Efficacy and Neural Mechanisms of Individualized Neuromodulation Combined With Think/No-Think Training in Individuals With Internalizing Disorders (INTS)

Participants in this arm will receive individualized temporal interference stimulation (TIS) combined with autobiographical Think/No-Think (TNT) thought suppression training. Approximately 30 outpatients aged 18-50 years with internalizing disorders will be enrolled, including patients with anxiety disorders, depressive disorders, comorbid anxiety and depressive disorders, obsessive-compulsive disorder, or post-traumatic stress disorder. Participants with schizophrenia spectrum disorders, bipolar disorders, current suicidal behavior, or high aggression/impulsive risk will not be included. TIS parameters will be individualized based on participant-specific neurophysiological characteristics. During the intervention period, TIS will be administered concurrently with autobiographical TNT training to investigate whether modulation of deep emotional-memory related neural circuits enhances thought suppression ability and emotional regulation.

Individualized temporal interference stimulation (TIS) will be used to non-invasively modulate deep brain networks involved in emotional processing and cognitive control. The stimulation target will be determined based on participant-specific neuroimaging and neurophysiological characteristics. Stimulation parameters, including frequency configuration, will be individualized according to the study protocol. In the combined intervention arm, TIS will be administered concurrently with autobiographical Think/No-Think thought suppression training to examine whether modulation of deep emotional-memory related circuits improves thought suppression ability and emotional regulation.

Autobiographical Think/No-Think (TNT) training is a behavioral intervention designed to enhance the ability to regulate unwanted thoughts and memories. Participants will generate personally relevant autobiographical events and learn cue-event associations before training. During Think trials, participants will intentionally retrieve the associated event, whereas during No-Think trials, participants will practice suppressing retrieval of the associated event when presented with the cue. The training is designed to improve cognitive control over unwanted mental content and will be administered according to the study protocol.

Participants in this arm will receive individualized transcranial alternating current stimulation (tACS) combined with autobiographical Think/No-Think (TNT) thought suppression training. Approximately 30 outpatients aged 18-50 years with internalizing disorders will be enrolled, including anxiety disorders, depressive disorders, comorbid anxiety and depressive disorders, obsessive-compulsive disorder, or post-traumatic stress disorder. Participants with schizophrenia spectrum disorders, bipolar disorders, current suicidal behavior, or high aggression/impulsivity risk will be excluded. tACS stimulation parameters will be individualized according to participant-specific EEG characteristics, with targeting of cortical regions involved in cognitive control. tACS will be delivered during TNT training to examine whether enhancing prefrontal neural regulation improves suppression of unwanted thoughts and emotional regulation.

Autobiographical Think/No-Think (TNT) training is a behavioral intervention designed to enhance the ability to regulate unwanted thoughts and memories. Participants will generate personally relevant autobiographical events and learn cue-event associations before training. During Think trials, participants will intentionally retrieve the associated event, whereas during No-Think trials, participants will practice suppressing retrieval of the associated event when presented with the cue. The training is designed to improve cognitive control over unwanted mental content and will be administered according to the study protocol.

Individualized transcranial alternating current stimulation (tACS) targeting the right anterior dorsolateral prefrontal cortex (aDLPFC) will be administered to modulate cortical oscillatory activity associated with cognitive control and thought suppression. Stimulation frequency will be individualized according to each participant's resting-state EEG beta-band peak. tACS will be delivered according to the study protocol, including predefined stimulation intensity, duration, and session schedule. In the combined intervention arm, tACS will be administered concurrently with autobiographical Think/No-Think thought suppression training to investigate whether individualized modulation of prefrontal neural oscillations enhances cognitive control and emotional regulation.

Participants in this arm will receive sham neuromodulation combined with autobiographical Think/No-Think (TNT) thought suppression training. Approximately 30 outpatients aged 18-50 years with internalizing disorders will be enrolled, including anxiety disorders, depressive disorders, comorbid anxiety and depressive disorders, obsessive-compulsive disorder, or post-traumatic stress disorder. Participants with schizophrenia spectrum disorders, bipolar disorders, current suicidal behavior, or high aggression/impulsivity risk will not be included. Sham stimulation procedures will mimic the sensory experience and experimental procedures of active stimulation without delivering the active neuromodulatory intervention. Participants will complete the same TNT training protocol as active stimulation groups, allowing evaluation of the additional effects of individualized neuromodulation beyond behavioral thought suppression training.

