Repetitive Transcranial Magnetic Stimulation in Early Psychosis and The Functional Connectivity Biotypes

Repetitive Transcranial Magnetic Stimulation in Subjects With Early Psychosis and The Functional Connectivity Biotypes

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.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Psychosis; Clinical High Risk; First Episode Psychosis
• Intervention / Treatment: Device: repetitive transcranial magnetic stimulation (rTMS)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jijun Wang, M.D, Ph.D; Phone Number: 86-21-34773065; Email: jijunwang27@163.com

Study Locations

• China
  • Shenzhen, China
    • Recruiting
    • Shenzhen Kangning Hospital
    • Contact: Lingyun Zeng
  • Tianjin, China
    • Recruiting
    • Tianjin Anding Hospital
    • Contact: Bin Zhang
  • Guangdong
    • Guangzhou, Guangdong, China
      • Not yet recruiting
      • The Affiliated Brain Hospital of Guangzhou Medical University
      • Contact: Liping Cao
  • Jiang Su
    • Nantong, Jiang Su, China, 226000
      • Recruiting
      • Nantong Fourth People's Hospital & Nantong Brain Hospital
      • Contact: Xing Chen
  • Jiangsu
    • Suzhou, Jiangsu, China
      • Recruiting
      • SuZhou GuangJi Hospital
      • Contact: Li Hui, PhD
  • Shanghai
    • Shanghai, Shanghai, China, 200030
      • Recruiting
      • Shanghai Mental Health Center
      • Contact: Jijun Wang, MD, PhD; Email: jijunwang27@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active TMS targeting both cerebellum and right dorsolateral prefrontal cortex.; Subjects identified as with prominent negative symptoms will be randomized into active group, who will receive active rTMS over cerebellum and right dorsolateral prefrontal cortex navigated by individual MRI.	Device: repetitive transcranial magnetic stimulation (rTMS); All subjects with early psychosis will be divided into three subgroups determined by their psychotic symptoms and cognition. There are three rTMS strategies: (1) For subgroup 1, characterized by negative symptoms, iTBS over cerebellum and 1 Hz over right DLPFC; (2) For subgroup 2, characterized by cognition deficits, 20 Hz over the left inferior parietal cortex; (3) For subgroup 3, characterized by positive symptoms: 10 Hz over ACC. Ten to twenty sessions of rTMS will be delivered to each patients during the intervention period.
Sham Comparator: Sham TMS targeting both cerebellum and right dorsolateral prefrontal cortex; Subjects identified as with prominent negative symptoms will be randomized into sham group, who will receive sham rTMS over cerebellum and right dorsolateral prefrontal cortex navigated by individual MRI.	Device: repetitive transcranial magnetic stimulation (rTMS); All subjects with early psychosis will be divided into three subgroups determined by their psychotic symptoms and cognition. There are three rTMS strategies: (1) For subgroup 1, characterized by negative symptoms, iTBS over cerebellum and 1 Hz over right DLPFC; (2) For subgroup 2, characterized by cognition deficits, 20 Hz over the left inferior parietal cortex; (3) For subgroup 3, characterized by positive symptoms: 10 Hz over ACC. Ten to twenty sessions of rTMS will be delivered to each patients during the intervention period.
Active Comparator: Active TMS targeting left inferior parietal lobule; Subjects identified with prominent cognition deficits wil be randomized into active group, who will receive active rTMS over left inferior parietal lobule, navigated by individual MRI and functional connectivity map with left hippocampus.	Device: repetitive transcranial magnetic stimulation (rTMS); All subjects with early psychosis will be divided into three subgroups determined by their psychotic symptoms and cognition. There are three rTMS strategies: (1) For subgroup 1, characterized by negative symptoms, iTBS over cerebellum and 1 Hz over right DLPFC; (2) For subgroup 2, characterized by cognition deficits, 20 Hz over the left inferior parietal cortex; (3) For subgroup 3, characterized by positive symptoms: 10 Hz over ACC. Ten to twenty sessions of rTMS will be delivered to each patients during the intervention period.
Placebo Comparator: Sham TMS targeting left inferior parietal lobule; Subjects identified with prominent cognition deficits wil be randomized into sham group, who will receive sham rTMS over left inferior parietal lobule, navigated by individual MRI and functional connectivity map with left hippocampus.	Device: repetitive transcranial magnetic stimulation (rTMS); All subjects with early psychosis will be divided into three subgroups determined by their psychotic symptoms and cognition. There are three rTMS strategies: (1) For subgroup 1, characterized by negative symptoms, iTBS over cerebellum and 1 Hz over right DLPFC; (2) For subgroup 2, characterized by cognition deficits, 20 Hz over the left inferior parietal cortex; (3) For subgroup 3, characterized by positive symptoms: 10 Hz over ACC. Ten to twenty sessions of rTMS will be delivered to each patients during the intervention period.
Active Comparator: Active deep TMS using Brainways H7 coil targeting ACC; Subjects identified as with positive symptoms will be randomized into active group, who will receive active deep rTMS over ACC using H7 coil.	Device: repetitive transcranial magnetic stimulation (rTMS); All subjects with early psychosis will be divided into three subgroups determined by their psychotic symptoms and cognition. There are three rTMS strategies: (1) For subgroup 1, characterized by negative symptoms, iTBS over cerebellum and 1 Hz over right DLPFC; (2) For subgroup 2, characterized by cognition deficits, 20 Hz over the left inferior parietal cortex; (3) For subgroup 3, characterized by positive symptoms: 10 Hz over ACC. Ten to twenty sessions of rTMS will be delivered to each patients during the intervention period.
Placebo Comparator: Sham deep TMS using Brainways H7 coil targeting ACC; Subjects identified with positive symptoms will be randomized into sham group, who will receive sham deep rTMS over ACC using H7 coil.	Device: repetitive transcranial magnetic stimulation (rTMS); All subjects with early psychosis will be divided into three subgroups determined by their psychotic symptoms and cognition. There are three rTMS strategies: (1) For subgroup 1, characterized by negative symptoms, iTBS over cerebellum and 1 Hz over right DLPFC; (2) For subgroup 2, characterized by cognition deficits, 20 Hz over the left inferior parietal cortex; (3) For subgroup 3, characterized by positive symptoms: 10 Hz over ACC. Ten to twenty sessions of rTMS will be delivered to each patients during the intervention period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate (the number of non-responders) for subgroup 1 and subgroup 3	Response or responder will be determined by the reduction of PANSS total scores >= 25%	Within 24 hours after the rTMS intervention
Improvement on cognition for subgroup 2	Change in BVMT-R score as measured by MCCB	Within 24 hours after the rTMS intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
side effect and safety	the frequency and severity of side effects	during and after rTMS intervention
clinical outcome	remission, non-remission or relapse	1 year
Improvement of psychotic symptoms	The changes of PANSS scores and sub-scale scores	Within 24 hours after the rTMS intervention
Improvement of prodromal symptoms	The changes of SOPS scores and sub-scale scores	Within 24 hours after the rTMS intervention
Improvement of cognitive function	The changes of all cognitive domains assessed by MCCB	Within 24 hours after the rTMS intervention
Improvement of global functioning	The GAF changes	Within 24 hours after the rTMS intervention
Functional connectivity	changes of whole-brain functional connectivity patterns	Within 1week after the rTMS intervention
The accuracy of prediction with functional connectivity biotypes at baseline	The association of clinical outcomes after rTMS intervention with functional connectivity biotypes at baseline	1 year
change in individualized psychosis risk score	For subjects at clinical high risk of psychosis, individualized psychosis risk score will be calculated using clinical symptoms and cognition, which indicate the psychosis risk in the future.	Within 24 hours after the rTMS intervention

