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.

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 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