The goal of this clinical trial is to learn whether non-invasive brain stimulation, called transcranial temporal interference stimulation (tTIS), can reduce negative affect, and how expectations shaped by care providers influence these effects.

The main questions this study aims to answer are: (1)Does active tTIS reduce negative affect more effectively than sham (inactive) tTIS? (2)Do positive treatment expectations enhance the effects compared to negative expectations?

Participants will: (1) Receive either active or sham tTIS. (2) Be provided with positive or negative messaging regarding treatment effectiveness. (3) Interact with care providers and complete assessments measuring negative affect and physiological responses.

The study employs a within-subject, crossover factorial design, consisting of two experiments.

Experiment 1

In Experiment 1, 36 participants ('patients') will complete all combinations of two independent variables-stimulation type (active vs. sham tTIS) and placebo manipulation (positive vs. negative placebo messaging)-resulting in four sessions:

• Session A: Positive Placebo + Active tTIS
• Session B: Positive Placebo + Sham tTIS
• Session C: Negative Placebo + Active tTIS
• Session D: Negative Placebo + Sham tTIS

Participants complete three multimodal negative affect tasks (MNAT) before and after each stimulation session. Active tTIS delivers two signals at 2000 Hz and 2010 Hz, generating an 10 Hz interference beat targeted at the anterior/mid-cingulate cortex (aMCC) at 2 mA for 20 minutes. Sham tTIS uses same frequencies (2000 Hz and 2010 Hz), targeting the same region for only 80 seconds.

Sessions are administered in a counterbalanced order based on a Williams Balanced Latin Square to minimize order effects, with at least 48 hours between sessions. Participants thus serve as their own controls.

Experiment 2

Experiment 2 includes 160 participants divided into two groups: 120 'patients' and 40 'doctors'.

A within-subject crossover design is employed, focusing specifically on placebo manipulation effects. Patients complete two experimental sessions involving sham tTIS only:

• Session E: On-Placebo + Sham tTIS (with social placebo intervention)
• Session F: Off-Placebo + Sham tTIS (without placebo intervention)

In both sessions, patients complete the same MNAT tasks before and after stimulation. Sham tTIS involves a brief 15-second stimulation followed by no current for the remainder of the session, preserving the illusion of active stimulation.

'Doctors' are trained to administer the sham stimulation and deliver the placebo manipulation. During placebo induction sessions, providers simulate a "personalization" procedure, adjusting sham parameters while covertly reducing pain stimulus intensity to enhance placebo effects. Providers also monitor patients' nonverbal behavior and reported affect, offering feedback to enhance engagement and perceived treatment quality.

Participants undergo MRI scanning, physiological monitoring, and behavioral assessments during Experiment 2. Multimodal physiological data-including ECG, respiration, skin conductance, photoplethysmography (PPG), and trans-radial electrical bioimpedance velocimetry (TRVE)-are collected using the BIOPAC 160 system.

Inclusion Criteria:

'Doctors' are recruited from medical students at the Geisel School of Medicine and resident physicians at Dartmouth Hitchcock Medical Center (DHMC).

Exclusion Criteria:

• No self-reported current or history of depression, bipolar disorder, or other psychiatric diagnosis
• No self-reported current seizure disorder (i.e., seizure within past 10 years), or history of stroke or other major neurological diagnosis that can cause cognitive impairment
• No self-reported current chronic pain, or acute pain within three months of the study period
• No current migraine disorder (i.e., 15 headache days or more in 1 month)
• No use of central nervous system-effective medication or other medication for neurological/psychiatric treatment
• No self-reported substance abuse within the last six months
• No contraindication to MRI or tTIS (e.g., pregnancy, claustrophobia, pacemakers, ear/cochlear implants, shrapnel injuries, clips, or other ferromagnetic/electrical objects/devices, diagnosed brain abnormality such as tumor, or skin lesions on the scalp.)
• No contraindications for induced pain (e.g., no heart disease, high blood pressure, heart surgery, heart problems of any kind, severe asthma, respiratory problems of any kind, fibromyalgia, Raynaud's Syndrome or Disease, chronic pain, diabetes)
• Participants must be capable of performing experimental tasks (e.g., are able to read), are fluent or native speakers of English
• Participants must be able to tolerate the maximum level of thermal pain stimuli (for thermal stimuli)