RECOVERS - Realigning Emotion and COgnition Via prEcision Regulation networkS

A Multiphase Program of Multimodal Computational Modeling and Hybrid Interventions Including EEG-Synchronized Transcranial Magnetic Stimulation and Cognitive Behavioral Therapy

In this research study, investigators examine how brain activity changes during tests of emotional processing, attention, and memory using multimodal neuroimaging methods including electroencephalography (EEG), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIRS). Transcranial magnetic stimulation (TMS) is used to probe and modulate brain networks related to cognitive flexibility and emotion regulation.

The study includes multiple related sub-studies involving healthy participants and participants with depression. Some study components focus on mechanistic modeling using non-therapeutic neurostimulation in healthy participants, while other components include interventional approaches such as individualized EEG-synchronized repetitive TMS (rTMS), cognitive tasks, and brief cognitive behavioral therapy (CBT) in participants with depression. Certain study components also evaluate CBT alone without TMS to assess behavioral intervention effects.

Study Overview

• Status: Recruiting
• Conditions: Depression; Suicidal Ideation; Major Depressive Disorder
• Intervention / Treatment: Device: Single-Pulse Transcranial Magnetic Stimulation; Behavioral: Cognitive Flexibility and Emotion Regulation Tasks; Device: EEG-Synchronized Repetitive Transcranial Magnetic Stimulation (rTMS); Behavioral: Cognitive Behavioral Therapy (CBT); Device: Non-Synchronized Repetitive Transcranial Magnetic Stimulation

Detailed Description

Investigators aim to characterize and modulate brain networks underlying cognitive flexibility (CF) and emotion regulation (ER) using a multimodal, precision neuroscience approach. The central hypothesis is that functional coupling within CF and ER networks is indexed by the phase of the brain's alpha oscillations, and that targeted modulation of these networks through individualized neurostimulation can induce neuroplastic changes associated with improved clinical outcomes in depression and suicidality.

To test this hypothesis, investigators utilize a novel integrated system that enables simultaneous functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and transcranial magnetic stimulation (TMS) to identify individualized stimulation parameters associated with optimal network coupling. A complementary system using functional near-infrared spectroscopy (fNIRS), EEG, and TMS is also used to extend these findings in a more scalable and accessible format.

This protocol includes multiple related sub-studies (Studies 1-4) conducted under a single IRB approval. These sub-studies are parallel investigations with differing populations and interventions and are not randomized arms of a single trial.

Study 1 is a proof-of-principle mechanistic study conducted in healthy adult participants. In this study, single-pulse TMS is delivered during EEG and neuroimaging sessions as a non-therapeutic probe to assess cortical excitability and functional connectivity during cognitive flexibility and emotion regulation tasks.

Study 2 is a proof-of-principle interventional study in participants with depression. It incorporates individualized, EEG-synchronized repetitive transcranial magnetic stimulation (rTMS) designed to entrain neural oscillatory dynamics within CF and ER networks. Participants may receive rTMS alone or in combination with cognitive tasks and brief cognitive behavioral therapy (CBT), with the goal of enhancing neuroplasticity and improving clinical symptoms.

Study 3 builds upon Study 2 and includes similar EEG-synchronized rTMS and CBT-based interventions in participants with depression, with ongoing refinements to stimulation parameters, task paradigms, and treatment delivery. This study further evaluates the reproducibility and effectiveness of individualized neurostimulation approaches.

Study 4 includes participants with depression who receive a course of cognitive behavioral therapy (CBT) along with MRI and behavioral assessments, without the use of TMS or EEG-based neurostimulation. This study allows for evaluation of behavioral intervention effects independent of neurostimulation.

Across interventional studies, rTMS may be delivered alone or in combination with cognitive flexibility and emotion regulation tasks or paired with CBT to promote synergistic effects on network engagement and neuroplasticity. These approaches are designed to test whether targeted modulation of CF and ER networks produces measurable changes in behavior, brain function, and clinical outcomes.

Participants in interventional studies may also complete ecological momentary assessment (EMA) surveys via mobile devices to monitor mood, stress, and safety in real time. These data may be used to capture dynamic changes in symptoms and may trigger predefined safety protocols and clinical follow-up when indicated.

Outcome measures across studies include changes in clinical symptoms (e.g., depression, anxiety, and suicidal ideation), behavioral performance on cognitive tasks, and neuroimaging-based measures of network connectivity and synchronization.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lisa McTeague, PhD; Phone Number: 843-792-8274; Email: MCTEAGUE@MUSC.EDU
• Study Contact Backup: Name: Christina Marsicano; Email: recovers@musc.edu

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical Univeristy of South Carolina
      • Contact: Lisa M McTeague, PhD; Phone Number: 843-792-8274; Email: mcteague@musc.edu
      • Contact: Christina Marsicano; Email: chm275@musc.edu

Participation Criteria

Eligibility Criteria

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

Study Population

Participants are healthy and depressed volunteers from the community.

