Neural Mechanisms of Interpersonal Expectations on Negative Affect

Trustees of Dartmouth College190 enrolled

Overview

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, 30 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 2080 Hz, generating an 80 Hz interference beat targeted at the anterior/mid-cingulate cortex (aMCC) at 2 mA for 20 minutes. Sham tTIS uses identical frequencies (2000 Hz and 2000 Hz) with no effective interference. Sessions are administered in a counterbalanced order based on a 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.

Interventions

Session A: Positive Placebo + Active tTISBEHAVIORAL

Participants receive active tTIS, with two signals set at 2000 Hz and 2080 Hz, creating an 80 Hz interference beat targeting the anterior/mid-cingulate cortex (aMCC). Stimulation is delivered at 2 mA for 20 minutes. The stimulation is combined with a positive social placebo intervention delivered by the care provider. Participants complete three multimodal negative affect tasks (MNAT) before and after the stimulation.

Session B: Positive Placebo + Sham tTISBEHAVIORAL

Participants receive sham tTIS, using two identical 2000 Hz signals that produce no low-frequency interference. The device mimics active parameters (2 mA, 20 minutes) without delivering effective stimulation. The sham stimulation is paired with a positive social placebo intervention. Participants complete three MNAT tasks before and after the session.

Session C: Negative Placebo + Active tTISBEHAVIORAL

Participants receive active tTIS (2000 Hz and 2080 Hz signals, 2 mA, 20 minutes) combined with a negative social placebo intervention (neutral or skeptical messaging about treatment efficacy). Participants complete three MNAT tasks before and after the stimulation.

Session D: Negative Placebo + Sham tTISBEHAVIORAL

Participants receive sham tTIS (identical 2000 Hz signals, mimicking active stimulation) combined with a negative social placebo intervention. Participants complete three MNAT tasks before and after the session.

Session E: On-Placebo + Sham tTISBEHAVIORAL

Participants receive sham tTIS (brief 15-second stimulation followed by no current) paired with a positive social placebo intervention. Participants complete three MNAT tasks before and after the session.

Session F: Off-Placebo + Sham tTISBEHAVIORAL

Participants receive sham tTIS (brief 15-second stimulation, then no current) without any placebo intervention. Participants complete three MNAT tasks before and after the session.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Cognitive effort ratings

Participants report cognitive effort after each trial on a Generalized Linear Magnitude scale (GLMS) with anchors of "No effort" and "Most effort imaginable". Raw units are on a 0-180 scale.

Time frame: 3-10 sec post-stimulus throughout testing sessions, with all sessions complete within 1 month

Subjective fear ratings

Participants report subjective fear experience after each trial on a well-validated Generalized Linear Magnitude scale (GLMS) with anchors of "No fear" and "Most intense fear imaginable". Raw units are on a 0-180 scale.

Time frame: 3-10 sec post-stimulus throughout testing sessions, with all sessions complete within 1 month

Pain ratings

Participants report subjective pain experience after each trial on a well-validated Generalized Linear Magnitude scale (GLMS) with anchors of "No pain" and "Most intense pain imaginable". Raw units are on a 0-180 scale.

Time frame: 3-10 sec post-stimulus throughout testing sessions, with all sessions complete within 1 month

Secondary Outcomes

Electrodermal autonomic responses to painful heat, fear-related images and cognitive effort

Skin conductance (EDA) is recorded continuously throughout test sessions and per-stimulus amplitude of canonical stimulus-locked EDA responses is reported in microsiemens (uS). Higher values indicate a higher EDA response.

Time frame: Peri-stimulus throughout testing sessions, with all sessions complete within 1 month

Neural Mechanisms of Interpersonal Expectations on Negative Affect

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts