Transcranial Alternating Current Stimulation to Enhance Mindfulness Therapy in Generalized Anxiety Disorder

Generalized anxiety disorder is characterized by excessive and difficult-to-control worry, often accompanied by physical symptoms and impaired daily functioning. Mindfulness-based therapy may help patients observe worry and anxiety-related bodily sensations with greater awareness and acceptance. Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique that may modulate neural oscillations related to cognitive control and emotion regulation.

This study will enroll 99 adults with generalized anxiety disorder. Eligible participants will be randomly assigned in a 1:1:1 ratio to one of three intervention groups: synchronous tACS plus mindfulness therapy, desynchronous tACS plus mindfulness therapy, or sham tACS plus mindfulness therapy. All groups will receive the same standardized mindfulness therapy program. The active tACS conditions will target the frontoparietal network, with stimulation parameters individualized according to each participant's alpha-band neurophysiological characteristics. The sham stimulation condition will mimic the initial and final sensation of stimulation while delivering no active current during the main stimulation period.

Clinical, behavioral, and neurophysiological assessments will be collected at baseline and follow-up visits. Outcome assessments will include anxiety severity, depressive symptoms, worry, mindfulness, attention control, cognitive performance, adverse effects related to tACS, and multimodal measures such as electroencephalography, magnetic resonance imaging, and eye tracking. The study aims to determine whether individualized alpha-frequency tACS can improve the therapeutic effects of mindfulness therapy and to explore potential neural mechanisms underlying treatment response.

• Synchronous Individualized Alpha-Frequency tACS (Device), also known as Synchronous tACS, In-Phase tACS, Transcranial Alternating Current Stimulation: Individualized alpha-frequency transcranial alternating current stimulation (tACS) will be delivered to the frontoparietal network. Stimulation electrodes will be placed over F3 and P3, corresponding to the left dorsolateral prefrontal cortex and left inferior parietal lobule. In the synchronous tACS condition, the F3 and P3 stimulation electrodes will deliver in-phase sinusoidal alternating current. The stimulation frequency will be individualized based on each participant's alpha-band phase locking value peak between F3 and P3.
• Desynchronous Individualized Alpha-Frequency tACS (Device), also known as Desynchronous tACS, Anti-Phase tACS, 180-Degree Phase Difference tACS: Individualized alpha-frequency tACS will be delivered using the same stimulation targets and general setup as the synchronous tACS condition. Stimulation electrodes will be placed over F3 and P3, corresponding to the left dorsolateral prefrontal cortex and left inferior parietal lobule. In the desynchronous tACS condition, the phase difference between the F3 and P3 stimulation electrodes will be set at 180 degrees.
• Sham tACS (Device), also known as Sham Transcranial Alternating Current Stimulation: Sham tACS will be delivered with the electrodes placed in the same positions as in the active tACS conditions. The sham condition will include 30-second ramp-up and ramp-down periods at the beginning and end of stimulation to mimic the sensation of active stimulation. No active current will be delivered during the main 20-minute stimulation period, while the electrodes will remain in place to maintain blinding.
• Mindfulness Therapy (Behavioral), also known as Mindfulness Meditation Training, Standardized Mindfulness Training: Participants will receive a standardized mindfulness therapy program for 2 weeks, with 10 sessions in total. Each session will last 40 minutes. The program follows a progressive structure of awareness, acceptance, and application. The first five sessions focus on breath awareness and body scan practices. The last five sessions focus on observing anxiety-related bodily sensations and worry-related thoughts with a nonjudgmental and accepting attitude, and on using breathing space practices to redirect attention to the present moment.

Primary outcomes

• Change from baseline in Hamilton Anxiety Rating Scale total score at Week 2 post-randomization [Baseline and Week 2]: The Hamilton Anxiety Rating Scale (HAMA) is a clinician-administered scale used to assess the severity of anxiety symptoms. The total score ranges from 0 to 56, with higher scores indicating more severe anxiety symptoms. This outcome is defined as the change in HAMA total score from baseline to Week 2 post-randomization, calculated as the Week 2 score minus the baseline score. A greater reduction indicates greater improvement in anxiety symptoms.