Autobiographical Think/No-Think (TNT) training is a behavioral intervention designed to enhance the ability to regulate unwanted thoughts and memories. Participants will generate personally relevant autobiographical events and learn cue-event associations before training. During Think trials, participants will intentionally retrieve the associated event, whereas during No-Think trials, participants will practice suppressing retrieval of the associated event when presented with the cue. The training is designed to improve cognitive control over unwanted mental content and will be administered according to the study protocol.

Sham neuromodulation will be used as a control condition to evaluate the specific effects of active stimulation. The procedure will use the same electrode placement and initial stimulation procedures as active neuromodulation conditions but will not deliver sustained active stimulation. Participants will undergo the same study procedures and, where applicable, the same autobiographical Think/No-Think thought suppression training as active intervention groups.

Participants in this arm will receive individualized transcranial alternating current stimulation (tACS) without concurrent Think/No-Think (TNT) thought suppression training. Approximately 30 outpatients aged 18-50 years with internalizing disorders will be enrolled, including anxiety disorders, depressive disorders, comorbid anxiety and depressive disorders, obsessive-compulsive disorder, or post-traumatic stress disorder. Participants with schizophrenia spectrum disorders, bipolar disorders, current suicidal behavior, or high aggression/impulsivity risk will not be included. Individualized tACS parameters will be determined according to participant-specific EEG characteristics and applied to modulate neural oscillatory activity associated with cognitive control and emotional regulation. This arm is designed to evaluate the effects of neuromodulation alone on clinical symptoms and neural mechanisms without simultaneous cognitive training.

Individualized transcranial alternating current stimulation (tACS) targeting the right anterior dorsolateral prefrontal cortex (aDLPFC) will be administered to modulate cortical oscillatory activity associated with cognitive control and thought suppression. Stimulation frequency will be individualized according to each participant's resting-state EEG beta-band peak. tACS will be delivered according to the study protocol, including predefined stimulation intensity, duration, and session schedule. In the combined intervention arm, tACS will be administered concurrently with autobiographical Think/No-Think thought suppression training to investigate whether individualized modulation of prefrontal neural oscillations enhances cognitive control and emotional regulation.

Participants in this arm will receive individualized temporal interference stimulation (TIS) without concurrent Think/No-Think (TNT) thought suppression training. Approximately 30 outpatients aged 18-50 years with internalizing disorders will be enrolled, including anxiety disorders, depressive disorders, comorbid anxiety and depressive disorders, obsessive-compulsive disorder, or post-traumatic stress disorder. Participants with schizophrenia spectrum disorders, bipolar disorders, current suicidal behavior, or high aggression/impulsivity risk will not be included. TIS stimulation parameters will be individualized based on participant-specific neurophysiological characteristics and used to modulate deep brain networks associated with emotional processing and cognitive control. This arm is designed to examine the independent effects of individualized deep-brain neuromodulation on clinical symptoms and neural mechanisms.

Individualized temporal interference stimulation (TIS) will be used to non-invasively modulate deep brain networks involved in emotional processing and cognitive control. The stimulation target will be determined based on participant-specific neuroimaging and neurophysiological characteristics. Stimulation parameters, including frequency configuration, will be individualized according to the study protocol. In the combined intervention arm, TIS will be administered concurrently with autobiographical Think/No-Think thought suppression training to examine whether modulation of deep emotional-memory related circuits improves thought suppression ability and emotional regulation.

Thought control ability will be assessed using the 25-item Thought Control Ability Questionnaire (TCAQ). Each item is rated on a 5-point Likert scale（1-5）, and the total score ranges from 25 to 125. Higher scores indicate greater perceived ability to control unwanted thoughts and represent a better outcome. The outcome measure will be the change in total TCAQ score from baseline to immediately post-intervention and from baseline to the 1-month and 6-month follow-ups.

