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.

• continuous theta burst stimulation(cTBS) (Device): 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.

Primary outcomes

• Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline to Day 5 [Baseline and Day 5 (End of Treatment)]: 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.

Secondary outcomes

• Clinical Response Rate [Day 3, Day 5, Week 2, Month 1, and Month 2 from baseline]: 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.
• Clinical Remission Rate [Day 3 , Day 5 , Week 2, Month 1, and Month 2 from baseline]: 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.
• Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline [Baseline, Day 3, Week 2, Month 1, and Month 2]: 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.
• Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score From Baseline [Baseline, Day 3, Day 5, Week 2, Month 1, and Month 2 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.
• Change in Beck Scale for Suicide Ideation (BSI) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Generalized Anxiety Disorder-7 (GAD-7) Score From Baseline [Baseline, Day 3, Day 5, Week 2 and Month 1 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.
• Change in Patient Health Questionnaire-15 (PHQ-15) Score From Baseline [Baseline, Day 3, Day 5, Week 2 and Month 1 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.
• Change in Patient Health Questionnaire-9 (PHQ-9) Score From Baseline [Baseline, Day 3, Day 5, Week 2 and Month 1 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.
• Change in Pittsburgh Sleep Quality Index (PSQI) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Penn State Worry Questionnaire (PSWQ) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Intolerance of Uncertainty Scale (IUS) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Cognitive Test Performance From Baseline to Day 5 [Baseline and Day 5 (End of Treatment)]: 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.
• Change in State-Trait Anxiety Inventory (STAI) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Perceived Stress Scale-10 (PSS-10) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Ruminative Responses Scale (RRS) Score From Baseline [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Anxiety and Depression Visual Analogue Scale Scores From Baseline [Baseline, Day 1, Day 3, Day 5 and Week 2 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.
• Treatment-Emergent Side Effects During the Intervention and Follow-up Period [Day 1, Day 3, Day 5 and Week 2 from baseline]: 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.
• Change in Heart Rate Variability From Baseline to Day 5 [Baseline and Day 5 (End of Treatment)]: 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.
• Change in Magnetic Resonance Imaging Measures From Baseline to Day 5 [Baseline and Day 5 (End of Treatment)]: 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.
• Dysfunctional Attitudes Scale (DAS) Score at Baseline [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.
• Childhood Trauma Questionnaire (CTQ) Score at Baseline [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.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Outpatients or inpatients at the Second Xiangya Hospital who are confirmed by two experienced psychiatrists to meet the International Classification of Diseases 11th Revision (ICD-11) diagnostic criteria for generalized anxiety disorder.
* Aged 18 to 65 years, regardless of gender.
* Right-handed.
* Junior high school education or above, with the ability to provide informed consent and complete cognitive assessments.
* Able to receive anti-anxiety treatment during the follow-up period according to the instructions of outpatient or inpatient physicians.
* Hamilton Anxiety Rating Scale (HAMA) score ≥14 and Patient Health Questionnaire-15 (PHQ-15) score ≥5.

Exclusion Criteria:

* Presence of psychotic symptoms.
* Diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, current psychiatric symptoms, or post-traumatic stress disorder based on SCID-5 assessment, either currently or within the past year.
* Organic brain disease or severe somatic diseases, such as thyroid disease, lupus, diabetes, lung disease, liver disease, kidney disease, infection, or major trauma.
* Intracranial implants.
* Clinically significant sensory impairments that cannot be corrected, such as color blindness or hearing impairment.
* Pregnant or breastfeeding women.
* Positive urine drug screen.
* Abnormal thyroid function tests.
* Personal history of epilepsy or family history of epilepsy.
* Receipt of physical therapy within the past six months, such as repetitive transcranial magnetic stimulation or electroconvulsive therapy.
* Suspected or confirmed history of alcohol or drug dependence.
* Use of anticoagulants, such as heparin or warfarin, corticosteroids, or thyroid disease treatments within the past three months.
* Current use of psychoactive medications.
* Receipt of neurocognitive assessments similar to those used in this study within the past 12 months.

• Yan Zhang, PhD, Study chair, Second Xiangya Hospital of Central South University
• Yumeng Ju, PhD, Principal investigator, Second Xiangya Hospital of Central South University