Neurofeedback for Bipolar Disorder (NEUROFEED-BD)

Real-time fMRI Neurofeedback as Treatment for Inter-critical Mood Symptoms in Bipolar Disorder : a Randomized Controlled Multicentric Trial

Bipolar Disorder (BD) is a severe mood disorder affecting between 1% and 3% of the general population. It is characterized by the succession of depressive and manic episodes, with periods of stabilization during which patients may present "residual" depressive or anxious symptoms, which are characterized by sadness and emotional hyper-reactivity. Although subthreshold, these residual symptoms are very disabling for their daily lives and are associated with the risk of recurrence and poor global functioning. The effect of pharmacological and psychotherapeutic treatments is demonstrated in the management of acute episodes but remains insufficient on residual symptoms. Therefore, there are so far few therapeutic options to target the inter-episode residual symptoms in BD. One novel approach is the real-time functional magnetic resonance imaging (fMRI) neurofeedback (NFB), which has already been shown to be an efficient method for self-regulating brain function, behavior and treating depression.

Hypothesis/Objective :

This study aims at assessing the efficacy of 3-weeks neurofeedback training with real-time fMRI on the treatment of residual mood symptoms in patients with BD. The investigators will specifically target depressive symptoms by training the patients to regulate the emotional network hemodynamic response to emotional stimuli.

Method :

The investigators will include 64 stabilized patients with BD. The investigators will recruit them in three French expert centers for BD and will randomly assign them to the experimental group, receiving feedback from the emotional brain network hemodynamic activity, or to the control group, receiving the signal from control brain areas not involved in emotion processing. Both groups will be trained to regulate their brain activity while they are presented with negatively valenced emotional pictures, based on the neurofeedback shown immediately after the trial. They will continue their usual treatment (as prescribed) throughout the duration of the study. Clinical scales and cognitive tests will enable us to evaluate the symptomatic, emotional, and cognitive changes after NFB training. The investigators will also measure resting-state functional connectivity and brain morphology before and after NFB to assess brain plasticity and to explore the neural mechanisms associated with successful regulation.

Study Overview

• Status: Not yet recruiting
• Conditions: Bipolar Disorder
• Intervention / Treatment: Other: Real-time fMRI Neurofeedback

• Study Type: Interventional
• Enrollment (Anticipated): 64
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Josselin HOUENOU, Professor (MD, PhD); Phone Number: (+33)1 49 81 30 51; Email: josselin.houenou@aphp.fr
• Study Contact Backup: Name: Pauline Favre, Associate researcher (PhD); Phone Number: (+33)1 69 08 24 81; Email: pauline.favre@cea.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients diagnosed with bipolar disorder I or II (DSM-5 criteria);
• Aged between ≥ 18 and ≤ 65;
• Absence of major mood episode for at least 3 months before inclusion (MADRS scores < 12; YMRS score < 10);
• Presence of residual depressive symptoms, as assessed by the MADRS (score > 5);
• Stabilized dose of mood stabilizer medication for at least 3 months before inclusion.
• Written consent
• Affiliation to a social security system
• Effective contraception for women of childbearing age

Exclusion Criteria:

