A Study on the Brain Mechanism of cTBS in Improving Medication-resistant Auditory Hallucinations in Schizophrenia

Study Overview
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Brief Summary
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This study is dedicated to exploring the brain mechanism of medication-resistant auditory hallucinations and developing effective treatment methods for them by using both cross-sectional and longitudinal designs. The continuous theta burst stimulation(cTBS) treatment mode, with the left cerebellum Crus II as the stimulation target, is applied to treat the schizophrenia patients with the medication-resistant auditory hallucinations. At the same time, the first-episode schizophrenia patients with auditory hallucinations were recruited as a test cohort to examine that brain mechanism of general auditory hallucinations in schizophrenia may be the structural and functional abnormalities in the temporoparietal circuit.

Detailed Description
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Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) targeted at the temporal-parietal junction can effectively treat genenal auditory hallucinations in schizophrenia, but it is not the case for medication-resistant auditory hallucinations. Studies suggested that rTMS targeted at the left Crus II might be effective for medication-resistant auditory hallucinations. This study is dedicated to exploring the brain mechanism of medication-resistant auditory hallucinations and developing effective treatment methods for them by using both cross-sectional and longitudinal designs. The continuous theta burst stimulation(cTBS) treatment mode, with the left cerebellum Crus II as the stimulation target, is applied to treat the schizophrenia patients with the medication-resistant auditory hallucinations. Assessment with symptomatology, neuropsychology, neuroimaging, and machine learning methods is utilized to examine the investigators hypothesis that structural and functional abnormalities of the cerebral cortico-cerebellar-thalamic-cortical circuit (CCTCC) may contribute to brain mechanism of medication-resistant auditory hallucinations in schizophrenia. At the same time, the first-episode schizophrenia patients with auditory hallucinations were recruited as a test cohort to examine that brain mechanism of general auditory hallucinations in schizophrenia may be the structural and functional abnormalities in the temporoparietal circuit, whereas structural and functional abnormalities of the CCTCC may contribute to brain mechanism of medication-resistant auditory hallucinations in schizophrenia.

Official Title
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A Study on the Brain Mechanism of cTBS in Improving Medication-resistant Auditory Hallucinations in Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Antipsychotic drugs
* Device: cTBS（the left temporoparietal cortex as the stimulation target）
* Device: cTBS （the left cerebellum Crus II as the stimulation target）


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent 18-45 years old, right-handed Meet the diagnostic criteria for schizophrenia according to the Structural Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) After a sufficient course of antipsychotic treatment (more than 6 weeks, two or more antipsychotic drugs, at least one of which is the second generation of atypical antipsychotic drugs), auditory hallucinations occurred more than 5 times a day for more than 6 months Stable antipsychotic medication 4 weeks before and during the treatment (except auditory hallucination symptoms) Exclusion Criteria: A history of epilepsy, convulsions, stroke or other serious brain diseases There are serious infectious diseases, malignant tumors, and severe somatic comorbidity Mental retardation, personality disorder and so on Contraindications for magnetic resonance imaging Diagnose of substance dependence or abuse as primary clinical problem Pregnancy Participants had received Modified Electraconvulsive Therapy (MECT) or TMS treatment in recent 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The schizophrenia patients with medication-resistant auditory hallucinations<br>Drug + cTBS intervention (the left cerebellum Crus II as the stimulation target) | Drug: Antipsychotic drugs<br>* Stable antipsychotic medication 4 weeks before and during the treatment. Chlorpromazine (CPZ) equivalent dosages were calculated for second- and first-generation antipsychotic drugs<br>* Other names: MRI scan;Device: cTBS （the left cerebellum Crus II as the stimulation target）<br>* Participants received 3 daily sessions of cTBS treatment. One session of cTBS was 40 seconds in duration and consisted of 3-pulse bursts at 50 Hz repeated every 200 milliseconds (5 Hz) until a total of 600 pulses was reached. To achieve cumulative aftereffects, this protocol was repeated 3 times and (1800 pulses in total) separated by two 15 minute breaks<br>* Other names: MRI scan;|
| Active Comparator: The schizophrenia patients with general auditory hallucinations<br>Drug intervention | Drug: Antipsychotic drugs<br>* Stable antipsychotic medication 4 weeks before and during the treatment. Chlorpromazine (CPZ) equivalent dosages were calculated for second- and first-generation antipsychotic drugs<br>* Other names: MRI scan;|
| No Intervention: The healthy controls<br>MRI scan at baseline and no drugs treatment | |
| Experimental: Drug + cTBS intervention: the first-episode schizophrenia patients with auditory hallucinations<br>Drug + cTBS intervention (the left temporoparietal cortex as the stimulation target) | Drug: Antipsychotic drugs<br>* Stable antipsychotic medication 4 weeks before and during the treatment. Chlorpromazine (CPZ) equivalent dosages were calculated for second- and first-generation antipsychotic drugs<br>* Other names: MRI scan;Device: cTBS（the left temporoparietal cortex as the stimulation target）<br>* Participants received 3 daily sessions of cTBS treatment. One session of cTBS was 40 seconds in duration and consisted of 3-pulse bursts at 50 Hz repeated every 200 milliseconds (5 Hz) until a total of 600 pulses was reached. To achieve cumulative aftereffects, this protocol was repeated 3 times and (1800 pulses in total) separated by two 15 minute breaks<br>* Other names: MRI scan;|
| Active Comparator: Drug intervention: the first-episode schizophrenia patients with auditory hallucinations<br>Drug intervention | Drug: Antipsychotic drugs<br>* Stable antipsychotic medication 4 weeks before and during the treatment. Chlorpromazine (CPZ) equivalent dosages were calculated for second- and first-generation antipsychotic drugs<br>* Other names: MRI scan;|
| Experimental: The schizophrenia patients with medication-resistant auditory hallucinations from the fourth arm<br>Drug + cTBS intervention (the left cerebellum Crus II as the stimulation target) | Drug: Antipsychotic drugs<br>* Stable antipsychotic medication 4 weeks before and during the treatment. Chlorpromazine (CPZ) equivalent dosages were calculated for second- and first-generation antipsychotic drugs<br>* Other names: MRI scan;Device: cTBS （the left cerebellum Crus II as the stimulation target）<br>* Participants received 3 daily sessions of cTBS treatment. One session of cTBS was 40 seconds in duration and consisted of 3-pulse bursts at 50 Hz repeated every 200 milliseconds (5 Hz) until a total of 600 pulses was reached. To achieve cumulative aftereffects, this protocol was repeated 3 times and (1800 pulses in total) separated by two 15 minute breaks<br>* Other names: MRI scan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psychotic Symptom Rating Scales-Auditory Hallucination Subscale (PSYRATS-AH) | The Psychotic Symptom Rating Scales-Auditory Hallucination Subscale (PSYRATS-AH) is an instrument designed to quantify the severity of hallucinations before and after treatment at different follow up point. Raw score range is 0-44. A higher score indicates a worse outcome. | From baseline to 10 weeks | 
| Structural and Function MRI data | A 3.0 T Siemens scanner was used to obtain the fMRI images in the Second Xiangya Hospital of Central South University.The MRI data wii be obtained before and after treatment at different follow up point. | From baseline to 10 weeks | 
| Positive and Negative Syndrome Scale (PANSS) | The PANSS total scores, subscale scores were used to evaluate the severity of psychotic symptoms for schizophrenia before and after treatment at different follow up point.The total score of the PANSS was more than 60.The higher scores mean a worse outcome. | From baseline to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Pre-post assessment of cognitive function via Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | From baseline to 10 weeks | 
| The Stroop test | Pre-post assessment of cognitive function via the Stroop test | From baseline to 10 weeks | 
| Wisconsin Card Sorting Test (WCST) | Pre-post assessment of cognitive function via Wisconsin Card Sorting Test (WCST) | From baseline to 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medication-Resistant Auditory Hallucinations, Continuous theta burst stimulation，cTBS, Neuroimaging