Approximately 1% of the general population will be affected by schizophrenia over the course of their lives, with life expectancy being reduced by 20 years on average and quality of life being severely diminished in affected individuals. One third of patients suffering from schizophrenia will evolve towards a resistant form of the disease, amongst which many will suffer from auditory-verbal hallucinations (AVH) that current therapeutic approaches struggle to alleviate. Previous work from our team has demonstrated the possibility of robustly inferring the periods of occurrence of AVH from fMRI data, paving the way for the development of a closed-loop neuromodulation system comprised of an electrode array positioned in Broca's area, which would detect AVH in real time, and effector electrodes which would stimulate the temporo-parietal cortex to interrupt them. The aim of this project is to assess the feasibility of this system. To do so, we will first test the ability of transcranial magnetic stimulation of the "continuous theta burst" (cTBS) type, applied at the time of AVH onset, to reduce their duration and intensity, and assess whether this is associated with therapeutic response to the current gold standard rTMS protocol for AVH reduction through neuroplasticity induction. Demonstrating the feasibility of acute suppression of AVH by cortical neurostimulation is an essential element in the feasibility of a closed-loop reactive neuromodulation system.

The research project comprises two phases:

-Phase 1: randomized controlled clinical trial (1 weekly session per patient over 12 weeks: 6 active stimulation sessions and 6 sham sessions) evaluating the phasic effects of rTMS on AVHs as they appear during the sessions.

Phase 2: open-label study offering patients a routine rTMS protocol which has demonstrated its effects on AVH (10 TMS sessions over one workweek - twice daily with 1-hour intervals, MULTIMODHAL study, NCT01373866).

Inclusion Criteria:

• Age > 18 years old
• Schizophrenic Disorder (Diagnostic and statistical manual of mental disorders, DSM-5-TR, American Psychiatric Association, 2013)
• AVHs that have resisted to at least two properly conducted antipsychotic therapies at an effective dose for at least 8 weeks (criteria of Kinon et al., 1993)
• Frequent AVHs (at least 10 times per hour) (Fovet et al., 2022)
• Unmodified antipsychotic dosage for 30 days prior to inclusion in the protocol
• AVH are the main residual symptom of schizophrenia.
• Consent to participate in the study

Exclusion Criteria:

• Pregnancy (based on date of last menstrual period with possibility of urine test if in doubt)
• Anticonvulsant therapy
• Neurological disorder (e.g., multiple sclerosis, epilepsy)
• Current addictive behavior (except tobacco and cannabis, widely used in this clinical population; Fovet et al., 2022)
• Contraindication to MRI (i.e., presence of ferromagnetic material or implanted neurostimulation devices due to the risk of displacement or dysfunction such as cochlear implants, cardiac pacemakers, metal splinters in the body following an accident, permanent makeup applied less than 6 months ago, neurosurgical clips, deep brain or vagus nerve stimulation devices, baclofen pumps) (Lefaucheur et al., 2011)
• Morphological criteria: weight > 130 Kg, abdominal circumference conditioned by the opening of the magnet, shoulder width
• Lack of coverage by the social security system
• Current participation in another interventional research protocol or being in the exclusion period of a previous research protocol
• Refusal to be informed of an brain anomaly detected in the MRI
• Person under guardianship or curatorship
• Behavioral disorders or delusions likely to prevent the MRI or rTMS from being performed under good conditions (left to the discretion of the investigator at baseline).

Only the person conducting the experiment will know which condition each patient is in.