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine
• Collaborators: Guangzhou Psychiatric Hospital; Suzhou Psychiatric Hospital; Tianjin Anding Hospital; Shenzhen Kangning Hospital; Nantong Fourth People's Hospital & Nantong Brain Hospital
• Investigators: Principal Investigator: Jijun Wang, M.D., Ph.D, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine

Publications and helpful links

General Publications

• Brady RO Jr, Gonsalvez I, Lee I, Ongur D, Seidman LJ, Schmahmann JD, Eack SM, Keshavan MS, Pascual-Leone A, Halko MA. Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia. Am J Psychiatry. 2019 Jul 1;176(7):512-520. doi: 10.1176/appi.ajp.2018.18040429. Epub 2019 Jan 30.
• Cui H, Giuliano AJ, Zhang T, Xu L, Wei Y, Tang Y, Qian Z, Stone LM, Li H, Whitfield-Gabrieli S, Niznikiewicz M, Keshavan MS, Shenton ME, Wang J, Stone WS. Cognitive dysfunction in a psychotropic medication-naive, clinical high-risk sample from the ShangHai-At-Risk-for-Psychosis (SHARP) study: Associations with clinical outcomes. Schizophr Res. 2020 Dec;226:138-146. doi: 10.1016/j.schres.2020.06.018. Epub 2020 Jul 18.
• Wang J, Zhou Y, Gan H, Pang J, Li H, Wang J, Li C. Efficacy Towards Negative Symptoms and Safety of Repetitive Transcranial Magnetic Stimulation Treatment for Patients with Schizophrenia: A Systematic Review. Shanghai Arch Psychiatry. 2017 Apr 25;29(2):61-76. doi: 10.11919/j.issn.1002-0829.217024.
• Zhuo K, Tang Y, Song Z, Wang Y, Wang J, Qian Z, Li H, Xiang Q, Chen T, Yang Z, Xu Y, Fan X, Wang J, Liu D. Repetitive transcranial magnetic stimulation as an adjunctive treatment for negative symptoms and cognitive impairment in patients with schizophrenia: a randomized, double-blind, sham-controlled trial. Neuropsychiatr Dis Treat. 2019 May 8;15:1141-1150. doi: 10.2147/NDT.S196086. eCollection 2019.
• Tang Y, Jiao X, Wang J, Zhu T, Zhou J, Qian Z, Zhang T, Cui H, Li H, Tang X, Xu L, Zhang L, Wei Y, Sheng J, Liu L, Wang J. Dynamic Functional Connectivity Within the Fronto-Limbic Network Induced by Intermittent Theta-Burst Stimulation: A Pilot Study. Front Neurosci. 2019 Sep 13;13:944. doi: 10.3389/fnins.2019.00944. eCollection 2019.
• Tang Y, Xu L, Zhu T, Cui H, Qian Z, Kong G, Tang X, Wei Y, Zhang T, Hu Y, Sheng J, Wang J. Visuospatial Learning Selectively Enhanced by Personalized Transcranial Magnetic Stimulation over Parieto-Hippocampal Network among Patients at Clinical High-Risk for Psychosis. Schizophr Bull. 2023 Jul 4;49(4):923-932. doi: 10.1093/schbul/sbad015.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: March 31, 2021
• First Submitted That Met QC Criteria: April 18, 2021
• First Posted (Actual): April 21, 2021

Study Record Updates

• Last Update Posted (Actual): December 29, 2023
• Last Update Submitted That Met QC Criteria: December 21, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: schizophrenia; prodromal phase; biotypes; precision calculation; target optimizing
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Mental Disorders
• Other Study ID Numbers: CRC2018ZD01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No