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

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.

• Change from Baseline in Hamilton Anxiety Rating Scale (HAMA) Total Score [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Baseline and immediately post-intervention (Week 1).]