STIMULUS: Noninvasive Dynamic Patterns of Neurostimulation Using Spatio-Temporal Interference.

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.

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.

Challenges in Recruitment for the Study of Noninvasive Brain Stimulation in Stroke: Lessons from Deep Brain Stimulation

tVNS affects and depends on autonomous and central nervous system states

Classification of high resolution SAR images is difficult due to the presence of speckle noise. We propose to use a multiscale decomposition that allows different trade-off between spatial precision (resolution) and radiometric uncertainty (noise reduction). Classification decisions at large scale are certain but spatially imprecise whereas decisions at high resolution are uncertain but spatially precise. We first decompose the SAR image in low and high frequency images at different scales using a stationary wavelet transformation. Then low pass images are classified by maximum likelihood based on a Gaussian mixture estimation. Wavelet coefficients in high frequency images enable us to identify stationary homogeneous regions within the image where classification decisions are expected to be stable across scales. Decisions at different scales are merged using Dempster-Shafer theory which gives us an adequate framework to manipulate both uncertainty and imprecision. Finally, resulting multiscale decisions are injected in a stochastic classification algorithm (MPM) as a hidden "evidential" Markov random field. The proposed algorithm is evaluated on artificial SAR images. We also propose to filter wavelet coefficients based on the resulting multiscale confidence map.

Exploring magneto-electric nanoparticles (MENPs): a platform for implanted deep brain stimulation

Non-invasive brain stimulation (NIBS) methods carry particular appeal as non-pharmacological approaches to inducing or improving sleep. However, intense research efforts to use transcranial magnetic stimulation (TMS) and electrical stimulation (tES) for sleep modulation have not yet delivered evidence-based NIBS treatments in sleep medicine. The main obstacles lie in insufficiently robust stimulation protocols that affect neurophysiological and self-reported sleep parameters, inadequately controlled-and explained-placebo effects, and heterogeneity in patient populations and outcome parameters. Recent technological advances, e.g., transcranial ultrasound stimulation (TUS) and temporal interference stimulation (TIS), make deep brain structures feasible targets. Real-time approaches, e.g., closed-loop auditory stimulation (CLAS), demonstrate efficacious modulation of different sleep oscillations by tuning stimulation to ongoing brain activity. The identification of sleep-regulatory regions and cell types in the cerebral cortex and thalamus provides new specific targets. To turn this neuroscientific progress into therapeutic advancement, conceptual reframing is warranted. Chronic insomnia may not be optimally suited to demonstrate NIBS efficacy due to the mismatch between self-reported symptoms and polysomnographic sleep parameters. More feasible initial approaches could be to (1) modulate specific sleep oscillations to promote specific sleep functions, (2) modify nightmares and traumatic memories with targeted memory reactivation, (3) increase 'wake intensity' in patients with depression to improve daytime fatigue and elevate sleep pressure and (4) disrupt pathological activity in sleep-dependent epilepsies. Effective treatments in these areas of sleep medicine seem in reach but require rigorously designed clinical trials to identify which NIBS strategies bring real benefit in sleep medicine.

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.

Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms.One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area.Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.

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.

In this review, we discuss the clinical and electrophysiological effects and the future directions of invasive and noninvasive brain stimulations in Parkinson's disease (PD). Deep brain stimulation (DBS) can improve motor symptoms in moderate to advanced PD. However, the optimal stimulation paradigm for nonmotor symptoms (NMS), freezing of gait, and the optimal timing of DBS are still under investigation. The findings of pathological oscillations and abnormal frequency to amplitude coupling provide models to develop adaptive DBS. Transcranial magnetic stimulation (TMS) revealed abnormal cortical excitability and plasticity in PD. Consecutive sessions of high-frequency, repetitive TMS on the motor cortex showed promising results. Paired TMS and DBS at specific times provided a novel way to investigate PD pathophysiology and have potential as a future treatment. Transcranial direct current stimulation or transcranial alternating current stimulation with multifocal electrodes or at specific phases of oscillation are also potential future strategies.

Temporal interference (TI) as a new neuromodulation technique can be applied to non-invasive deep brain stimulation. In order to verify its effectiveness in the regulation of motor behavior in animals, this paper uses the TI method to focus the envelope electric field to the ventral posterior lateral nucleus (VPL) of the thalamus in the deep brain of mouse to regulate left- and right-turning motor behavior. The focusability of TI in the mouse VPL was analyzed by finite element method, and the focus area and volume were obtained by numerical calculation. A stimulator was used to generate TI current to stimulate the mouse VPL to verify the effectiveness of the TI stimulation method, and the accuracy of the focus location was further determined by c-Fos immunofluorescence experiments. The results showed that the electric field generated by TI stimulation was able to focus on the VPL nuclei when the stimulation current reached 800 μA; the mouse were able to make corresponding left and right turns according to the stimulation position; and the c-Fos positive cell markers in the VPL nuclei increased significantly after stimulation. This study confirms the feasibility of TI in regulating animal motor behavior and provides a non-invasive stimulation method for brain tissue for animal robots.

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.

T002 Non-invasive brain stimulation for Parkinson’s disease