An interventional study of Temporal Interference transcranial Alternating Current Stimulation (TI-tACS) and Temporal Interference transcranial Alternating Current Stimulation (TI-tACS) in Generalized Anxiety Disorder (GAD), sponsored by Central South University. Not yet recruiting at 4 sites in China. Open to participants aged 18 Years to 55 Years. Per ClinicalTrials.gov, last updated 2026-11-02.
Sponsored by Central South University · Not applicable, Interventional, and Treatment
This randomized controlled trial will use a three-arm, parallel-group design to evaluate the efficacy and safety of 5-Hz Temporal Interference transcranial Alternating Current Stimulation (TI-tACS) in adults with generalized anxiety disorder (GAD). A total of 75 participants will be randomized in a 1:1:1 ratio to receive stimulation targeting the right bed nucleus of the stria terminalis (BNST), stimulation targeting the right amygdala, or sham stimulation. Participants will receive three 20-minute sessions per day, with 1-hour intervals between sessions, for 7 consecutive days (21 sessions in total). The primary outcome is the change in Hamilton Anxiety Rating Scale (HAMA) total score from baseline to Week 1. Secondary and exploratory assessments will include clinical symptoms, intolerance of uncertainty and related cognitive characteristics, treatment tolerability, adverse events, and EEG and MRI measures. Follow-up assessments will be conducted at Week 1, Week 4, and Week 8 from baseline to assess the durability of clinical effects and safety.
Generalized anxiety disorder (GAD) is characterized by persistent and excessive anxiety and worry. Intolerance of uncertainty is an important cognitive feature associated with pathological worry. The amygdala and bed nucleus of the stria terminalis (BNST) contribute to threat processing, with evidence suggesting differences in their responses to brief and sustained threats. Comparing interventions targeting these regions may help clarify their contributions to anxiety symptoms, intolerance of uncertainty, and persistent worry.
Temporal interference stimulation uses two kilohertz-frequency alternating currents with a small frequency difference to generate an amplitude-modulated electric field envelope at the difference frequency. This study will compare right BNST-targeted and right amygdala-targeted stimulation using a 5-Hz envelope, with sham stimulation as the control.
Individualized head models will be constructed from each participant's T1-weighted magnetic resonance images. Electric field modeling will guide scalp electrode placement for the assigned target. Stimulation intensity will be individually adjusted according to participant tolerability within a range of 1.5-3.5 mA per channel, expressed as zero-to-peak amplitude.
Electroencephalography and magnetic resonance imaging will be used to investigate changes in theta-band activity and functional connectivity within anxiety-related networks. Associations between these changes and improvements in clinical symptoms and cognitive measures will be examined to explore the neural mechanisms of stimulation at the two targets. Peripheral blood samples will be collected at baseline, Week 1, and Week 8 and stored for future exploratory biomarker analyses related to GAD and treatment response.
151 studies on the registry are indexed under Generalized Anxiety Disorder; 89 are open to participants now.
This study's planned enrollment of 75 is below the median of 98 across 124 interventional studies indexed under Generalized Anxiety Disorder.
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Participants will receive 5-Hz temporal interference stimulation targeting the right bed nucleus of the stria terminalis (BNST), for 20 minutes per session, three sessions per day with 1-hour intervals, for 7 consecutive days, for a total of 21 sessions.
Device: Temporal Interference transcranial Alternating Current Stimulation (TI-tACS)
Participants will receive 5-Hz temporal interference stimulation targeting the right amygdala, for 20 minutes per session, three sessions per day with 1-hour intervals, for 7 consecutive days, for a total of 21 sessions.
Device: Temporal Interference transcranial Alternating Current Stimulation (TI-tACS)
Participants will receive sham temporal interference stimulation, for 20 minutes per session, three sessions per day with 1-hour intervals, for 7 consecutive days, for a total of 21 sessions.
Device: Sham Temporal Interference transcranial Alternating Current Stimulation (TI-tACS)
Temporal Interference Transcranial Alternating Current Stimulation (TI-tACS) is a non-invasive neuromodulation technique that generates an envelope field (particularly 5 Hz) in deep brain regions, particularly the right BNST, through the interaction of two currents (2000 Hz, 2005Hz).
