Continuous Theta Burst Stimulation for Generalized Anxiety Disorder

• Continuous Theta Burst Stimulation of the Right Posterior Parietal Cortex (Device): Continuous theta burst stimulation (cTBS) is delivered to the right posterior parietal cortex (R-PPC), identified at the P4 location of the international 10-20 EEG system. Each session consists of 600 pulses delivered at 80% of the resting motor threshold (RMT). Participants receive two sessions per treatment day, separated by 30 ± 5-minute intervals, for a total of 10 sessions over approximately 1 week.
• Continuous Theta Burst Stimulation of the Right Dorsolateral Prefrontal Cortex (Device): Continuous theta burst stimulation (cTBS) is delivered to the right dorsolateral prefrontal cortex (R-DLPFC), identified using the Beam F4 approach. Each session consists of 600 pulses delivered at 100% of the resting motor threshold (RMT). Participants receive one session per treatment day, 5 days per week for 4 weeks, for a total of 20 sessions.

Primary outcomes

• Change in Hamilton Anxiety Rating Scale (HAM-A) Total Score [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: The Hamilton Anxiety Rating Scale (HAM-A) is used to assess the severity of anxiety symptoms. The scale consists of 14 items, each rated from 0 to 4, yielding a total score ranging from 0 to 56, with higher scores indicating greater anxiety severity. The primary outcome is the change in HAM-A total score from baseline (T0) to the end-of-treatment assessment (T4).

Secondary outcomes

• Change in World Health Organization Quality of Life-BREF (WHOQOL-BREF) Scores [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: Quality of life is assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF), which evaluates four domains: physical health, psychological health, social relationships, and environment. Each domain score is transformed to a 0-100 scale, with higher scores indicating better quality of life. Change in each domain score from baseline to the end-of-treatment assessment will be evaluated.
• Change in Pittsburgh Sleep Quality Index (PSQI) Global Score [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: The Pittsburgh Sleep Quality Index (PSQI) is used to assess subjective sleep quality over the previous month. It comprises seven component scores that are summed to produce a global score ranging from 0 to 21, with higher scores indicating poorer sleep quality. The outcome is the change in PSQI global score from baseline (T0) to the end-of-treatment assessment (T4).
• Change in Montreal Cognitive Assessment (MoCA) Total Score [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: The Montreal Cognitive Assessment (MoCA) is used to assess global cognitive function across multiple cognitive domains. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance. The outcome is the change in MoCA total score from baseline (T0) to the end-of-treatment assessment (T4).
• Change in Mini-Mental State Examination (MMSE) Total Score [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: The Mini-Mental State Examination (MMSE) is used to assess global cognitive function. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance. The outcome is the change in MMSE total score from baseline (T0) to the end-of-treatment assessment (T4).
• Incidence of Adverse Events and Serious Adverse Events [From the first treatment session through the end-of-treatment assessment (T4)]: Safety and tolerability will be assessed by monitoring adverse events (AEs) and serious adverse events (SAEs) throughout the treatment period. Adverse events potentially associated with iTBS, including headache, scalp discomfort, dizziness, and other reported adverse events, will be recorded. The number and proportion of participants experiencing at least one AE or SAE will be summarized by treatment group.

Other outcomes

• Change in Individual Alpha Frequency (IAF) [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: Individual alpha frequency (IAF) will be derived from resting-state electroencephalography (EEG). Change in IAF from baseline to the post-treatment neurophysiological assessment will be evaluated as an exploratory neurophysiological outcome.
• Change in TMS-Evoked N45 Amplitude [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) will be used to measure the N45 component of the TMS-evoked potential. Change in N45 amplitude from baseline (T0) to the end-of-treatment assessment (T4) will be evaluated as an exploratory neurophysiological outcome.
• Change in TMS-Evoked P60 Amplitude [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) will be used to measure the P60 component of the TMS-evoked potential. Change in P60 amplitude from baseline (T0) to the end-of-treatment assessment (T4) will be evaluated as an exploratory neurophysiological outcome.
• Change in TMS-Evoked N100 Amplitude [Baseline (T0) and 24-72 hours after the final treatment session (T4)]: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) will be used to measure the N100 component of the TMS-evoked potential. Change in N100 amplitude from baseline (T0) to the end-of-treatment assessment (T4) will be evaluated as an exploratory neurophysiological outcome.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Age 18 to 65 years.
* Right-handed.
* Diagnosis of generalized anxiety disorder (GAD) according to ICD-10 criteria (F41.1), confirmed by a psychiatrist.
* GAD must be the primary diagnosis and the main reason for treatment at the time of enrollment. Current or past comorbid major depressive disorder will be identified and recorded.
* Hamilton Anxiety Rating Scale (HAM-A) total score >18 at screening/baseline.
* Able and willing to provide written informed consent and comply with essential study procedures.
* Participants may be psychotropic-medication naïve or may be receiving psychotropic medication. Participants currently receiving psychotropic medication must have maintained the same medication(s) and dose(s) for at least 2 weeks before randomization; for fluoxetine, the required stable period is at least 4 weeks.

Exclusion Criteria:

* Intracranial or head/neck metallic foreign bodies or implants that constitute a contraindication to TMS or MRI.
* Implanted electronic devices such as a cardiac pacemaker, implantable cardioverter-defibrillator, or deep brain stimulator.
* Untreated or clinically unstable thyroid dysfunction based on abnormal TSH and/or free T4 levels.
* Clinically significant intracranial structural abnormalities that may affect TMS safety, neuropsychiatric presentation, or study neurophysiological measures.
* History of epilepsy or seizures, except febrile seizures in childhood.
* Bipolar disorder.
* Other major psychiatric disorders, including schizophrenia, delusional disorder, or eating disorders.
* Acute suicide risk, including clear suicidal ideation or behavior.
* Alcohol or substance abuse or dependence within the previous 6 months.
* A medical condition associated with a high seizure risk or a history of cranial surgery.
* Current use of medication judged by the screening physician to substantially increase seizure risk, or rapid reduction/discontinuation of benzodiazepines, antiseizure medications, or other centrally acting medications associated with withdrawal or increased seizure risk.
* Serum vitamin D level <20 ng/mL that has not been adequately corrected.
* Elevated C-reactive protein associated with clinically significant acute infection or acute inflammatory illness that, in the investigator's judgment, may affect participant safety or study outcome assessment.
* Pregnant or breastfeeding.
* Unable to understand or complete essential study procedures. Participants with potentially reversible temporary exclusion conditions may be rescreened once the condition has been adequately corrected or clinically stabilized.