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

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:

• 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).
• 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.
• 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:

• 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

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