Overcoming the Barriers to Effective Transcranial Temporal Interference Stimulation in Humans

Transcranial temporal interference stimulation (TIS) is an emerging novel tool for non-invasive transcranial brain stimulation that holds the potential for focal and steerable neuromodulation, and the possibility to stimulate focally at depth. TIS involves combining two high frequency waveforms to create a waveform with a "beat" frequency that is physiological relevant for neuromodulation. Successful applications to deep brain targets as well as steerability of the stimulation focus have been demonstrated in mice. Numerous recent investigations in humans have shown great clinical potential for this technology, however several questions about the basic mechanism of TIS action remain. The investigators will apply TIS to the motor cortex of humans and use established transcranial magnetic stimulation techniques to assess cortical excitability in relation to the phase of the TIS waveform. Using TMS, the investigators will i) validate that effects of TIS are due to the "beat" frequency and not the high frequency carrier signal, ii) evaluate the effect of the TIS carrier frequency, and iii) evaluate that whether changes in corticospinal excitability outlast the period of stimulation. Knowledge gained from this experiment will provide a basis for the future use of TIS for clinical applications, including informing parameter optimization.

Study Overview

• Status: Recruiting
• Conditions: Healthy Adult Participants
• Intervention / Treatment: Device: transcranial Temporal Interference Stimulation

Detailed Description

Remedies for treatment resistance in psychiatric and neurological disorders is a great unmet need. Invasive neuromodulation, such as deep brain stimulation (DBS), applied to a targeted brain region is one option that has helped regulate or modify, abnormal electrical patterns in many patients with neurological deficits; However, invasive approaches carry significant risks while having limited targeting flexibility. Transcranial temporal interference stimulation (TIS) is a non-invasive neuromodulation method with much more favorable focus in deep brain targets than traditional forms of transcranial alternating current stimulation (tACS). tTIS achieves its focal effect by delivering two sinusoidal currents, that are both high in frequency, but that are slightly different from one another (e.g. 1000 kHz and 1020 kHz) through electrodes placed on the scalp. Frequencies that are in the kilohertz range alone do not elicit neuronal response, however the interaction of the two high-frequency currents creates an electric field with a high-frequency carrier (fc, e.g. 1010 kHZ) that is modulated by a low-frequency beat (fb, e.g. 20 Hz). If fc is high enough (>1 kHz) and fb low enough (<100 Hz), neurons respond much more strongly to fb than fc.

Safety and tolerability of TIS has recently been demonstrated in humans with findings indicating that TIS poses no greater risk than other common non-invasive techniques for transcranial current stimulation (TCS). The spatial distribution of the beat field (Eb) is distinct from other noninvasive stimulation methods in three ways: 1) it is focal, 2) it can peak deep in the brain, 3) it can be steered through the brain without moving the electrodes. These features have been demonstrated in mouse experiments, and in human simulation studies.

In humans, motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) applied to the motor cortex provide an established assay of corticospinal excitability. TMS experiments have provided direct evidence that phase-dependent neuromodulation can be induced by transcranial alternating current stimulation (tACS), a form of transcranial current stimulation that is similar to temporal interference stimulation (TIS) but lacks focality and steerability, yet has been key to understanding its neurophysiological effects in humans. For example, recent experimental results showed that TMS pulses time locked to tACS over motor cortex induced MEP amplitude modulation that was dependent on the phase of the tACS oscillatory currents. Building on this finding, the investigators will provide TMS pulses to motor cortex during tTIS and investigate whether neuromodulation of corticospinal excitability depends on the phase of beat frequency (fb). Similar to the experiments that showed neural activation in mice, the investigators will also investigate whether the strength of the effect depends on the carrier frequency (fc). The investigators will use computationally optimized electrode placement, with high- and low-frequency controls, to test that effects are unambiguously due to fb. Finally, the investigators will assess corticospinal excitability PRE and POST stimulation to investigate neuroplasticity induced by TIS. The knowledge gained in this experiment will demonstrate the extent to which modulation effects of TIS in humans are due entrainment of neural activity at fb. This information will provide a basis for the future use of tTIS for clinical applications.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Joanne Hall, M.Sc.; Phone Number: 17027828483; Email: hall.joa@northeastern.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115-5724
      • Recruiting
      • Northeastern University
      • Contact: Mathew Yarossi, PhD; Phone Number: 7027828483; Email: m.yarossi@northeastern.edu
      • Principal Investigator: Mathew Yarossi, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Free of neurological or orthopedic conditions that may impact the ability to participate.
• Right-hand dominant (self-reported)
• Aged 18-65 years