Description

Study 1 (Healthy Participants)

Inclusion Criteria:

• Age 18-65 years
• Medically and psychiatrically healthy with no history of psychiatric or neurological disorders
• English-speaking
• Capacity to provide informed consent
• Willingness and ability to complete study procedures
• Negative pregnancy test for participants of childbearing potential

Exclusion Criteria:

• Any current or past psychiatric diagnosis
• Neurological disorders or history of central nervous system disease
• History of seizure or epilepsy or use of medications that lower seizure threshold
• Significant head injury or loss of consciousness
• Implanted metal or contraindications to MRI or TMS
• Substance use disorder (excluding nicotine or caffeine)
• Pregnancy or plans to become pregnant during study participation
• Inability to complete study procedures

Studies 2, 3, and 4 (Participants with Depression)

Inclusion Criteria:

• Age 18-65 years
• Current diagnosis of Major Depressive Disorder (MDD)
• Depression severity consistent with study criteria (e.g., HAM-D ≥ 17)
• No history of psychotic or bipolar disorders
• English-speaking
• Capacity to provide informed consent
• Willingness and ability to complete study procedures
• Negative pregnancy test for participants of childbearing potential

Exclusion Criteria:

• Neurological disorders or history of central nervous system disease
• History of seizure or epilepsy or use of medications that lower seizure threshold
• Significant head injury or loss of consciousness
• Implanted metal or contraindications to MRI or TMS
• Substance use disorder (excluding nicotine or caffeine)
• Current participation in another interventional clinical trial
• Pregnancy or plans to become pregnant during study participation
• Any condition that would interfere with safe participation or completion of study procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy Participants (Study 1); Healthy adult participants with no history of psychiatric or neurological illness who undergo mechanistic and modeling procedures, including multimodal neuroimaging, behavioral cognitive tasks, and non-therapeutic neurostimulation, to characterize brain networks underlying cognitive flexibility and emotion regulation.	Device: Single-Pulse Transcranial Magnetic Stimulation; Single-pulse transcranial magnetic stimulation delivered during EEG or neuroimaging sessions for non-therapeutic mapping of cortical excitability and functional connectivity.; Behavioral: Cognitive Flexibility and Emotion Regulation Tasks; Behavioral tasks designed to engage and assess cognitive flexibility and emotion regulation processes, performed during or adjacent to neurostimulation sessions or as part of study assessments.
Experimental: Depressed Participants - EEG-Synchronized rTMS (Studies 2 and 3); Participants with major depressive disorder who receive individualized, EEG-synchronized repetitive transcranial magnetic stimulation (rTMS), delivered alone or in combination with cognitive tasks and/or brief cognitive behavioral therapy (CBT), to modulate neural networks underlying cognitive flexibility and emotion regulation.	Device: Single-Pulse Transcranial Magnetic Stimulation; Single-pulse transcranial magnetic stimulation delivered during EEG or neuroimaging sessions for non-therapeutic mapping of cortical excitability and functional connectivity.; Behavioral: Cognitive Flexibility and Emotion Regulation Tasks; Behavioral tasks designed to engage and assess cognitive flexibility and emotion regulation processes, performed during or adjacent to neurostimulation sessions or as part of study assessments.; Device: EEG-Synchronized Repetitive Transcranial Magnetic Stimulation (rTMS); Repetitive transcranial magnetic stimulation delivered using individualized, EEG-derived stimulation parameters designed to synchronize stimulation timing with participants' alpha oscillatory phase. This closed-loop approach is intended to modulate neural networks underlying cognitive flexibility and emotion regulation. Stimulation may be delivered in accelerated sessions across multiple days.; Behavioral: Cognitive Behavioral Therapy (CBT); A structured, brief cognitive behavioral therapy program targeting depression and related symptoms, including cognitive restructuring, emotion regulation, and coping skill development, delivered in an accelerated format during the study period.
Active Comparator: Depressed Participants - Non-Synchronized rTMS Comparator; Participants with major depressive disorder who receive repetitive transcranial magnetic stimulation delivered using standard stimulation parameters without EEG phase synchronization, serving as a comparator condition.	Device: Single-Pulse Transcranial Magnetic Stimulation; Single-pulse transcranial magnetic stimulation delivered during EEG or neuroimaging sessions for non-therapeutic mapping of cortical excitability and functional connectivity.; Behavioral: Cognitive Flexibility and Emotion Regulation Tasks; Behavioral tasks designed to engage and assess cognitive flexibility and emotion regulation processes, performed during or adjacent to neurostimulation sessions or as part of study assessments.; Device: Non-Synchronized Repetitive Transcranial Magnetic Stimulation; Repetitive transcranial magnetic stimulation delivered using standard stimulation parameters without EEG phase synchronization, serving as a comparator condition.
