EEG-based Neurofeedback to Improve Emotion Regulation in Major Depressive Disorder: A Randomized Clinical Trial

NCT07041073 | Recruiting FDA Device

• 1 other identifier: 101149645
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to evaluate whether EEG-based neurofeedback targeting the emotion regulation network through swLORETA can improve emotional regulation and reduce symptoms in adults with Major Depressive Disorder (MDD) who have not responded sufficiently to first-line treatments. The main questions it aims to answer are:

• Does EEG-neurofeedback improve emotional self-regulation and reduce clinical symptoms in patients with MDD with or without anxiety symptoms?
• Are changes in EEG resting-state activity and stress biomarkers (e.g., cortisol) associated with clinical improvement? Researchers will compare an active neurofeedback group, a sham (placebo) neurofeedback group, and a treatment-as-usual control group to see if real-time EEG-neurofeedback leads to greater improvement in mood, emotional regulation, and neurophysiological indicators than placebo or no additional intervention. Participants will:
• Receive 10 sessions of either real or sham EEG-neurofeedback (or no sessions in the control group) over 5 weeks.
• Complete clinical, psychological, and neurophysiological assessments before (week 0) and after the intervention (week 6).
• Provide repeated saliva samples to assess stress-related biomarkers at week 0 and week 6.
• Continue their standard pharmacological treatment throughout the study.

Conditions

Major Depression With Comorbid Anxiety Symptoms; Major Depressive Disorder (MDD)

Keywords

neurofeedback; eeg; MDD; anxiety; depression; emotion regulation

Outcome Measures

Primary Outcomes (9)

• Change in depressive symptom severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), from baseline to post-intervention.

  The MADRS is a validated clinician-administered scale widely used to assess the severity of depressive symptoms. A clinically significant response is defined as a reduction of more than 50% from the baseline score. Clinical remission is defined as a final score of 10 or below. The Spanish version of the MADRS, validated for use in the study population, will be administered by trained clinicians at three time points: baseline (pre-intervention), mid-treatment (after session 5), and post-intervention (after session 10).

  From enrollment (week 0) to the end of treatment (week 6)

• Change in depressive symptoms measured by the Hamilton Depression Rating Scale (HAM-D), from baseline to post-treatment

  The HAM-D is a clinician-administered scale that evaluates a broad range of depressive symptoms, including insomnia, anxiety, and somatic complaints. It complements the MADRS by covering additional symptom domains and will be administered at baseline and post-treatment to assess clinical change.

  From enrollment (week 0) to the end of treatment (week 6)

• Change in self-reported anxiety symptoms measured by the Beck Anxiety Inventory (BAI), from baseline to post-intervention

  The BAI is a 21-item self-report instrument designed to assess the severity of anxiety symptoms. It will be used to evaluate the potential impact of the neurofeedback intervention on co-occurring anxiety.

  From enrollment (week 0) to the end of treatment (week 6)

• Change in self-reported depressive symptoms measured by the Beck Depression Inventory-II (BDI-II), from baseline to post-intervention

  The BDI-II is a widely used self-report questionnaire designed to assess the presence and severity of depressive symptoms.It will be administered at baseline and post-treatment to complement clinician-rated measures and capture subjective aspects of depression, such as patient-reported changes in mood, cognition, and physical symptoms related to depression.

  From enrollment (week 0) to the end of treatment (week 6)

• Change in salivary cortisol levels (Cortisol Awakening Response and Diurnal Slope)

  Cortisol will be measured from saliva samples collected at five time points across the day (awakening, +30 min, +60 min, 10:00h, 21:00h), over two consecutive days at the enrollment and post-intervention. AUCi, AUCg, and diurnal slope will be calculated as biomarkers of HPA axis activity and stress response.

  From enrollment (week 0) to the end of treatment (week 6)

• Change in cognitive emotion regulation strategies measured by the Cognitive Emotion Regulation Questionnaire (CERQ)

  The CERQ is a self-report instrument that evaluates the use of specific cognitive strategies in response to negative life events. It assesses both adaptive and maladaptive regulation strategies such as reappraisal, catastrophizing, and rumination. The scale will be used to determine whether the neurofeedback intervention promotes changes in cognitive emotion regulation patterns that are relevant to the development and maintenance of depressive symptoms.

  From enrollment (week 0) to the end of treatment (week 6)

• Change in transient mood states measured by the Profile of Mood States (POMS)

  The POMS is a standardized questionnaire that measures transient mood states. It will be administered before and after each neurofeedback session to monitor short-term mood fluctuations during training.

  Before and after each neurofeedback session (Sessions 1-10; Weeks 1-5)

• Change in resting-state EEG activity

  Resting-state EEG will be recorded before and after each Neurofeedback session to examine changes in spectral power and connectivity within emotion regulation networks. EEG activity will be analyzed using swLORETA and qEEG metrics.

  From baseline (week 0) to Post-treatment (Week 6); Before and after each neurofeedback session (Sessions 1-10; Weeks 1-5)

• Change in emotion regulation skills measured by the Emotion Regulation Skills Questionnaire (ERSQ)

  The ERSQ evaluates the use of adaptive emotion regulation strategies in daily life. It will be used to assess whether skills acquired during neurofeedback training transfer to real-world emotional functioning.

