Generalized Anxiety Disorder (GAD) is a common psychiatric disorder associated with persistent anxiety, functional impairment, and incomplete response to existing treatments. Although transcranial magnetic stimulation (TMS) has shown therapeutic potential in anxiety disorders, conventional treatment schedules often require several weeks and may not provide sufficiently rapid symptom relief. This study aims to evaluate the efficacy and safety of precision-targeted accelerated continuous theta-burst stimulation (cTBS) guided by individualized functional connectivity between the intraparietal sulcus (IPS) and the amygdala in patients with GAD.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
75
Accelerated cTBS treatment was administered over 5 days, five times daily (1800 pulses per session, a total of 9000 pulses per day, with 50-minute intervals between sessions), at a stimulation intensity of 80%-120% of the resting motor threshold. The precise stimulation group targeted locations based on individual baseline functional MRI data, calculating the coordinates of strongest functional connectivity between the right IPS and the right basolateral amygdala (BLA), and implemented via neuronavigation system registration; the non-precise stimulation group targeted the cortical projection coordinates of the P4 electrode site according to the international 10-20 EEG system; the sham stimulation group used the same parameters but with a sham coil.
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline to Day 5
Anxiety symptom severity will be assessed using the Hamilton Anxiety Rating Scale (HAMA), a 14-item clinician-administered scale with a total score range of 0 to 56. Higher scores indicate greater anxiety symptom severity, which represents a worse outcome. The outcome will be calculated as the change in HAMA total score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Clinical Response Rate
Clinical response will be assessed using the Hamilton Anxiety Rating Scale (HAMA), a 14-item clinician-administered scale with a total score range of 0 to 56. Higher scores indicate greater anxiety symptom severity, which represents a worse outcome. Clinical response is defined as a reduction of at least 50% in HAMA total score compared with baseline.
Time frame: Day 3, Day 5, Week 2, Month 1, and Month 2 from baseline
Clinical Remission Rate
Clinical remission will be assessed using the Hamilton Anxiety Rating Scale (HAMA), a 14-item clinician-administered scale with a total score range of 0 to 56. Higher scores indicate greater anxiety symptom severity, which represents a worse outcome. Clinical remission is defined as a HAMA total score of 7 or less at the corresponding assessment time point.
Time frame: Day 3 , Day 5 , Week 2, Month 1, and Month 2 from baseline
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline
Anxiety symptom severity will be assessed using the Hamilton Anxiety Rating Scale (HAMA), a 14-item clinician-administered scale with a total score range of 0 to 56. Higher scores indicate greater anxiety symptom severity, which represents a worse outcome. The outcome will be calculated as the change in HAMA total score from baseline to each post-baseline assessment time point.
Time frame: Baseline, Day 3, Week 2, Month 1, and Month 2
Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score From Baseline
Depressive symptom severity will be assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17), a clinician-administered scale with a total score range of 0 to 52. Higher scores indicate greater depressive symptom severity, which represents a worse outcome. The outcome will be calculated as the change in HAMD-17 total score from baseline to each post-baseline assessment time point.
Time frame: Baseline, Day 3, Day 5, Week 2, Month 1, and Month 2 from baseline
Change in Beck Scale for Suicide Ideation (BSI) Score From Baseline
Suicidal ideation will be assessed using the Beck Scale for Suicide Ideation (BSI), a 19-item scale with a total score range of 0 to 38. Higher scores indicate more severe suicidal ideation, which represents a worse outcome. The outcome will be calculated as the change in BSI score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Generalized Anxiety Disorder-7 (GAD-7) Score From Baseline
Anxiety symptom severity will be assessed using the Generalized Anxiety Disorder-7 (GAD-7), a 7-item self-report questionnaire with a total score range of 0 to 21. Higher scores indicate greater anxiety symptom severity, which represents a worse outcome. The outcome will be calculated as the change in GAD-7 score from baseline to each post-baseline assessment time point.
Time frame: Baseline, Day 3, Day 5, Week 2 and Month 1 from baseline
Change in Patient Health Questionnaire-15 (PHQ-15) Score From Baseline
Somatic symptom severity will be assessed using the Patient Health Questionnaire-15 (PHQ-15), a 15-item self-report questionnaire with a total score range of 0 to 30. Higher scores indicate greater somatic symptom severity, which represents a worse outcome. The outcome will be calculated as the change in PHQ-15 score from baseline to each post-baseline assessment time point.
Time frame: Baseline, Day 3, Day 5, Week 2 and Month 1 from baseline
Change in Patient Health Questionnaire-9 (PHQ-9) Score From Baseline
Depressive symptom severity will be assessed using the Patient Health Questionnaire-9 (PHQ-9), a 9-item self-report questionnaire with a total score range of 0 to 27. Higher scores indicate greater depressive symptom severity, which represents a worse outcome. The outcome will be calculated as the change in PHQ-9 score from baseline to each post-baseline assessment time point.
