fMRI-based Neurofeedback to Relieve Drug-resistant Auditory Hallucinations (INTRUDE)

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

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.

The visual feedback will correspond to instructions, adapted to the current hallucinatory state and decoded online from the fMRI signal.

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.

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.

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.

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

Change from baseline Questionnaire for Psychotic Experiences (QPE) measure for severity of hallucinations

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).

Brain activity at rest and connectivity metrics will be measured at t0 (randomization) and at 1 month after treatment

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