  From enrollment (week 0) to the end of treatment (week 6)

Secondary Outcomes (3)

• Change in sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI)

  Baseline (Week 0), Post-treatment (Week 6)

• Change in rumination measured by the Ruminative Responses Scale (RRS)

  Baseline (Week 0), Post-treatment (Week 6)

• Change in sensitivity to punishment and reward measured by the SPSRQ

  Baseline (Week 0), Post-treatment (Week 6)

Study Arms (3)

Active Neurofeedback (EEG-NF)

EXPERIMENTAL

Participants in this arm will receive 10 sessions of active EEG-based neurofeedback over 5 weeks, while continuing their standard pharmacological treatment. Neurofeedback will be delivered using swLORETA Z-score training via NeuroGuide software, targeting key regions of the fronto-limbic emotional regulation network (e.g., anterior cingulate cortex, medial prefrontal cortex, amygdala, insula).

Device: Active swLORETA Z-score Neurofeedback

Yoked-sham Neurofeedback

SHAM COMPARATOR

Participants in this arm will undergo 10 sessions of sham neurofeedback with the same structure, duration, and appearance as the active intervention, while continuing their standard pharmacological treatment. However, the feedback presented on screen will be non-contingent and based on pre-recorded EEG activity from a participant in the active group (yoked design). This design ensures participants receive no real-time modulation of their own brain activity, serving as a placebo control while preserving participant blinding. After completing the study, these participants will be offered the opportunity to receive the active neurofeedback intervention in a separate phase.

Device: Yoked-sham swLORETA Z-score Neurofeedback

Treatment as Usual (Control)

NO INTERVENTION

Participants in this arm will continue their standard pharmacological treatment without receiving any additional intervention during the study period. This group serves as a control condition to assess the effects of neurofeedback relative to usual care.

Interventions

Active swLORETA Z-score Neurofeedback DEVICE

Participants receive 10 sessions (25 minutes each, twice per week for 5 weeks) of EEG-based neurofeedback using the NeuroGuide® software and a 24-channel EEG recording system (eego™, ANT Neuro). The neurofeedback protocol is based on real-time swLORETA Z-score training targeting brain regions involved in emotion regulation. Feedback is provided via gamified visual displays when EEG activity moves toward normative patterns. This is an operant conditioning-based protocol designed to enhance emotional self-regulation.

Active Neurofeedback (EEG-NF)

Yoked-sham swLORETA Z-score Neurofeedback DEVICE

Participants receive 10 sessions identical in appearance and duration to the active neurofeedback condition. However, the feedback provided is not based on their own EEG activity. Instead, it is pre-recorded data from a matched participant in the active group ("yoked" design), ensuring no real-time neurophysiological modulation occurs. The same EEG equipment and visual feedback interface are used to maintain blinding.

Yoked-sham Neurofeedback

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A primary diagnosis of Major Depressive Disorder (MDD), established by qualified psychiatrists according to DSM-5 criteria.
• Patients with comorbid anxiety or anxiety symptoms will be included, provided that MDD is the primary diagnosis.
• Participants must score at least 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS), indicating a moderate level of depression.
• All participants must be on a stable psychopharmacological treatment for at least 6 weeks before beginning of the study.

You may not qualify if:

• Patients with a concurrent diagnosis of MDD and other severe psychiatric disorders.
• Patients with serious physical illnesses that could interfere with study participation or the interpretation of results.
• Participants currently undergoing structured psychotherapy or other interventions unrelated to standard psychopharmacological treatment.
• Patients presenting with active suicidal ideation, as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS), at the time of screening will not be eligible due to associated risks.
• Active substance abuse or dependence (except nicotine).
• Intellectual disability or conditions that interfere with the ability to provide informed consent and complete the intervention (e.g., severe visual or hearing impairments).
• Pregnancy.

Sponsors & Collaborators

• Corporacion Parc Tauli: lead
• Horizon 2020 - European Commission: collaborator

Study Sites (1)

Corporació Sanitària Parc Taulí de Sabadell

Sabadell, Barcelona, Cataluña, 08208, Spain

RECRUITING

Related Publications (1)

• Wu YC, Yu HE, Yen CF, Yeh YC, Jian CR, Lin CW, Lin IM. The effects of swLORETA Z-score neurofeedback for patients comorbid with major depressive disorder and anxiety symptoms. J Affect Disord. 2024 Apr 1;350:340-349. doi: 10.1016/j.jad.2024.01.020. Epub 2024 Jan 8.

  PMID: 38199411 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Anxiety Disorders; Depression; Emotional Regulation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior; Self-Control; Social Behavior

Central Study Contacts

Virginia Soria, MD,PhD

CONTACT

+34 937231010; vsoria@gmail.com

Diego Palao, MD, PhD

CONTACT

+34 937231010; dpalao@tauli.cat

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Adults Mental Health Department

Model Details: This study follows a parallel assignment model in which participants are randomized into one of three groups: active neurofeedback (EEG-NF), yoked-sham neurofeedback (sham-NF), or treatment-as-usual (control). Each participant completes the assigned intervention arm over the study period without crossover. However, to ensure ethical access to the potentially beneficial intervention, participants initially assigned to the sham-NF group or to the control group will be offered the opportunity to receive the active EEG-NF protocol after the completion of their participation in the study. These individuals may be re-enrolled into a subsequent phase as part of the experimental group and undergo the full EEG-NF training. This optional post-trial access is designed to address ethical considerations and maximize participant benefit while maintaining the scientific integrity of the initial randomized design.

Study Record Dates

• First Submitted: June 18, 2025
• First Posted: June 27, 2025
• Study Start: May 19, 2025
• Primary Completion: March 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: June 27, 2025

Record last verified: 2025-06

Locations

ES (1)