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

Condition(s) studied

Investigational drug(s) / intervention(s)

Active swLORETA Z-score Neurofeedback: 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.

Yoked-sham swLORETA Z-score Neurofeedback: 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.

Study 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.

Eligibility

Primary outcome measure(s)

• Change in depressive symptom severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), from baseline to post-intervention. — From enrollment (week 0) to the end of treatment (week 6)
  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).
• Change in depressive symptoms measured by the Hamilton Depression Rating Scale (HAM-D), from baseline to post-treatment — From enrollment (week 0) to the end of treatment (week 6)
  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.
• Change in self-reported anxiety symptoms measured by the Beck Anxiety Inventory (BAI), from baseline to post-intervention — From enrollment (week 0) to the end of treatment (week 6)
  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.
• Change in self-reported depressive symptoms measured by the Beck Depression Inventory-II (BDI-II), from baseline to post-intervention — From enrollment (week 0) to the end of treatment (week 6)
  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.
• Change in salivary cortisol levels (Cortisol Awakening Response and Diurnal Slope) — From enrollment (week 0) to the end of treatment (week 6)
  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.
• Change in cognitive emotion regulation strategies measured by the Cognitive Emotion Regulation Questionnaire (CERQ) — From enrollment (week 0) to the end of treatment (week 6)
  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.
• Change in transient mood states measured by the Profile of Mood States (POMS) — Before and after each neurofeedback session (Sessions 1-10; Weeks 1-5)
  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.
• Change in resting-state EEG activity — From baseline (week 0) to Post-treatment (Week 6); Before and after each neurofeedback session (Sessions 1-10; Weeks 1-5)
  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.
• Change in emotion regulation skills measured by the Emotion Regulation Skills Questionnaire (ERSQ) — From enrollment (week 0) to the end of treatment (week 6)
  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.

Trial sites (1)

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