Mechanistic Validation of Human Multipolar TES-TI: Amplitude Modulation, Frequency, and Benchmarking

Overview

This study is to find out whether and how a type of non-invasive electrical brain stimulation called transcranial electrical stimulation with temporal interference (TES-TI) can temporarily change brain activity in healthy adults. A structural MRI scan will be used to customize where the stimulation electrodes are placed for each participant to deliver TES-TI during three afternoon sessions at rest with eyes closed. Brain activity is recorded with high-density EEG. Up to 24 participants will be enrolled and on study for 3 to 12 weeks.

Detailed description

This is an experimental study using a within-subject, single-blind, randomized, counterbalanced crossover design in which each participant serves as their own control. Healthy adults will complete (or provide an existing) structural MRI scan (T1/T2) to support individualized electric-field modeling and personalized montage optimization for thalamic targeting, followed by three afternoon stimulation sessions with simultaneous high-density EEG during eyes-closed wakefulness; sessions will be scheduled on separate days at least one week apart. Each session includes four stimulation conditions administered in randomized/counterbalanced order, with each condition consisting of a fixed 3-minute pre-stimulation baseline, 3-minute stimulation period, and 3-minute post-stimulation recording to enable STIM-PRE and POST-PRE comparisons.

* Session A tests amplitude-modulation specificity (in-phase mTI, a mixed unipolar+HF condition with the same montage/current, a carrier-only HF control, and sham) * Session B benchmarks in-phase mTI against unipolar TES-TI at 5 mA and 8 mA (plus sham); and * Session C characterizes frequency dependence of in-phase mTI (10, 50, 130 Hz; plus sham).

Primary Objectives:

1. Determine whether active multipolar TES-TI (mTI) produces envelope-driven EEG effects (primary contrast: STIM-PRE) by comparing in-phase mTI to SHAM, to a carrier-only no-envelope high-frequency (HF) control, and to a mixed unipolar+HF condition (same montage/current; one pair as unipolar TES-TI producing an AM envelope, the other pair as a non-interacting HF carrier with no envelope contribution). 2. Benchmark mTI against unipolar TES-TI across stimulation intensity by comparing in-phase mTI to unipolar TES-TI at 5 mA and 8 mA, each evaluated relative to SHAM (primary contrast: STIM-PRE), and estimating effect sizes to inform future study design. 3. Characterize envelope-frequency dependence of in-phase mTI effects by comparing EEG spectral power changes across 10, 50, and 130 Hz conditions (each relative to SHAM; primary contrast: STIM-PRE).

Secondary Objectives: 4. Assess persistence of stimulation-related EEG changes by quantifying post-stimulation effects (POST-PRE) across conditions (in-phase, mixed unipolar+HF, HF, unipolar) and sessions

Interventions

• Device TES-TI with hdEEG
  4 conditions per session. Each condition will follow a standardized block structure consisting of 3 minutes pre-stimulation baseline, 3 minutes stimulation, and 3 minutes post-stimulation recording (PRE, STIM, POST)

Primary outcome measures

• Change in band-limited, topography-resolved EEG spectral power during stimulation for conditions in Session A [Time frame: data collected for 3 minutes prior to stimulation and 3 minutes during stimulation for each of 4 conditions during Session A (approximately 3 hours long)]
• Change in band-limited, topography-resolved EEG spectral power during stimulation for conditions in Session B [Time frame: data collected for 3 minutes prior to stimulation and 3 minutes during stimulation for each of 4 conditions during Session B (approximately 3 hours long)]
• Change in band-limited, topography-resolved EEG spectral power during stimulation for conditions in Session C [Time frame: data collected for 3 minutes prior to stimulation and 3 minutes during stimulation for each of 4 conditions during Session C (approximately 3 hours long)]

Secondary outcome measures (1)

• Change in band-limited, topography-resolved EEG spectral power in the post-stimulation interval (POST-PRE) across all tested conditions [Time frame: data collected for 3 minutes prior to stimulation and 3 minutes post stimulation for each of 4 conditions during each of 3 sessions (each session is approximately 3 hours long, with at least one week between sessions)]

Eligibility criteria

Inclusion criteria

• Medically healthy (based on self-report and study team review)
• U.S. citizen or holding permanent resident status
• English-speaking (able to provide consent and complete questionnaires)

Exclusion criteria

• Current or past history of clinically significant neurological disorder or acquired neurological disease (e.g., stroke, traumatic brain injury), including intracranial lesions (including clinically significant findings identified on the structural MRI)
• History of inpatient psychiatric hospitalization
• History of head trauma resulting in prolonged loss of consciousness; or a history of >3 grade I concussions
• Current poorly controlled headaches, including intractable or frequent migraines
• Any systemic illness or unstable medical condition that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
• History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG, or family history of treatment resistant epilepsy except for a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist
• Possible pregnancy or plan to become pregnant in the next 6 months (self reported)
• Any metal in the head
• Any medical devices or implants (i.e. cardiac pacemaker, medication infusion pump, cochlear implant, vagal nerve stimulator)
• Dental implants
• Permanent retainers
• Any hair braid, dreadlocks, hair pieces, or extensions which cannot be taken out before the study sessions
• Any head coverings or headdress that participant feels uncomfortable removing for the purposes of study sessions
• Current use of medications known to substantially lower seizure threshold, specifically chlorpromazine, clozapine, bupropion, clomipramine, or maprotiline; or other medications at doses known to substantially lower seizure threshold in the judgment of the PI
• Active scalp lesions, broken skin, or skin conditions at planned electrode sites that would preclude safe electrode application
• Claustrophobia (a fear of small or closed places)
• Back problems that would prevent lying flat for up to two hours

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Basic science

Study locations

United States · 1 center

• University of Wisconsin - Madison — Madison

Identifiers

NCT: NCT07752745 · 2026-1006 · R&D funding · Protocol Version · SMPH | Psychiatry

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