fMRI-based Neurofeedback to Relieve Drug-resistant Auditory Hallucinations

Study Overview
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Brief Summary
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The INTRUDE trial aims at assessing the efficacy of an fMRI-based neurofeedback procedure on drug-resistant auditory hallucinations. Hallucinations are complex and transient mental states associated with subtle and brain-wide patterns of activity for which we were recently able to validate an fMRI multivariate decoder. Based on this progress, we can track patients' hallucinatory status using real-time fMRI. We will test whether schizophrenia patients with drug-resistant hallucinations can be trained to maintain the brain state associated with a no-hallucination condition using appropriate strategies and thus reduce overall severity. We will refer to a double-blind randomized placebo-controlled design. A total of 86 patients will be enrolled and equally split in an active neurofeedback group (n=43) and a sham group (n=43), matched for sex, age and PANSS scores. Each patient will benefit from 4 runs of either active or sham neurofeedback. The primary outcome measure will be the mean decrease of AHRS scores relative to baseline, and at 1 month post-treatment. We expect significant clinical benefits from fMRI-based neurofeedback on drug-resistant hallucinations compared with the sham group.

Official Title
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Treat Refractory Auditory Hallucinations in Schizophrenia Patients With fMRI-guided Neurofeedback: a Randomized-controlled Trial

Conditions
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Schizophrenia, Hallucinations, Auditory, Hallucinations, Visual

Intervention / Treatment
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* Other: Active neurofeedback procedure
* Other: Sham neurofeedback procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Schizophrenia (according to the DSM-5 classification) Frequent auditory hallucinations (SAPS item #1 ≥ 4) Stable medication for at least 30 days Absence of chronic neurological disorder (including seizure) Able to provide free written consent to participate in the research Exclusion Criteria: Pregnancy Contraindication to MRI scan Claustrophobia No social insurance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>The visual feedback will correspond to instructions, adapted to the current hallucinatory state and decoded online from the fMRI signal. | Other: Active neurofeedback procedure<br>* Patients will perform 5 fMRI sessions. Four consecutive fMRI runs (1/ day) during which they will continuously receive visual feedback computed from the fMRI signal analyzed with the hallucinations decoder. Patients will be trained to maintain the brain state associated with the no-hallucination state using appropriate coping strategies. A 5th fMRI scan will be performed at 1 month post-treatment.<br>|
| Sham Comparator: Sham<br>The visual feedback will correspond to random instructions independently of the fMRI signal. | Other: Sham neurofeedback procedure<br>* Patients will perform 5 fMRI sessions. Four consecutive fMRI runs (1/ day) during which they will receive a random feedback and a 5th run at 1 month post-treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Auditory Hallucination Rating Scale (AHRS) measure of hallucinations severity | AHRS will be measured at t0 (randomization) and at 1 month after treatment Minimum score is 2, maximum score is 41, higher score indicates more severe symptoms. | 1 month after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Positive and Negative Syndrome Scale (PANSS) measure of hallucinations severity | PANSS will be measured at t0 (randomization) and at 1 month after treatment The PANSS contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. rate from 1 to 7 on each symptom scale. The total score is the sum of all scales with a minimum score of 30 and a maximum score of 210 | 1 month after treatment | 
| Change from baseline Questionnaire for Psychotic Experiences (QPE) measure for severity of hallucinations | QPE will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 
| Change from baseline Simplified Acute Physiology Score (SAPS) measure for severity of hallucinations | SAPS will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 
| Change from baseline Visual analogue scale (VAS) measure for severity of hallucinations | VAS will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 
| Changes in global functioning relative to baseline | Global Assessment of Functioning (GAF) is a numeric scale be measured at t0 (randomization) and at 1 month after treatment Scores range from 100 (extremely high functioning) to 1 (severely impaired). | 1 month after treatment | 
| Changes in quality of life relative to baseline | SQLS score will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 
| Changes in structural MRI markers relative to baseline | Cortical thickness will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 
| Changes in structural MRI markers relative to baseline | Gyrification Index will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 
| Changes in functional MRI markers relative to baseline | Brain activity at rest and connectivity metrics will be measured at t0 (randomization) and at 1 month after treatment | 1 month after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hallucinations, Drug-resistance, functional MRI, Neurofeedback, Machine-Learning., Schizophrenia