The present study plans to explore different cortical targets of repetitive transcranial magnetic stimulation (rTMS) for populations at the early phase of psychosis, including those at clinical high risk of psychosis and in the first episode of psychosis. The clinical augmentation efficacy will be associated with the brain functional connectivity of these populations.

Schizophrenia is a life long illness, the management of its early stage is the key in its long term outcomes. The early stage of schizophrenia includes the prodromal and first episode, during which the patients present psychotic symptoms (positive symptoms, negative symptoms) and cognition deficits. Antipsychotics are often prescribed to treat these symptoms, but more than one third patients do not respond well. Regarding cognition deficits, for example, while the visual spatial learning evaluated using Brief Visuospatial Memory Test-Revised (BVMT-R) of The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) may play an important role in the conversion of psychosis in the prodromal phase, there is still no corresponding intervention.

Repetitive transcranial magnetic stimulation (rTMS) is a new non-invasive brain stimulation. In previous studies, its applications mainly focus on negative symptoms and demonstrate promising findings. However, its efficacy has much needing improvement, urgently needing target optimizing and precision, especially according to the prominent complaints of patients. To solve this issue, the present project proposed to make efforts in 3 aspects: to recruit patients in early phase of illness, to administer rTMS of different protocols according to the symptoms and cognition, and to associate the biotypes of functional connectivity with rTMS's efficacy. All subjects will receive MRI scan before rTMS intervention in the present study. The clinical efficacy of rTMS of the present protocol will be applied to validate the biotypes of functional connectivity in early psychosis. The biotypes will be determined using an existing independent dataset, which include 650 available cases of resting MRI (including 400 patients in prodromal phase, 100 patients with first episode and 150 controls).

Individual rTMS target will be optimized basing individual neuroimaging navigation. In the present protocol, we will recruit 300 new cases and perform a multicenter and randomized clinical trial to test the efficacy of our optimized rTMS protocols. All patients will be stratified according to their negative symptoms, positive symptom and cognition, and this will be determined by a panel of psychiatrists and rTMS therapists. It is estimated that about 100 cases in each of three subgroups. Subgroup 1 is characterized by prominent negative symptoms and will receives rTMS over cerebellum and right dorsolateral prefrontal cortex. Subgroup 2 is characterized by prominent cognition deficits and will receive rTMS over left inferior parietal lobule, navigated by individual MRI and functional connectivity map with left hippocampus. Subgroup 3 is characterized by positive symptoms and will receive deep rTMS over ACC using H7 coil. The present project, if being performed successfully, will promote the non-invasive physical therapy in psychiatry to a significantly higher level.

For subjects at clinical high-risk for psychosis

Inclusion Criteria:

• Meeting the syndrome of clinical high risk of psychosis, identified by a face-to-face interview using the Chinese version of Structured Interview for Prodromal Syndromes / Scale of Prodromal Symptoms (SIPS/SOPS);
• Given the written consent for participation.
• Age between 14-45 years old;
• IQ>69;
• PANSS total scores >= 55 or BVMT-R score <= 26;

Exclusion Criteria:

• any contraindication to TMS treatment or magnetic resonance imaging (MRI)
• substance or alcohol abuse within recent three months
• any sensorimotor disorder (e.g., hearing disorder, lose one's sight), or any neurological disease (brain injury, epilepsy ) or any other physical disease which may lead to psychotic symptoms.

For subjects with first-episode schizophrenia

Inclusion Criteria:

• Meeting the DSM-V diagnostic criteria for schizophrenia spectrum disorders;
• Given the written consent for participation.
• Age between 14-45 years old;
• IQ>69;
• during the first episode without a full remission;
• PANSS total scores >= 55 or BVMT-R score <= 26;
• within receiving rTMS, patients can receive second-generation antipsychotics except clozapine with stable dosages

Exclusion Criteria:

• any contraindication to TMS treatment or magnetic resonance imaging (MRI)
• substance or alcohol abuse within recent three months
• any sensorimotor disorder (e.g., hearing disorder, lose one's sight), or any neurological disease (brain injury, epilepsy) or any other physical disease which may lead to psychotic symptoms.