Exclusion Criteria:

• Ferromagnetic metal implants in the brain/skull or elsewhere (dental implants excluded).
• Any implanted electronic device (e.g. cardiac pacemaker, cochlear implant, deep brain stimulator, medication infusion pump; vagal nerve stimulator)
• Diseased or damaged skin on face or scalp
• History of migraines, fainting, seizures/epilepsy, or psychiatric illness
• Neurological disorder or intracranial lesion
• Frequent or severe headaches
• Prior adverse reaction to transcranial magnetic stimulation
• Currently pregnant
• Suspected or diagnosed heart problems (e.g. arrhythmia, cardiac disturbances).
• Insulin-dependent diabetes
• Suspected or diagnosed epilepsy or a familial history of epilepsy
• Use of alcohol or recreational drugs in the prior 12 hours
• Use of prescription and over the counter medications will be grounds for exclusion except for: contraceptive (birth control) drugs (e.g. those containing ethinyl estradiol and/or norethindrone), and seasonal allergy medications (e.g. cetirizine (Zyrtec), fexofenadine (Allegra), and loratadine (Claritin)).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 990-1010 Hz fb	Device: transcranial Temporal Interference Stimulation; We will apply temporal interference stimulation (tTIS) for 20 minutes over the motor cortex concurrent with single-pulse transcranial magnetic stimulation (TMS) (also over the motor cortex). Motor evoked potentials will be recorded using electromyography (EMG).
Experimental: 1990-2010 Hz fb	Device: transcranial Temporal Interference Stimulation; We will apply temporal interference stimulation (tTIS) for 20 minutes over the motor cortex concurrent with single-pulse transcranial magnetic stimulation (TMS) (also over the motor cortex). Motor evoked potentials will be recorded using electromyography (EMG).
Experimental: 1000-1000 Hz fb	Device: transcranial Temporal Interference Stimulation; We will apply temporal interference stimulation (tTIS) for 20 minutes over the motor cortex concurrent with single-pulse transcranial magnetic stimulation (TMS) (also over the motor cortex). Motor evoked potentials will be recorded using electromyography (EMG).
Experimental: 2000-2000 Hz fb	Device: transcranial Temporal Interference Stimulation; We will apply temporal interference stimulation (tTIS) for 20 minutes over the motor cortex concurrent with single-pulse transcranial magnetic stimulation (TMS) (also over the motor cortex). Motor evoked potentials will be recorded using electromyography (EMG).
Experimental: 20 Hz	Device: transcranial Temporal Interference Stimulation; We will apply temporal interference stimulation (tTIS) for 20 minutes over the motor cortex concurrent with single-pulse transcranial magnetic stimulation (TMS) (also over the motor cortex). Motor evoked potentials will be recorded using electromyography (EMG).
Sham Comparator: sham	Device: transcranial Temporal Interference Stimulation; We will apply temporal interference stimulation (tTIS) for 20 minutes over the motor cortex concurrent with single-pulse transcranial magnetic stimulation (TMS) (also over the motor cortex). Motor evoked potentials will be recorded using electromyography (EMG).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Online phase-dependent modulation of corticospinal excitability using the relevance value (R.V.)	Explained variance (R2) of best-fit sinusoids will be multiplied by the variance of measured values to obtain the established "relevance value" (R.V.), to be used as our primary outcome. Relevance values assume phase-dependent modulation with a large amplitude is more meaningful than one with small amplitude and the same R2. Critically, phase-dependent responses to TIS represent direct evidence of modulation at beat frequency (fb).	Periprocedural

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Offline neuroplastic effects from pre to post	We define neuro- plastic effects as sustained modulation of excitability fol- lowing cessation of transcranial current sitmulation (tCS). Fifteen single-pulse MEPs will be acquired at the FDI hotspot prior to and at 0, 15 and 30 minutes after tCS (tpre, t0, t15, t30). Our primary outcome will be MEP amplitude change from tpre to t0.	Periprocedural
Offline neuroplastic post effects	Retention of neuromodulation at t15 and t30.	Periprocedural

Collaborators and Investigators

• Sponsor: Northeastern University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Mathew Yarossi, PhD, Northeastern University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: May 5, 2026
• First Submitted That Met QC Criteria: May 14, 2026
• First Posted (Actual): May 18, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: transcranial temporal interference stimulation
• Other Study ID Numbers: 25-02-54; 5R01NS133229 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes