Efficacy and Mechanisms of TUS on Cognitive Deficits in Schizophrenia: Based on the Hippocampal-Prefrontal Circuit

Efficacy and Mechanisms of Transcranial Ultrasound Stimulation (TUS) on Cognitive Deficits in Schizophrenia：based on the Hippocampal-Prefrontal Circuit

Cognitive deficit is a core symptom of schizophrenia related to poorer functional outcome. Prior studies indicated that abnormalities in the hippocampus-prefrontal circuit and glutamate/GABA imbalances may lead to cognitive deficits. Based on the current background and our previous studies, it has been proved that TUS can modulate neural excitability and plasticity in the hippocampus. In this double-blind, randomized study, the efficacy of different treatment options and mechanisms of TUS on cognitive deficits will be investigated.

Study Overview

• Status: Not yet recruiting
• Conditions: Cognitive Deficit in Schizophrenia
• Intervention / Treatment: Device: Transcranial ultrasound stimulation

Detailed Description

Cognitive deficit is a core symptom of schizophrenia related to poorer functional outcome which remains largely treatment refractory. Prior studies indicated that abnormalities in the hippocampus-prefrontal circuit and glutamate/GABA imbalances may be the root causes of cognitive deficits. Transcranial ultrasound stimulation (TUS), an emerging non-invasive neuromodulation technique with deep penetration ability, can modulate neural excitability and plasticity in the hippocampus. This is a 4-week double-blind randomized trial of TUS for cognitive deficits in schizophrenia, with either left hippocampus or left dorsolateral prefrontal cortex (DLPFC) or both targeted. This study aims to determine the efficacy of TUS and to reveal its underlying neural mechanism, especially with the hippocampus-prefrontal circuit, by means of TUS, as to assess cortical inhibition and excitability, EEG source imaging, and multi-model MRI. 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.

• Study Type: Interventional
• Enrollment (Estimated): 105
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dengtang LIU; Phone Number: 021-34773434; Email: liudengtang@smhc.org.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200030
      • Shanghai Mental Health Center
      • Contact: Dengtang LIU; Phone Number: 021-34773434; Email: liudengtang@smhc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Meet the DSM-5 diagnostic criteria for schizophrenia ;
• Age18-50, right-handed, Han nationality;
• Presence of cognitive deficit: defined as d' value <0.5 in associative memory test;
• 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, pregnancy 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 benzodiazepine drugs (diazepam > 10mg/day, clonazepam > 2mg/day etc.), if necessary, remain unchanged during the course of treatment;
• Contraindications to TUS and MRI are present.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: single target group : left DLPFC; 35 eligible patients will be treated with active TUS for 4 weeks on the left DLPFC	Device: Transcranial ultrasound stimulation; The TUS was administered using Transcranial Ultrasound Stimulator UNS-III (model UNS-III), which has passed the safety test for medical electrical equipment (GB9706.1-2007). Transcranial ultrasound stimulation on the target. Duration:20 days (workdays for four consecutive weeks).
Active Comparator: single target group : left hippocampus; 35 eligible patients will be treated with active TUS for 4 weeks on the left hippocampus	Device: Transcranial ultrasound stimulation; The TUS was administered using Transcranial Ultrasound Stimulator UNS-III (model UNS-III), which has passed the safety test for medical electrical equipment (GB9706.1-2007). Transcranial ultrasound stimulation on the target. Duration:20 days (workdays for four consecutive weeks).
Active Comparator: both-target group : left DLPFC and left hippocampus; 35 eligible patients will be treated with active TUS for 4 weeks on the left DLPFC and left hippocampus	Device: Transcranial ultrasound stimulation; The TUS was administered using Transcranial Ultrasound Stimulator UNS-III (model UNS-III), which has passed the safety test for medical electrical equipment (GB9706.1-2007). Transcranial ultrasound stimulation on the target. Duration:20 days (workdays for four consecutive weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in associative memory test score	Change from baseline in the associative memory test score at 4 weeks and 8 weeks.	baseline, 4 weeks and 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 information processing speed and attention/vigilance	Change from baseline in 4 MCCB subtests score at 4 weeks and 8 weeks.	baseline, 4 weeks and 8 weeks
Change of working memory	Change from baseline in N-back task at 4 weeks and 8 weeks. The outcome measures include accuracy, D-prime value, and reaction time.	baseline, 4 weeks and 8 weeks
Change of CGI score	Change from baseline in Clinical Global Impression (CGI) at 4 weeks and 8 weeks.	baseline, 4 weeks and 8 weeks
Change from baseline in UCSD Performance-based Skills Assessment-Brief (UPSA-B)	Change from baseline in UCSD Performance-based Skills Assessment-Brief (UPSA-B) at 4 weeks and 8 weeks.	baseline, 4 weeks and 8 weeks
Change of TEPs	TMS-evoked potentials (TEPs) from target regions will be measured in participants at baseline, after a single TUS intervention, and at 4 weeks. The study aimed to clarify the effects of TUS treatment on the components of TEPs in individuals with schizophrenia, as well as the association between changes in TEP components and cognitive deficits.	baseline and 4 weeks
Change of 64 channels EEG	64 channels EEG data will be acquired.	baseline and 4 weeks

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: March 25, 2025
• First Submitted That Met QC Criteria: March 25, 2025
• First Posted (Actual): April 1, 2025

Study Record Updates

• Last Update Posted (Actual): April 1, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Schizophrenia; Cognitive Deficit; Transcranial Ultrasound Stimulation; Hippocampus- Prefrontal Circuit
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Neurocognitive Disorders; Schizophrenia; Cognitive Dysfunction; Cognition Disorders
• Other Study ID Numbers: 82371504

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