Precise Intervention Technology and Application of Low Intensity TUS on Negative Symptoms of Schizophrenia

Study Overview
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Brief Summary
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Based on the current background and our previous studies, TUS has been proved that rTUS intervention could induce long-term potentiation like (LTP-like) plasticity and neuromodulate the brain cortex in schizophrenia patients. rTUS over the left dorsolateral prefrontal cortex (DLPFC) can alleviate the negative symptoms in schizophrenia. In this double-blind, randomized, sham-controlled study, the efficacy of different treatment options and mechanisms of low-intensity rTUS on negative symptoms will be investigated.

Detailed Description
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Negative symptoms is a core symptom of schizophrenia related to poor functional outcome which remains largely treatment refractory. Prior studies indicated that abnormalities in the prefrontal-temporal circuit and glutamate/GABA imbalances may be the root causes of negative symptoms. Transcranial ultrasound stimulation (TUS), an emerging non-invasive neuromodulation technique, can modulate neural excitability and plasticity in the prefrontal and temporal cortex. In this double-blind, randomized, sham-controlled study, the efficacy of different treatment options and mechanisms of low-intensity rTUS on negative symptoms will be investigated. A total of 102 schizophrenia inpatients will be recruited and randomly allocated into single-target group (left DLPFC), both-target group (both left DLPFC and right STG) or sham group in ratio of 1:1:1. This study aims to determine the efficacy of TUS and to reveal its underlying neural mechanism. MEPs, fNIRS ,and multi-modal MRI will be detected. Neuropsychological assessments will also be conducted to develop the optimized treatment strategy. The study points to a novel and promising therapeutic neuromodulation approach that may improve the functional outcome of schizophrenia, which has been the main cause of mental disability.

Official Title
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Precise Intervention Technology and Application of Low Intensity Transcranial Ultrasound Stimulation (TUS) on Negative Symptoms of Schizophrenia

Conditions
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Negative Symptoms of Schizophrenia

Intervention / Treatment
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* Device: low-intensity transcranial ultrasound stimulation (TUS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet the DSM-5 diagnostic criteria for schizophrenia or schizoaffective disorder; Age18-50, right-handed, Han nationality; Score of at least 1 item from N1 to N7 in PANSS is ≥4 (moderate or above); Be in a stable condition, received second-generation antipsychotics for at least 4 weeks or more; Written informed consent; Exclusion Criteria: Current or past neurological illness, severe physical diseases, substance abuse or alcohol dependence, mental retardation, pregnant or lactation; Uncooperative or risky patients with high excitement, stupor, disorder of words and deeds, negative suicide, etc.; History of MECT or other physical therapy within 6 months; History of epilepsy, or epileptic waves on the baseline EEG; Ruled out share antiepileptic drugs, carbamazepine, valproic acid salt) or larger doses of benzodiazepines drugs (> 10 mg/day, diazepam clonazepam 2 mg/day, 1 mg/day, alprazolam lorazepam 2 mg/day, midazolam 10 mg/day, 20 mg/day, Mr Shah diazepam triazolam 0.5 mg/day), avoid the use of chlorine drug, (in principle, to avoid the use of antiepileptic drugs and clonazepam;Other antipsychotic drugs, if necessary, remain unchanged during the course of treatment; Contraindications to TUS and MRI are present.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: single-target group (left DLPFC)<br>34 eligible patients will be treated with active TUS for 4 weeks on the left DLPFC | Device: low-intensity transcranial ultrasound stimulation (TUS)<br>* The rTUS was administered using an immersion-type focused ultrasound transducer (V391-SU, Olympus NDT, Waltham, USA). Low-intensity transcranial ultrasound stimulation on the target. Duration:20 days (workdays for four consecutive weeks).<br>|
| Active Comparator: both-target group (both left DLPFC and right STG)<br>34 eligible patients will be treated with active TUS for 4 weeks on the both left DLPFC and right STG | Device: low-intensity transcranial ultrasound stimulation (TUS)<br>* The rTUS was administered using an immersion-type focused ultrasound transducer (V391-SU, Olympus NDT, Waltham, USA). Low-intensity transcranial ultrasound stimulation on the target. Duration:20 days (workdays for four consecutive weeks).<br>|
| Sham Comparator: sham group<br>34 eligible patients will be treated with sham TUS for 4 weeks on the left DLPFC | Device: low-intensity transcranial ultrasound stimulation (TUS)<br>* The rTUS was administered using an immersion-type focused ultrasound transducer (V391-SU, Olympus NDT, Waltham, USA). Low-intensity transcranial ultrasound stimulation on the target. Duration:20 days (workdays for four consecutive weeks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Scale for Assessment of Negative Symptoms(SANS) | Change from baseline in the Scale for Assessment of Negative Symptoms(SANS) at 4 weeks and 8 weeks. The minimum to maximum value is 0-120. Lower scores mean a better outcome. | baseline, 4 weeks and 8 weeks | 
| Change from baseline in Positive and Negative Syndrome Scale(PANSS) | Change from baseline in Positive and Negative Syndrome Scale(PANSS) at 4 weeks and 8 weeks. The minimum to maximum value is 30-210. Lower scores mean a better outcome. | baseline, 4 weeks and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Function | Change from baseline in MATRICS MCCB | baseline, 4 weeks and 8 weeks | 
| Change of Multi-modal Brain Neuroimaging in structure | Brain structure data will be acquired. | baseline and 4 weeks | 
| Change of Multi-modal Brain Neuroimaging in resting- state fMRI | Resting-state fMRI data will be acquired. | baseline and 4 weeks | 
| Change of Multi-modal Brain Neuroimaging in 1H-MRS | 1H-MRS data will be acquired. | baseline and 4 weeks | 
| Change of functional near-infrared spectroscopy (fNIRS) | Functional near-infrared spectroscopy (fNIRS), a non-invasive neuroimaging technique that reflects changes in Oxy-Hb and Deoxy-Hb during brain activity, will be measured on left M1 region at baseline to evaluate the neuromodulation effect of TUS on neural activity. | baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Negative Symptoms, Transcranial Ultrasound Stimulation