Structural and Functional Correlates of Clinical Response to rTMS Treatment in Schizophrenia Patients With Resistant Auditory Hallucinations

Study Overview
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Brief Summary
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The potential of non-invasive Transcranial Magnetic Stimulation (TMS) as a therapeutic tool for improving schizophrenic symptoms, in particular resistant hallucinations, has been increasingly studied over the past decades. Several studies have demonstrated that low-frequency patterns of repetitive TMS (rTMS) applied over the left Temporoparietal Junction (TPJ), which are known to decrease local activity, significantly reduced auditory verbal hallucinations in schizophrenic patients. In spite of highly promising results, a high level of inter-individual variability in the responses to non-invasive brain stimulation treatments, and the fact that rTMS may prove ineffective in some patients, keep spurring controversy about the efficacy of these approaches (as currently performed), as well as about how to increase its efficacy and consistency. Accordingly, the objectives of this project are to better understand the impact of rTMS on the brains of patients with resistant auditory hallucinations, and to use this information not only to better understand this condition but to develop more efficient and consistent therapies. Thus, in this study, the investigators focus more specifically on resistant auditory hallucinations in schizophrenia, which is a common symptom in schizophrenic patients, and can be treated by rTMS. The investigators hypothesize that there is a baseline difference in anatomical and/or functional connectivity between responder and non-responder patients who are treated with rTMS. Therefore, our project will aim to determine some anatomical and functional connectivity markers of response to rTMS treatment in patients with schizophrenia

Detailed Description
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The potential of non-invasive Transcranial Magnetic Stimulation (TMS) as a therapeutic tool for improving schizophrenic symptoms, in particular resistant hallucinations, has been increasingly studied over the past decades. Several studies have demonstrated that low-frequency patterns of repetitive TMS (rTMS) on the left temporoparietal junction (TPJ), which are known to decrease local activity, significantly reduce auditory verbal hallucinations in schizophrenic patients. In spite of highly promising results, a high level of inter-individual variability in the response to non-invasive brain stimulation treatments, and the fact that rTMS may prove ineffective in some patients, keep spurring controversy on the efficacy of these approaches as currently performed, and on how to increase its efficacy and consistency. To date, few studies have aimed to explain this variability when, in fact, a better understanding of this common phenomena in the neurostimulation domain would clearly increase the effectiveness of this treatment, and lead to individualized therapeutic approaches specifically tailored to the conditions of each patient. Moreover, many questions stand, particularly regarding the influence of rTMS treatment on the anatomical and functional connectivity in schizophrenic patients. Accordingly, the objectives of this project are to better understand the impact of rTMS on the brains of patients with resistant auditory hallucinations, and to use this information not only to better understand this condition but to develop more efficient and consistent therapies. The investigators hypothesize that there is a baseline difference in anatomical and/or functional connectivity between responder and non-responder patients who are treated with rTMS. Therefore, this project aims to determine some anatomical and functional connectivity markers of response to rTMS treatment in patients with schizophrenia. For this, the investigators compare the patterns of diffusion tensor imaging (DTI) white matter tractography and resting-state functional magnetic resonance imaging (fMRI) data between responder and non-responder patients to rTMS treatment. Moreover, the investigators believe that rTMS can increase the functional connectivity between frontal and temporo-parietal cortices in schizophrenic patients associated with improvements in auditory hallucinations. Therefore, the second objectives of this work are to evaluate the impact of rTMS in functional connectivity in patients with schizophrenia by comparing the DTI and resting-state fMRI data before and after rTMS treatment in both responder and non-responder patients.

Official Title
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Structural and Functional Correlates of Clinical Response to Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment in Schizophrenia Patients With Resistant Auditory Hallucinations

Conditions
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Schizophrenia

Intervention / Treatment
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* Device: Repetitive Transcranial Magnetic Stimulation (rTMS)
* Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with a diagnosis of schizophrenia according to DSM-V (Diagnostic and Statistical Manual of Mental Disorder V, 2013) criteria Clinically stabilized for at least 3 months Patient with resistant auditory hallucinations Male or female, 18 to 65 years old A written agreement from the patient's legal guardian/s, if applicable Right-handed A good knowledge of the French language Signed consent form Exclusion Criteria: Other diseases than schizophrenia Indulging in an addiction (alcohol, psychoactive substances) over the last 12 months Patient who has received rTMS treatment in the last 12 months Patient who is participating in a concurrent research protocol Patient with a history of seizures rTMS contraindications: patient with epilepsy, brain surgery and/or head trauma in the past, use of cardiac pacemaker, or surgical staples on the scalp MRI contraindications: pregnancy or lactating (n.b. a negative pregnancy test will be required if the patient is a female in reproductive years who does not use contraception); use of cardiac pace maker or surgical staples; patient with a neurological disorder, head trauma or claustrophobia Patient with severe cardiovascular disease Patient with medication which reduces the epileptic threshold (bupropion, methadone and theophylline) Patients placed in psychiatric care either by the state or a third party

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Active Comparator: Active Repetitive Transcranial Magnetic Stimulation (rTMS)<br>low-frequency (1 Hertz) rTMS | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Participants are sequentially randomly assigned to either 20 active rTMS sessions or 20 sham rTMS sessions that were applied over the left temporoparietal junction. Treatments are administered daily, over a period of two weeks.<br>|
| Sham Comparator: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)<br>sham TMS | Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the integrity of white matter tracts between responder and non-responder patients |  | Baseline | 
| Changes in the variations of the blood-oxygen-dependent level (BOLD) signal between responder and non-responder patients |  | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AHRS (Auditory Hallucinations Rating Scale) |  | Baseline, 3 weeks, 7 weeks and 15 weeks | 
| HCS (Hallucinations Change Score) |  | Baseline, 3 weeks, 7 weeks and 15 weeks | 
| PANSS (Positive And Negative Syndrome Scale) |  | Baseline, 3 weeks, 7 weeks and 15 weeks | 
| PSYRATS (Psychotic Symptom Rating Scale) |  | Baseline, 3 weeks, 7 weeks and 15 weeks | 
| BDI (Beck Depression Inventory) |  | Baseline, 3 weeks, 7 weeks and 15 weeks | 
| Serum BDNF levels |  | Baseline, 3 weeks, 7 weeks and 15 weeks | 
| Measure of the amplitude of Motor-Evoked Potentials (MEPs) |  | Baseline, 3 weeks, 7 weeks and 15 weeks |