Intermittent Theta Burst Stimulation of the Prefrontal Cortex in Social Anxiety Disorder

Intermittent Theta-Burst Stimulation Targeting the Prefrontal Cortex for Social Anxiety Disorder: A Randomized, Parallel-Group Comparative Study

This study aims to investigate the therapeutic effects of intermittent theta burst stimulation on social anxiety disorder and to track physiological changes in the brain using electroencephalography (EEG). Eligible SAD participants, after voluntarily signing an informed consent form, will first complete basic information collection, baseline questionnaire completion, and a pre-treatment EEG data collection session lasting approximately 30 minutes (including resting-state and task-state recordings). Subsequently, participants will be randomly assigned to one of three groups (left iTBS group, right iTBS group, or sham stimulation group) to receive intensive treatment for one week (4 sessions daily for 5 consecutive days, totaling 20 sessions). Immediately following the intervention, the research team will conduct post-treatment EEG data collection and gather questionnaire assessments. Participants will also undergo follow-up visits at weeks 2, 4, 6, and 8 post-treatment to complete questionnaires and report any adverse events. All study procedures are strictly and safely conducted by trained professionals. Participation is entirely voluntary, and participants may withdraw unconditionally at any time during the study.

Study Overview

• Status: Recruiting
• Conditions: Social Anxiety Disorder (SAD)
• Intervention / Treatment: Device: Active Intermittent Theta-Burst Stimulation (iTBS); Device: Sham Intermittent Theta-Burst Stimulation (iTBS)

Detailed Description

Social Anxiety Disorder (SAD) is a disabling psychiatric disorder characterized by intense fear and avoidance behaviors in social situations. Current pharmacological and psychological treatments are limited by insufficient response rates and a delayed onset of action. Intermittent theta-burst stimulation (iTBS), a novel non-invasive neuromodulation technique, offers advantages such as shorter stimulation duration and better tolerability; however, its precise targeting and clinical efficacy in SAD require high-quality evidence from randomized controlled trials (RCTs). This study aims to conduct a randomized, double-blind, sham-controlled clinical trial to investigate the clinical efficacy of an intensive iTBS protocol targeting the prefrontal cortex (PFC) in patients with SAD. Concurrently, the study will utilize electroencephalography (EEG) to objectively record participants' neurophysiological activities, aiming to elucidate the potential neuroelectrophysiological mechanisms underlying the iTBS-induced improvement of social anxiety symptoms and to explore objective biomarkers for predicting treatment response.

To strictly control confounding factors and ensure the double-blind design and participant safety, rigorous screening criteria have been established for this study. Inclusion criteria require participants to be right-handed individuals aged 16 to 70 years who meet the DSM-5 diagnostic criteria for SAD. If participants are taking psychiatric medications, their dosage must have been stable for at least 4 weeks prior to enrollment, and they must voluntarily sign an informed consent form. Exclusion criteria encompass patients with severe neurological or somatic diseases (e.g., epilepsy, central nervous system tumors, or stroke), those meeting DSM-5 criteria for other major psychiatric disorders, individuals with metallic implants or TMS contraindications, those with a previous history of TMS treatment, and those who have taken adequate doses of benzodiazepines for more than 2 weeks currently or within the past 4 weeks.

The study spans approximately 9 weeks, comprising 1 week of intensive intervention and 8 weeks of follow-up. Upon enrollment, participants will first complete the collection of demographic data and baseline clinical scales, followed by a 30-minute pre-test of resting-state and task-state EEG. Subsequently, participants will be randomly assigned in a double-blind manner to the Left PFC-iTBS group, Right PFC-iTBS group, or Sham group. They will receive a 1-week intensive intervention at an intensity of 120% of the resting motor threshold (RMT), administered 4 times a day for 5 consecutive days, totaling 20 sessions. Immediately following the 1-week intervention, the research team will conduct an EEG post-test and synchronously collect scale data and record any adverse events. Thereafter, participants are required to attend regular follow-up visits at weeks 2, 4, 6, and 8 post-intervention to determine the long-term maintenance effects of the treatment.

Regarding outcome assessments, this study establishes a multidimensional evaluation system integrating clinical scales with objective electrophysiological measures. The primary clinical outcome measure is the Liebowitz Social Anxiety Scale (LSAS), which will be assessed at baseline, immediately post-intervention, and at all follow-up time points. Secondary clinical indicators include the Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), and a cognitive function assessment scale. Furthermore, the study will extract resting-state and task-state EEG features and conduct brain functional network analysis as key neurophysiological outcome measures to comprehensively evaluate changes in cerebral physiological states.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Han Yang, PhD; Phone Number: +8613314590507; Email: yang_han_life@163.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310013
      • Recruiting
      • Second Affiliated Hospital, School of Medicine, Zhejiang University
      • Contact: Zhiying MD Wu; Phone Number: +86 0571 87783759; Email: keyanlunli_zheer@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Eligible participants must be right-handed individuals aged 16 to 70 years who meet the diagnostic criteria for Social Anxiety Disorder (SAD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). If participants are taking concurrent psychiatric medications, their dosage must have been stable for at least 4 weeks prior to enrollment. Additionally, all individuals must voluntarily agree to participate in the study and provide written informed consent.

