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.

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 neuroplasticity 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. Schizophrenia inpatients with predominant negative symptoms 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, TEPs ,multi-modal MRI and rs-EEG 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.

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.