• Severe physical disorders that may be life-threatening;
• Major psychiatric (Axis 1) comorbidities except for anxiety disorders;
• Any current substance abuse except for tobacco or cannabis. Substance abuse will be defined by the DSM V criteria;
• Exclusion criteria applicable to MRI Panic disorder, claustrophobia, epilepsy Pace maker or neuronal stimulator, intraocular or intracerebral metallic foreign body, cochlear implant, cardiac valve or metallic surgical arterial material, non removable removable magnetizable metallic material
• Somatic disorder that may affect cognitive abilities and brain structures (e.g., HIV infection, MS, lupus, Parkinson's disease, epilepsy, dementia...);
• Ongoing non-pharmacological treatment: structured psychotherapeutic interventions (Cognitive Behavioral Therapy - CBT, Interpersonal and Social Rhythm Therapy - IPSRT) as well as brain stimulation techniques (Electroconvulsive Therapy - ECT, Transcranial Magnetic Stimulation - TMS, Deep Brain Stimulation - DBS);
• Subject included in clinical and / or therapeutic experimentation in progress.
• Patients under legal protection
• Prisoners
• Pregnancy
• Breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active feedback; Group receiving "real" neurofeedback (NFB) (activity of the emotional brain network)	Other: Real-time fMRI Neurofeedback; Neurofeedback with real-time fMRI is a recent technique that allows to record the BOLD signal from a particular brain region and to display it back in real-time to the participant. With this feedback on brain activity, subjects can learn to control the activity of selected brain areas. Trial after trial, participants develop their individual strategies to voluntarily regulate the signal. The main objective of the neurofeedback training is that the participant develops an enhanced ability to exert control over activity in the target area(s) even without feedback. By manipulating targeted brain circuits, this training can induce modifications in particular behaviors and promote selective plasticity within the corresponding brain networks.
Sham Comparator: Sham feedback; Group receiving "sham" NFB (activity from brain regions not implicated in emotion processing) to control for a potential placebo effect.	Other: Real-time fMRI Neurofeedback; Neurofeedback with real-time fMRI is a recent technique that allows to record the BOLD signal from a particular brain region and to display it back in real-time to the participant. With this feedback on brain activity, subjects can learn to control the activity of selected brain areas. Trial after trial, participants develop their individual strategies to voluntarily regulate the signal. The main objective of the neurofeedback training is that the participant develops an enhanced ability to exert control over activity in the target area(s) even without feedback. By manipulating targeted brain circuits, this training can induce modifications in particular behaviors and promote selective plasticity within the corresponding brain networks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	Evaluation of depressive symptoms. Total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms.	Baseline, 3 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery and Asberg Depression Rating Scale (MADRS)	Evaluation of depressive symptoms. Total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Young Mania Rating Scale (YMRS)	Evaluation of manic symptoms. Total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Bipolar Depression Rating Scale (BDRS)	Evaluation of bipolar depression. Total score ranging from 0 to 60, with higher scores indicating a greater severity of symptoms.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
State-Trait Anxiety Inventory (STAI A-B)	Evaluation of trait and state anxiety. Total score ranging from 20 to 80 for both subscales, with higher scores indicating a greater severity of symptoms.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Multidimensional Assessment of Thymic States - MAThyS	Evaluation of thymic state. Total score ranging from 0 to 200, lower scores indicate general inhibition, and higher scores indicate general excitation. A more descriptive approach can be done by analysing the sub-score.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Affective Intensity Measure - AIM	Evaluation of emotion reactivity. Total score ranging from 20 to 120, with higher scores indicating higher strength or intensity of people's emotional experiences.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Affective Lability Scale - ALS	Evaluation of mood lability. Total score ranging from 0 to 162, with higher scores indicating greater affective lability.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Cognitive Emotion Regulation Questionnaire - CERQ	Evaluation of emotion regulation abilities. Subscales scores ranging from 4 to 20, with higher subscale scores indicating greater use of a specific cognitive strategy.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Quality of life scale - QOLS	Quality of life assessment. Score ranging from 1 to 5, 5 indicating better quality of life	Baseline, 3 weeks, and 4, 8 weeks after the end of the training. .
Five Facets Mindfulness Questionnaire - FFMQ	Evaluation of trait mindfulness. Total score ranging from 39 to 195, higher scores are indicative of someone who is more mindful in their everyday life	Baseline, 3 weeks and 4, 8 weeks after the end of the training.
Global functioning assessment - GAF scale	Evaluation of global functioning. Total score ranging from 0 to 100, higher scores indicating better global functioning.	Baseline, 3 weeks, and 4, 8 weeks after the end of the training.
Questionnaire of Adherence to the technology	Evaluation of the score of the acceptability of neurofeedback. Total score ranging from 6 to 42, higher scores indicating better acceptability of the technology.	Baseline, 3 weeks.
Self-efficacy scale	Evaluation of personal efficiency. Total score ranging from 21 to 105, higher scores indicating stronger belief that one's actions are responsible for successful outcomes.	Baseline, 3 weeks.
The Ekman facial recognition test	Emotion recognition evaluation. Cognitive task	Baseline, 3 weeks.
The affective bias task	Evaluation of emotional bias. Cognitive task	Baseline, 3 weeks.
The Test battery for Attentional Performance (TAP)	Evaluation of attention. Cognitive task	Baseline, 3 weeks.
The choice reaction task	Evaluation of mindwandering, meta-awareness and ruminations. Cognitive task	Baseline, 3 weeks.
MRI T1-T2 weighted scan	Evaluation of grey and white matter (micro)structure. MRI measurement	Baseline, 3 weeks
MRI diffusion weighted scan	Evaluation of grey and white matter (micro)structure. MRI measurement	Baseline, 3 weeks
functional MRI resting-state scan	Evaluation of brain functional connectivity. MRI measurement	Baseline, 3 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2023
• Primary Completion (Anticipated): May 1, 2025
• Study Completion (Anticipated): August 1, 2025

Study Registration Dates

• First Submitted: February 28, 2023
• First Submitted That Met QC Criteria: March 27, 2023
• First Posted (Actual): April 6, 2023

Study Record Updates

• Last Update Posted (Actual): April 6, 2023
• Last Update Submitted That Met QC Criteria: March 27, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Emotion; fMRI; Bipolar disorder; Neurofeedback; Cognitive training; Residual symptoms
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Bipolar and Related Disorders; Disease; Bipolar Disorder
• Other Study ID Numbers: APHP180597

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: DATAS ARE OWN BY ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, PLEASE CONTACT SPONSOR FOR FURTHER INFORMATION

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No