Secondary outcomes

• Change in Generalized Anxiety Disorder-7 Score From Baseline to Follow-up [Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6]: The Generalized Anxiety Disorder-7 (GAD-7) is a 7-item self-report questionnaire used to assess the severity of anxiety symptoms. The total score ranges from 0 to 21, with higher scores indicating greater anxiety severity.
• Change in Penn State Worry Questionnaire Score From Baseline to Follow-up [Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6]: The Penn State Worry Questionnaire (PSWQ) is a 16-item self-report questionnaire used to assess the tendency to engage in excessive and uncontrollable worry. The total score ranges from 16 to 80, with higher scores indicating greater worry severity.
• Change in Five Facet Mindfulness Questionnaire Score From Baseline to Follow-up [Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6]: The Five Facet Mindfulness Questionnaire (FFMQ) is a self-report questionnaire used to assess mindfulness-related abilities,including observing, describing, acting with awareness, non-judging, and non-reactivity.. For the standard 39-item version, the total score ranges from 39 to 195, with higher scores indicating a higher level of mindfulness.
• Change in Attentional Control Scale Score From Baseline to Follow-up [Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6]: The Attentional Control Scale (ACS) is a 20-item self-report questionnaire used to assess perceived ability to focus and shift attention. The total score ranges from 20 to 80, with higher scores indicating better attentional control.
• tACS-Related Adverse Effects Assessed by the tACS Adverse Effects Questionnaire [Week 1 and Week 2]: The Transcranial Alternating Current Stimulation Adverse Effects Questionnaire (tACS-AEQ) will be used to assess stimulation-related adverse effects, including headache, dizziness, fatigue, skin redness, itching, tingling, burning sensation, scalp discomfort, and other adverse sensations. This outcome will report the presence and severity of adverse effects, with higher severity ratings indicating more severe adverse effects.
• Change in Hamilton Depression Rating Scale-17 Score From Baseline to Follow-up [Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6]: The Hamilton Depression Rating Scale-17 (HAMD-17) is a 17-item clinician-administered scale used to assess the severity of depressive symptoms. The total score ranges from 0 to 52, with higher scores indicating more severe depressive symptoms.

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Outpatients or inpatients of The Second Xiangya Hospital of Central South University.
* Diagnosis of generalized anxiety disorder as the primary diagnosis according to the International Classification of Diseases 11th Revision (ICD-11) diagnostic criteria, confirmed by two experienced psychiatrists.
* Hamilton Anxiety Rating Scale (HAMA) total score of 14 or higher.
* Aged 18 to 60 years, inclusive.
* Right-handed.
* Junior high school education or above, with sufficient ability to understand the study procedures, complete informed consent, clinical scales, and cognitive assessments.
* Currently not using anxiolytic or antidepressant medications, or receiving a stable medication regimen for at least 1 month before enrollment, with no planned changes in the medication regimen during the 2-week treatment period unless clinically necessary.
* Voluntarily agrees to participate in the study, signs the informed consent form, and is able to comply with study visits, treatment procedures, laboratory examinations, and other study requirements.

Exclusion Criteria:

* Presence of psychotic symptoms.
* Meeting ICD-11 diagnostic criteria for schizophrenia or other primary psychotic disorders, bipolar or related disorders, current depressive episode, dysthymic disorder, or post-traumatic stress disorder currently or within the past year.
* Organic brain disease or severe physical illness, including but not limited to thyroid disease, systemic lupus erythematosus, diabetes, severe pulmonary, hepatic, or renal impairment, infection, or major trauma.
* Clinically significant uncorrectable sensory impairment, such as hearing impairment that prevents effective communication.
* Pregnancy or lactation.
* Contraindications to transcranial electrical stimulation or related procedures, including metal implants in the body, intracranial hypertension, skull defects, brain tumor, severe heart disease, unstable vital signs due to serious physical illness, acute cerebrovascular disease, or a history of adverse reactions to electrical stimulation.
* Any other condition that, in the investigator's judgment, makes the participant unsuitable for this study.

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