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This randomized, double-blind, sham-controlled clinical trial will evaluate whether individualized alpha-frequency transcranial alternating current stimulation (tACS) can enhance the effects of mindfulness therapy in adults with generalized anxiety disorder. A total of 99 participants will be randomly assigned to one of three groups: synchronous tACS combined with mindfulness therapy, desynchronous tACS combined with mindfulness therapy, or sham tACS combined with mindfulness therapy.
All participants will receive a standardized mindfulness therapy program. The study will compare changes in anxiety symptoms, worry, mindfulness, attention control, cognitive performance, and neurophysiological measures across the three groups. Assessments will be conducted from baseline through follow-up visits to examine both clinical effects and possible neural mechanisms.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Synchronous tACS Plus Mindfulness Therapy | Experimental | Participants in this arm will receive individualized alpha-frequency transcranial alternating current stimulation (tACS) combined with standardized mindfulness therapy. The stimulation electrodes will be placed over F3 and P3, corresponding to the left dorsolateral prefrontal cortex and left inferior parietal lobule, and will deliver in-phase stimulation. Mindfulness therapy will be delivered using the same standardized program as in the other arms. |
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| Desynchronous tACS Plus Mindfulness Therapy | Active Comparator | Participants in this arm will receive individualized alpha-frequency tACS combined with the same standardized mindfulness therapy program. The stimulation targets, treatment duration, and general stimulation setup will be the same as in the synchronous tACS arm, but the phase difference between the F3 and P3 stimulation electrodes will be set at 180 degrees. |
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| Sham tACS Plus Mindfulness Therapy | Sham Comparator | Participants in this arm will receive sham tACS combined with the same standardized mindfulness therapy program. Sham stimulation will include 30-second ramp-up and ramp-down periods at the beginning and end of stimulation to mimic the sensation of active tACS. No active current will be delivered during the main 20-minute stimulation period, while the electrodes will remain in place to maintain blinding. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Synchronous Individualized Alpha-Frequency tACS | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline in Hamilton Anxiety Rating Scale total score at Week 2 post-randomization | 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. | Baseline and Week 2 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Generalized Anxiety Disorder-7 Score From Baseline to Follow-up | 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. | Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yumeng Ju, PhD | Contact | +86-18100731091 | yumeng.ju@csu.edu.cn | |
| Fanqi Zhou | Contact | +86-18711022278 | 2205228535@qq.com |
| Name | Affiliation | Role |
|---|---|---|
| Yan Zhang, PhD | Second Xiangya Hospital of Central South University | Study Chair |
| Yumeng Ju, PhD | Second Xiangya Hospital of Central South University | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Second Xiangya Hospital of Central South University | Changsha | Hunan | 410011 | China |
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Participants will be randomly assigned in a 1:1:1 ratio to one of three parallel groups: synchronous tACS plus mindfulness therapy, desynchronous tACS plus mindfulness therapy, or sham tACS plus mindfulness therapy. Each participant will receive only the assigned intervention throughout the treatment period. All groups will receive the same standardized mindfulness therapy program, and the groups will differ only in the tACS stimulation condition.
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Participants and outcome assessors will be masked to group assignment. Sham stimulation will include 30-second ramp-up and ramp-down periods at the beginning and end of stimulation to mimic the sensation of active tACS, while no active current will be delivered during the main 20-minute stimulation period. The psychotherapist, tACS operator, and data collectors will be independent research personnel, and outcome assessors will not be involved in treatment delivery.
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| Desynchronous Individualized Alpha-Frequency tACS | Device | 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. |
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| Sham tACS | Device | 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. |
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| Mindfulness Therapy | Behavioral | 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. |
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| Change in Penn State Worry Questionnaire Score From Baseline to Follow-up | 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. | Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6 |
| Change in Five Facet Mindfulness Questionnaire Score From Baseline to Follow-up | 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. | Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6 |
| Change in Attentional Control Scale Score From Baseline to Follow-up | 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. | Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6 |
| tACS-Related Adverse Effects Assessed by the tACS Adverse Effects Questionnaire | 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. | Week 1 and Week 2 |
| Change in Hamilton Depression Rating Scale-17 Score From Baseline to Follow-up | 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. | Baseline, Week 1, Week 2, Month 1, Month 2, Month 4, and Month 6 |
| ID | Term |
|---|---|
| D000098647 | Generalized Anxiety Disorder |
| ID | Term |
|---|---|
| D001008 | Anxiety Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
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