MRI-Guided Accelerated cTBS for Generalized Anxiety Disorder

Generalized Anxiety Disorder (GAD) is one of the most prevalent psychiatric disorders worldwide and is characterized by excessive and persistent anxiety, impaired psychosocial functioning, and reduced quality of life. Despite the availability of pharmacological and psychological treatments, a substantial proportion of patients continue to experience clinically significant symptoms. Pharmacological therapies often require several weeks before therapeutic benefits emerge, while access to evidence-based psychotherapies remains limited in many settings. Therefore, there is a critical need for novel interventions capable of producing rapid and durable anxiolytic effects. Transcranial magnetic stimulation (TMS) has emerged as a promising non-invasive neuromodulation technique for the treatment of psychiatric disorders. Continuous theta-burst stimulation (cTBS), a patterned form of repetitive TMS, substantially reduces treatment duration while maintaining efficacy and safety comparable to conventional repetitive TMS protocols. Previous studies have demonstrated therapeutic benefits of cTBS in patients with anxiety disorders; however, conventional treatment courses typically extend over several weeks and may not achieve rapid symptom relief. Accelerated stimulation protocols involving multiple daily treatment sessions over a short period have shown encouraging clinical effects in other psychiatric populations, suggesting potential applicability to anxiety disorders. Neuroimaging studies have identified the right intraparietal sulcus (IPS) as a key cortical region involved in attentional control, vigilance, salience processing, and anxiety-related arousal. Functional interactions between the IPS and the amygdala are thought to play an important role in regulating emotional and anxiety-related processes. Individual variability in these neural circuits may contribute to heterogeneity in treatment response. Consequently, personalized stimulation targeting based on functional neuroimaging may improve therapeutic outcomes compared with conventional fixed-target approaches. The present study aims to investigate the efficacy and safety of precision-targeted accelerated cTBS guided by individualized IPS-amygdala functional connectivity in patients with GAD and to explore potential neurobiological mechanisms underlying treatment response. Participants who meet ICD-11 diagnostic criteria for GAD will be randomly assigned in a 1:1:1 ratio to one of three intervention groups: a precision cTBS group, a non-precision cTBS group, or a sham stimulation group. All participants will receive accelerated cTBS treatment for 5 consecutive days, with five stimulation sessions per day. Each session will deliver 1800 pulses, resulting in a total of 9000 pulses per day, with 50-minute intervals between sessions. Stimulation intensity will be set at 80%-120% of the resting motor threshold. In the precision cTBS group, baseline functional MRI data will be used to identify the right IPS coordinate exhibiting the strongest functional connectivity with the right basolateral amygdala (BLA), and stimulation will be delivered using neuronavigation-guided targeting. In the non-precision cTBS group, stimulation will target a fixed right parietal cortical projection coordinate corresponding to the P4 site reported in previous cranio-cerebral correlation studies of the international 10-20 EEG system. Participants in the sham group will undergo identical procedures using a sham coil. The primary outcome measure is the change in the total score of the Hamilton Anxiety Rating Scale (HAMA) from baseline to day 5. Secondary outcomes include clinical response and remission rates, changes in relevant clinical symptoms, adverse events occurring during treatment, and neuroimaging indicators. Assessments will be conducted at baseline, during treatment, and at week 2, month 1, and month 2 from baseline to evaluate short-term and sustained treatment effects.