Time frame: Baseline, Day 3, Day 5, Week 2 and Month 1 from baseline
Change in Pittsburgh Sleep Quality Index (PSQI) Score From Baseline
Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a self-report questionnaire with a global score range of 0 to 21. Higher scores indicate poorer sleep quality, which represents a worse outcome. The outcome will be calculated as the change in PSQI global score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Penn State Worry Questionnaire (PSWQ) Score From Baseline
Worry severity will be assessed using the Penn State Worry Questionnaire (PSWQ), a 16-item self-report questionnaire with a total score range of 16 to 80. Higher scores indicate greater worry severity, which represents a worse outcome. The outcome will be calculated as the change in PSWQ score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Intolerance of Uncertainty Scale (IUS) Score From Baseline
Intolerance of uncertainty will be assessed using the Intolerance of Uncertainty Scale (IUS), a 27-item self-report questionnaire with a total score range of 27 to 135. Higher scores indicate greater intolerance of uncertainty, which represents a worse outcome. The outcome will be calculated as the change in IUS score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Cognitive Test Performance From Baseline to Day 5
Cognitive function will be assessed using neurocognitive tests administered in this study. The score range depends on the specific cognitive test or task. For accuracy-based cognitive measures, higher scores indicate better cognitive performance, which represents a better outcome; for time-based measures such as reaction time, higher values indicate slower performance, which represents a worse outcome. The outcome will be calculated as the change in cognitive test performance from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in State-Trait Anxiety Inventory (STAI) Score From Baseline
Anxiety symptoms and anxiety proneness will be assessed using the State-Trait Anxiety Inventory (STAI), a 40-item self-report questionnaire consisting of the State Anxiety and Trait Anxiety subscales. Each subscale has a score range of 20 to 80. Higher scores indicate greater anxiety, which represents a worse outcome. The outcome will be calculated as the change in STAI score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Perceived Stress Scale-10 (PSS-10) Score From Baseline
Perceived stress will be assessed using the Perceived Stress Scale-10 (PSS-10), a 10-item self-report questionnaire with a total score range of 0 to 40. Higher scores indicate higher perceived stress, which represents a worse outcome. The outcome will be calculated as the change in PSS-10 score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Ruminative Responses Scale (RRS) Score From Baseline
Rumination will be assessed using the Ruminative Responses Scale (RRS), a 22-item self-report questionnaire with a total score range of 22 to 88. Higher scores indicate greater rumination, which represents a worse outcome. The outcome will be calculated as the change in RRS score from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Anxiety and Depression Visual Analogue Scale Scores From Baseline
Subjective anxiety and depression severity will be assessed using visual analogue scale ratings for anxiety and depression. Each visual analogue scale score ranges from 0 to 10, with higher scores indicating greater subjective symptom severity, which represents a worse outcome. The outcome will be calculated as the change in visual analogue scale scores from baseline to each post-baseline assessment time point.
Time frame: Baseline, Day 1, Day 3, Day 5 and Week 2 from baseline
Treatment-Emergent Side Effects During the Intervention and Follow-up Period
Treatment-emergent side effects will be assessed using a physical treatment side-effect assessment that records the presence, type, severity, and relationship to the study intervention of adverse events. This outcome will be summarized as the occurrence and severity of treatment-emergent side effects during the intervention and follow-up period; higher severity indicates a worse safety outcome.
Time frame: Day 1, Day 3, Day 5 and Week 2 from baseline
Change in Heart Rate Variability From Baseline to Day 5
Heart rate variability will be assessed to evaluate autonomic nervous system function. Heart rate variability parameters may include time-domain and frequency-domain measures such as the standard deviation of normal-to-normal intervals and the root mean square of successive differences. The expected range depends on the specific heart rate variability parameter. In general, higher heart rate variability reflects better autonomic flexibility and may represent a better physiological outcome. The outcome will be calculated as the change in heart rate variability measures from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Change in Magnetic Resonance Imaging Measures From Baseline to Day 5
Brain structural and/or functional measures will be assessed using magnetic resonance imaging. The specific values and ranges depend on the imaging modality and derived measure, such as structural, functional connectivity, or brain network metrics. Interpretation will depend on the specific magnetic resonance imaging measure analyzed. The outcome will be calculated as the change in magnetic resonance imaging measures from baseline to Day 5.
Time frame: Baseline and Day 5 (End of Treatment)
Dysfunctional Attitudes Scale (DAS) Score at Baseline
Dysfunctional attitudes will be assessed using the Dysfunctional Attitudes Scale (DAS), a 40-item self-report scale with a total score range of 40 to 280. Higher scores indicate more dysfunctional attitudes, which represents a worse psychological profile. This measure will be assessed at baseline.
Time frame: Baseline
Childhood Trauma Questionnaire (CTQ) Score at Baseline
Childhood trauma exposure will be assessed using the Childhood Trauma Questionnaire (CTQ), a 25-item self-report questionnaire with a total score range of 25 to 125. Higher scores indicate greater childhood trauma exposure, which represents a worse psychosocial profile. This measure will be assessed at baseline.
Time frame: Baseline
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