enhancing usability. Building on this, we explored whether temporal interference (TI) stimulation, a technique leveraging high-frequency signals to create a low-frequency envelope at a targeted neural region, could enhance phosphene perception when optimized for the posterior retina. Our results demonstrate that TI stimulation significantly increases phosphene detection rates in sighted subjects, highlighting its potential to improve TES precision and effectiveness.Clinical relevanceThese findings have significant implications for the development of non-invasive neurostimulation technologies aimed at testing, restoring, or augmenting vision. The high performances of dry electrodes pave the way for more user-friendly, portable stimulation devices, reducing the reliance on cumbersome electrode preparations. Additionally, the enhancement of phosphene perception via TI suggests a pathway toward more selective, spatially targeted stimulation strategies, potentially refining TES for future clinical applications. Put together, these results contribute to the optimization of TES paradigms, bringing the technology closer to real-time, wearable neurostimulation solutions for visual rehabilitation and augmentation.

Spinal cord injury (SCI) can lead to permanent loss of motor, sensory, and autonomic functions, presenting a significant clinical challenge for rehabilitation. In addition to conventional rehabilitation approaches, epidural spinal cord stimulation (eSCI) is often used to enhance recovery. However, the invasive nature of eSCI limits patient acceptance and widespread application. Compared to traditional spinal cord stimulation, temporal interference (TI) stimulation offers a noninvasive approach to stimulate deep spinal cord regions, making it a promising technique for SCI treatment. A critical factor in achieving effective TI stimulation for SCI rehabilitation is the accurate placement of two electrode pairs on the skin surface to generate a high electric field envelope within the targeted spinal cord area. We propose a unique protocol that utilizes electric field simulations and parameter optimization to determine the optimal electrode placement for specific SCI regions. Additionally, this protocol provides a systematic description of how to efficiently implement the optimized electrode placement strategy in clinical TI stimulation.

This paper obtains strategies that can achieve spatially precise noninvasive deep brain stimulation using electrical currents. We provide the Spatio-Temporal Interference-based stiMULation focUsing Strategy (STIMULUS) that generates rich patterns of spatiotemporally interfering currents to stimulate precisely and deep inside the brain. To calibrate and compare the accuracy of stimulation using different techniques, we utilize computational Hodgkin-Huxley-type models for neurons and a model of current dispersion in the head. In this computational model, STIMULUS dramatically outperforms the recently proposed Temporal Interference (TI) stimulation strategy in spatial precision. Our results also suggest that STIMULUS can attain steerable and multisite stimulation, which can be important in giving feedback in brain-machine interfaces. Finally, by examining more mammalian neuron types, we also observe that not every neuron exhibits temporal-interference stimulation. Computer simulations suggest that the proposed STIMULUS strategy has potential to achieve noninvasive electrical deep brain stimulation with high spatial precision and, further, has the flexibility of generating rich stimulation patterns. The fact that some neuron types do not exhibit TI stimulation suggests that caution is needed in evaluating conclusions of application of TI stimulation on large mammalian brains. A technique to reliably, noninvasively, and precisely stimulate deep inside the human brain could revolutionize human neuroscience and clinical treatments. We obtain the first computational demonstration of the recently proposed TI stimulation. Advancing on that, we propose a novel strategy that can perform stimulation with high precision and flexibility.

Temporal interference (TI) is a method of non-invasive brain stimulation using transcutaneous electrodes which allows the targeting and modulation of deeper brain structures, not normally associated with non-invasive simulation, while avoiding unwanted stimulation of shallower cortical structures. The properties of TI have been previously demonstrated, however, the problem of decoupling stimulation focality from stimulation intensity has not yet been well addressed. In this paper, we provide a possible novel solution, multipolar TI (mTI), which allows increased independent control over both the size of the stimulated region and the stimulation intensity. The mTI method uses multiple carrier frequencies to create multiple overlapping amplitude-modulated envelopes, rather than using one envelope as in standard TI. The study presents an explanation of the concept of mTI along with experimental data gathered from Rhesus macaques and mice. We improved the focality at depth in anesthetized mice and monkeys, and using the new focality in awake monkeys, evoked targeted activity at depth in the superior colliculus. The mTI method could be an interesting and potentially useful new tool alongside other forms of non-invasive brain stimulation. Teaser Multipolar Temporal Interference Stimulation can produce a more focal brain stimulation at depth compared to Temporal Interference.