Temporal Interference Transcranial Alternating Current Stimulation (TI-tACS) is a non-invasive neuromodulation technique that generates an envelope field (particularly 5 Hz) in deep brain regions, particularly the right Amygdala, through the interaction of two currents (2000 Hz, 2005Hz)
Sham Temporal Interference transcranial Alternating Current Stimulation will mimic the sensory experience of active stimulation without delivering effective current.
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline to Week 1
Anxiety severity will be evaluated using the Hamilton Anxiety Rating Scale (HAMA), a clinician-administered instrument comprising 14 items. Total scores range from 0 to 56, with higher scores indicating more severe anxiety symptoms. The outcome is the change in HAMA total score from baseline to Week 1.
Time frame: Baseline and Week 1
Clinical Response Rate
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.
Time frame: Week 1, Week 4, and Week 8
Clinical Remission Rate
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.
Time frame: Week 1, Week 4, and Week 8
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score
Anxiety severity will be evaluated using the Hamilton Anxiety Rating Scale (HAMA), a clinician-administered instrument comprising 14 items. Total scores range from 0 to 56, with higher scores indicating more severe anxiety symptoms. The outcome is the change in HAMA total score from baseline to each subsequent assessment time point.
Time frame: Baseline, Week 1, Week 4, and Week 8
Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score
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.
Time frame: Baseline, Week 1, Week 4, and Week 8
Change in Generalized Anxiety Disorder-7 (GAD-7) Score
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.
Time frame: Baseline, Week 1, Week 4, and Week 8
Change in Intolerance of Uncertainty Scale (IUS) Score
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 total score from baseline to each post-baseline assessment time point.
Time frame: Baseline, Week 1, Week 4, and Week 8
Change in Anxiety and Depression Visual Analogue Scale Scores
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
Time frame: Baseline, Day 1, Week 1, Week 4, and Week 8
Treatment-Emergent Side Effects During the Intervention and Follow-up Period
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.
Time frame: Week 1, Week 4, and Week 8
Change in EEG Theta-Band Power
Brain electrophysiological activity will be assessed using electroencephalography (EEG). Theta-band power (4-8 Hz) will be assessed using EEG. The outcome will be calculated as the change in theta-band power from baseline to each post-baseline assessment.
Time frame: Baseline, Week 1, and Week 8
Change in Right Amygdala Seed-Based Resting-State Functional Connectivity
Resting-state functional magnetic resonance imaging (fMRI) will be used to assess functional connectivity between the right amygdala and other brain regions. Connectivity will be quantified using Fisher z-transformed Pearson correlation coefficients between regional blood oxygen level-dependent (BOLD) signal time series. Changes from baseline will be calculated at each post-baseline MRI assessment.
Time frame: Baseline, Week 1, and Week 8
Change in Right BNST Seed-Based Resting-State Functional Connectivity
Resting-state functional magnetic resonance imaging (fMRI) will be used to assess functional connectivity between the right bed nucleus of the stria terminalis (BNST) and other brain regions. Connectivity will be quantified using Fisher z-transformed Pearson correlation coefficients between regional blood oxygen level-dependent (BOLD) signal time series. Changes from baseline will be calculated at each post-baseline MRI assessment.
Time frame: Baseline, Week 1, and Week 8
Blinding Integrity at the End of Treatment
Blinding integrity will be assessed using a brief questionnaire completed independently by participants and outcome assessors after the week 1 primary outcome assessment. Respondents will indicate whether they believe the participant received active stimulation, sham stimulation, or "do not know." They will also be asked to guess the specific treatment assignment: right BNST-targeted stimulation, right amygdala-targeted stimulation, sham stimulation, or "do not know." The reasons for their guesses will be recorded. The percentages of correct guesses, incorrect guesses, and "do not know" responses will be summarized by randomized group, separately for participants and outcome assessors. Actual treatment assignments will not be disclosed during this assessment.
Time frame: Week 1
Plan to share: No — Individual participant data will not be shared because the dataset includes sensitive neuroimaging and biological data that may compromise participant confidentiality.
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