Experimental: Depressed Participants - Cognitive Behavioral Therapy Only (Study 4); Participants with major depressive disorder who receive a course of cognitive behavioral therapy (CBT) along with MRI and behavioral assessments, without transcranial magnetic stimulation or EEG-based neurostimulation. This group allows evaluation of behavioral intervention effects independent of neurostimulation.	Behavioral: Cognitive Flexibility and Emotion Regulation Tasks; Behavioral tasks designed to engage and assess cognitive flexibility and emotion regulation processes, performed during or adjacent to neurostimulation sessions or as part of study assessments.; Behavioral: Cognitive Behavioral Therapy (CBT); A structured, brief cognitive behavioral therapy program targeting depression and related symptoms, including cognitive restructuring, emotion regulation, and coping skill development, delivered in an accelerated format during the study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hamilton Depression Rating Scale (HAM-D) Score	Change in clinician-rated depression severity measured using the Hamilton Depression Rating Scale (HAM-D). Scores range from 0 to 52; higher scores indicate more severe depression.	Baseline to Day 7
Change in Patient Health Questionnaire-9 (PHQ-9) Score	Change in self-reported depression severity measured using the Patient Health Questionnaire-9 (PHQ-9). Scores range from 0 to 27; higher scores indicate more severe depression.	Baseline to Day 7
Change in Suicidal Ideation Severity (Passive and Active Suicidal Ideation Scale [PASIS])	Change in suicidal ideation severity measured using the Passive and Active Suicidal Ideation Scale (PASIS). Higher scores indicate greater severity of suicidal ideation.	Baseline to Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Reaction Time During Cognitive Flexibility Tasks	Change in reaction time (milliseconds) during cognitive flexibility and emotion regulation tasks under congruent and incongruent conditions.	Baseline to Day 7
Change in Accuracy on Cognitive Flexibility Tasks	Change in task accuracy (percentage correct responses) during cognitive flexibility and emotion regulation tasks.	Baseline to Day 7
Change in Generalized Anxiety Disorder-7 (GAD-7) Score	Change in anxiety severity measured using the Generalized Anxiety Disorder 7-item scale (GAD-7). Scores range from 0 to 21; higher scores indicate more severe anxiety.	Baseline to Day 7
Change in EEG Alpha Phase Synchronization	Change in EEG alpha phase synchronization measured as phase-locking value (PLV) during cognitive task performance and neurostimulation sessions.	Baseline to Day 7
Change in Functional Connectivity Strength (fMRI)	Change in functional connectivity within cognitive flexibility and emotion regulation networks measured using resting-state functional magnetic resonance imaging (fMRI), quantified as correlation coefficients between predefined brain regions.	Baseline to Day 7
Change in Functional Connectivity Strength (fNIRS)	Change in functional connectivity measured using functional near-infrared spectroscopy (fNIRS), quantified as coherence between cortical regions during task performance.	Baseline to Day 7
Proportion of Participants With ≥50% Reduction in HAM-D Score	Clinical response defined as a ≥50% reduction from baseline in Hamilton Depression Rating Scale (HAM-D) score.	Day 28
Proportion of Participants With ≥50% Reduction in PASIS Score	Clinical response defined as a ≥50% reduction from baseline in Passive and Active Suicidal Ideation Scale (PASIS) score.	Day 28

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: Columbia University; University of Wisconsin, Madison; University of Oklahoma; Defense Advanced Research Projects Agency
• Investigators: Principal Investigator: Lisa McTeague, PhD, Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: June 29, 2023
• First Submitted That Met QC Criteria: July 26, 2023
• First Posted (Actual): August 4, 2023

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: depression; neuroplasticity; transcranial magnetic stimulation; suicide prevention; cognitive behavioral therapy (CBT); EEG-synchronized rTMS; closed-loop neurostimulation
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Self-Injurious Behavior; Mood Disorders; Suicide; Depressive Disorder; Behavior; Suicide Prevention; Suicidal Ideation; Depression; Depressive Disorder, Major; Therapeutics; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Magnetic Field Therapy; Cognitive Behavioral Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: 00129566

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: No