Navigated cTBS for the Treatment of Generalized Anxiety Disorder

Official title

Efficacy and Neural Mechanisms of Navigated Continuous Theta Burst Stimulation (cTBS) for Generalized Anxiety Disorder (GAD)

Overview

The purpose of this study is to investigate the effectiveness of a non-invasive brain stimulation technique called continuous Theta Burst Stimulation (cTBS) for treating Generalized Anxiety Disorder (GAD). The researchers will use a neuronavigation system, which acts like a GPS for the brain based on a participant's own MRI scan, to guide the stimulation to a specific target in the brain's auditory association cortex. This area is involved in processing information and may play a role in anxiety. Participants who enroll will be randomly assigned to one of two groups. One group will receive active cTBS treatment, while the other will receive a sham (placebo) stimulation that feels similar but has no therapeutic effect. The treatment will be given three times a day for seven consecutive days. Before and after the treatment period, all participants will complete clinical questionnaires to measure their anxiety and related symptoms. They will also undergo Magnetic Resonance Imaging (MRI) scans to help researchers understand how cTBS affects brain activity. A follow-up assessment will be conducted two weeks after the treatment ends to check on symptoms.

Detailed description

This study is a randomized, triple-blind, sham-controlled trial designed to evaluate the efficacy and neural mechanisms of neuronavigation-guided continuous Theta Burst Stimulation (cTBS) in patients with Generalized Anxiety Disorder (GAD).

A total of 40 patients diagnosed with GAD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) will be recruited from the First and Second Affiliated Hospitals of Anhui Medical University. After providing informed consent, participants will be randomized in a 1:1 ratio to receive either active cTBS or sham cTBS.

The stimulation target is the left auditory association cortex (posterior superior temporal sulcus), with coordinates derived from previous literature (Neri et al., 2024; MNI coordinates: -62, -40, 10). The TMStarget software will be used to transform these coordinates into each participant's native brain space, and a Brainsight neuronavigation system will guide coil placement for precise targeting.

The active intervention will be delivered using a MagStim Rapid2 stimulator with a 70mm air-cooled figure-of-eight coil. Stimulation intensity will be set at 100% of the individual's resting motor threshold (RMT). The cTBS protocol consists of 3-pulse bursts at 50 Hz, repeated at a 5 Hz frequency, for a total of 600 pulses per session (duration of approximately 41 seconds). The sham intervention will utilize an identical-looking sham coil that produces similar sounds without inducing a significant magnetic field, ensuring the integrity of the blinding.

The treatment schedule consists of three sessions per day, with a 15-minute interval between sessions, for seven consecutive days (from Day 2 to Day 8 of the study protocol).

All participants will undergo comprehensive assessments at baseline (Day 1) and immediately after the final treatment session (Day 9). Assessments include a battery of clinical scales and multimodal magnetic resonance imaging (MRI). The MRI protocol includes high-resolution structural (3D-T1), resting-state functional MRI (rs-fMRI), Diffusion Tensor Imaging (DTI), and specific sequences targeting the Locus Coeruleus. A follow-up assessment of clinical symptoms will be conducted two weeks after the end of the intervention.

Interventions

• Device Mapsd Continuous Theta Burst Stimulation
  A non-invasive brain stimulation technique using a MagStim Rapid2 stimulator with a 70mm air-cooled figure-of-eight coil. The stimulation target is the left auditory association cortex (MNI: -62, -40, 10), located using a Brainsight neuronavigation system. The cTBS protocol consists of 3-pulse 50 Hz bursts repeated at a 5 Hz frequency for a total of 600 pulses, delivered at 100% of the individual's resting motor threshold (RMT).
• Device Sham Navigated Continuous Theta Burst Stimulation
  A placebo procedure using an inert sham coil that is identical in appearance and sound to the active coil but does not deliver a significant magnetic field to the cortex. All other aspects of the procedure, including neuronavigation, coil placement, duration, and sound, are identical to the active intervention to maintain the blind.

Primary outcome measures

• Change from Baseline in Hamilton Anxiety Rating Scale (HAMA) Score [Time frame: Baseline (Day 1), Post-intervention (Day 9), and a 2-week follow-up.]
• Change from Baseline in Self-Rating Anxiety Scale (SAS) Score [Time frame: Baseline (Day 1), Post-intervention (Day 9), and a 2-week follow-up.]
• Change from Baseline in Resting-State Neural Activity [Time frame: Baseline (Day 1) and Post-intervention (Day 9).]

Secondary outcome measures (4)

• Change from Baseline in Hamilton Depression Rating Scale (HAMD-17) Score [Time frame: Baseline (Day 1) and Post-intervention (Day 9).]
• Change from Baseline in Patient Health Questionnaire-15 (PHQ-15) Score [Time frame: Baseline (Day 1) and Post-intervention (Day 9).]
• Change from Baseline in Four-Dimensional Symptom Questionnaire (4DSQ) Somatization Subscale Score [Time frame: Baseline (Day 1) and Post-intervention (Day 9).]
• Change from Baseline in Pittsburgh Sleep Quality Index (PSQI) Score [Time frame: Baseline (Day 1) and Post-intervention (Day 9).]

Eligibility criteria

Inclusion criteria

• Diagnosis of Generalized Anxiety Disorder (GAD) according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), confirmed by at least two psychiatrists.
• Hamilton Anxiety Rating Scale (HAMA) score > 14.
• Age between 18 and 60 years.
• More than 5 years of education.
• Right-handed.
• Normal or corrected-to-normal visual acuity.
• Able to cooperate with the completion of all experimental procedures.
• Willing and able to provide written informed consent.

Exclusion criteria

• Presence of other psychiatric disorders, such as substance abuse, schizophrenia, schizoaffective disorder, hysteria, or autism.
• Presence of severe neurological diseases (e.g., stroke), or any personal or family history of epilepsy or seizures.
• Presence of severe somatic diseases, such as severe heart, liver, or renal insufficiency.
• Pregnant or lactating women.
• Contraindications to Transcranial Magnetic Stimulation (TMS) or Magnetic Resonance Imaging (MRI), such as the presence of a cardiac pacemaker, cochlear implant, cerebrovascular metal stent, or metal dentures.
• Inability to cooperate with experimental procedures due to conditions such as depressive stupor or severe claustrophobia.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 2 centers

• Anhui Medical University — Hefei
• Anhui Medical University — Hefei

Publications

• Ji GJ, Ren C, Li Y, Sun J, Liu T, Gao Y, Xue D, Shen L, Cheng W, Zhu C, Tian Y, Hu P, Chen X, Wang K. Regional and network properties of white matter function in Parkinson's disease. Hum Brain Mapp. 2019 Mar;40(4):1253-1263. doi: 10.1002/hbm.24444. Epub 2018 Nov 10. PMID 30414340
• Neri F, Cappello C, Viberti F, Donniacuo A, Burzi L, Cinti A, Benelli A, Luca Smeralda C, Romanella S, Santarnecchi E, Mandala M, Rossi S. rTMS of the auditory association cortex improves speech intelligibility in patients with sensorineural hearing loss. Clin Neurophysiol. 2024 Apr;160:38-46. doi: 10.1016/j.clinph.2024.02.007. Epub 2024 Feb 9. PMID 38395005

Identifiers

NCT: NCT07121712 · AnHuiMU-GAD-cTBS-2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