Exclusion Criteria: Individuals will be excluded if they have a history of neurological disorders or other severe somatic diseases, including but not limited to seizures, central nervous system tumors, stroke, or brain aneurysms. Participants meeting DSM-5 diagnostic criteria for other primary psychiatric disorders-such as schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, other anxiety disorders, obsessive-compulsive and related disorders, or somatic symptom and related disorders-are also ineligible. Furthermore, the study excludes those with metallic implants in the head or neck, any other clear contraindications to Transcranial Magnetic Stimulation (TMS), or a previous history of receiving TMS treatment, which is restricted to prevent potential unblinding. Finally, current use, or use within the past 4 weeks, of adequate doses of benzodiazepines for more than 2 weeks is an exclusion criterion, as it may limit the therapeutic efficacy of TMS.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Left PFC-iTBS; Participants will receive active intermittent theta-burst stimulation (iTBS) targeting the left prefrontal cortex.	Device: Active Intermittent Theta-Burst Stimulation (iTBS); Active iTBS is delivered using a real "figure-8" coil targeting the prefrontal cortex. Stimulation is delivered at 120% of the resting motor threshold (RMT). The protocol consists of 3 sets of 50 Hz pulses repeated at 5 Hz (2s on, 8s off), totaling 1,800 pulses per session. The intensive treatment schedule includes 4 sessions per day for 5 consecutive days (1 week), totaling 20 sessions.
Experimental: Right PFC-iTBS; Participants will receive active intermittent theta-burst stimulation (iTBS) targeting the right prefrontal cortex.	Device: Active Intermittent Theta-Burst Stimulation (iTBS); Active iTBS is delivered using a real "figure-8" coil targeting the prefrontal cortex. Stimulation is delivered at 120% of the resting motor threshold (RMT). The protocol consists of 3 sets of 50 Hz pulses repeated at 5 Hz (2s on, 8s off), totaling 1,800 pulses per session. The intensive treatment schedule includes 4 sessions per day for 5 consecutive days (1 week), totaling 20 sessions.
Sham Comparator: Sham iTBS; Participants will receive sham intermittent theta-burst stimulation (iTBS) targeting the prefrontal cortex.	Device: Sham Intermittent Theta-Burst Stimulation (iTBS); Sham iTBS is delivered using a visually identical sham "figure-8" coil. It produces similar acoustic clicks and scalp somatic sensations to mimic the active treatment, ensuring participant blinding. However, it uses same-direction currents causing opposing central currents, resulting in near-zero focal magnetic induction without therapeutic effect. The session schedule and apparent parameters strictly match the active group (4 sessions/day for 5 days).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Liebowitz Social Anxiety Scale (LSAS) Total Score	The LSAS is used to assess the severity of social anxiety symptoms by evaluating fear and avoidance across multiple social and performance situations. The total score ranges from 0 to 144. Higher scores indicate greater severity of social anxiety symptoms (worse outcome).	Baseline, immediately post-intervention (Week 1), and at Weeks 2, 4, 6, and 8 post-intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Hamilton Anxiety Rating Scale (HAMA) Total Score	The HAMA assesses the severity of generalized anxiety symptoms, encompassing both psychological and somatic anxiety. The total score ranges from 0 to 56. Higher scores indicate more severe anxiety symptoms (worse outcome).	Baseline, immediately post-intervention (Week 1), and at Weeks 2, 4, 6, and 8 post-intervention.
Change from Baseline in Hamilton Depression Rating Scale (HAMD) Total Score	The HAMD is used to evaluate the severity of depressive symptoms. The 17-item version total score ranges from 0 to 52. Higher scores indicate more severe depressive symptoms (worse outcome).	Baseline, immediately post-intervention (Week 1), and at Weeks 2, 4, 6, and 8 post-intervention.
Change from Baseline in Pittsburgh Sleep Quality Index (PSQI) Score	The PSQI assesses subjective sleep quality and disturbances over the past month. The global score ranges from 0 to 21. Higher scores indicate poorer sleep quality, with scores greater than 5 indicative of severe sleep difficulties (worse outcome).	Baseline, immediately post-intervention (Week 1), and at Weeks 2, 4, 6, and 8 post-intervention.
Change from Baseline in Resting-State and Task-State Electroencephalogram (EEG) Metrics	EEG will be used to measure neurophysiological brain activity. The specific metrics include changes in resting-state power (such as Alpha and Theta frequency bands) over the prefrontal cortex, as well as changes in the amplitudes of event-related potentials (ERPs) during cognitive tasks. These metrics serve as objective markers to evaluate the cortical activity changes induced by the iTBS intervention.	Baseline and immediately post-intervention (Week 1).

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Investigators: Principal Investigator: Lei Lei Zheng, MD, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 4, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation; Prefrontal Cortex; Social Anxiety Disorder; Intermittent Theta-Burst Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Phobic Disorders; Anxiety Disorders; Phobia, Social
• Other Study ID Numbers: 2025-1128

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) that underlie the results reported in this article will be shared. This includes clinical assessment scores and extracted neurophysiological (EEG) feature data.
• IPD Sharing Time Frame: Data will become available beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Data will be shared with researchers who provide a methodologically sound proposal to achieve aims in the approved proposal. Proposals should be directed to the corresponding author. To gain access, data requestors will need to sign a formal data access agreement, ensuring compliance with local data protection regulations regarding sensitive psychiatric data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No