Participants will rate personally relevant autobiographical events at baseline and immediately post-intervention on seven dimensions, each dimension will be rated independently on a 5-point Likert scale (1-5), with no composite or total score calculated.Higher scores generally indicate stronger subjective representations and emotional responses to the events:

Vividness: Vividness of the mental representation. Perceived likelihood: Perceived likelihood of occurrence within the next 2 years.

Event-related anxiety or joy: Anxiety associated with negative events or joy associated with positive events.

Frequency of thoughts: Frequency of thinking about the event. Current concern: Degree of current concern about the event. Perceived long-term impact: Anticipated duration or extent of long-term impact. Emotional intensity: Intensity of the emotional response. Changes in each dimension will be calculated from baseline to post-intervention.

Anxiety symptoms will be assessed using the 14-item Hamilton Anxiety Rating Scale (HAMA), a clinician-administered scale. The total score ranges from 0 to 56, with higher scores indicating greater anxiety symptom severity (worse outcome). The outcome will be the change in total HAMA score from baseline to each post-intervention and follow-up assessment.

Depressive symptoms will be assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17). The total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity (worse outcome). The outcome will be the change in total HAMD-17 score from baseline to each post-intervention and follow-up assessment.

Sleep quality will be assessed using the 19-item Pittsburgh Sleep Quality Index (PSQI), referring to the previous month. Seven components are scored from 0 to 3: (1) subjective sleep quality (item 6); (2) sleep latency (items 2 and 5a, combined); (3) sleep duration (item 4); (4) habitual sleep efficiency (calculated from items 1, 3, and 4); (5) sleep disturbances (items 5b-5j, combined); (6) use of sleeping medication (item 7); and (7) daytime dysfunction (items 8 and 9, combined). Raw responses are converted into component scores using the standard PSQI scoring algorithm. The seven component scores are summed to yield a global score of 0-21. Higher scores indicate poorer sleep quality. The outcome is the change in global score from baseline to each post-intervention and follow-up assessment.

Pathological worry will be assessed using the 16-item Penn State Worry Questionnaire (PSWQ). Each item is rated on a 5-point Likert scale (1-5), yielding a total score of 16-80. Higher scores indicate greater pathological worry (worse outcome). The outcome will be the change in total PSWQ score from baseline to each post-intervention and follow-up assessment.

Rumination will be assessed using the 22-item Ruminative Responses Scale (RRS). Each item is rated on a 4-point Likert scale (1-4), yielding a total score of 22-88. Higher scores indicate greater rumination severity (worse outcome). The outcome will be the change in total RRS score from baseline to each post-intervention and follow-up assessment.

Habitual thought suppression and related unwanted-thought experiences will be assessed using the 15-item White Bear Suppression Inventory (WBSI). Each item is rated on a 5-point Likert scale (1-5), yielding a total score of 15-75. Higher scores indicate greater endorsement of habitual thought suppression and related unwanted-thought experiences, rather than better suppression ability. The outcome will be the change in total WBSI score from baseline to each post-intervention and follow-up assessment.

Repetitive negative thinking will be assessed using the 15-item Perseverative Thinking Questionnaire (PTQ). Each item is rated on a 5-point Likert scale (0-4), yielding a total score of 0-60. Higher scores indicate more severe repetitive negative thinking (worse outcome). The outcome will be the change in total PTQ score from baseline to each post-intervention and follow-up assessment.

Obsessive-compulsive symptom severity will be assessed using the 10-item Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in participants for whom this assessment is applicable. Each item is rated on a 5-point scale (0-4), yielding a total score of 0-40. Higher scores indicate greater obsessive-compulsive symptom severity (worse outcome). The outcome will be the change in total Y-BOCS score from baseline to each subsequent assessment at which the scale is administered.

Obsessive-compulsive symptoms will be assessed using the 18-item Obsessive-Compulsive Inventory-Revised (OCI-R) in participants for whom this assessment is applicable. Each item is rated on a 5-point Likert scale (0-4), yielding a total score of 0-72. Higher scores indicate greater obsessive-compulsive symptom severity (worse outcome). The outcome will be the change in total OCI-R score from baseline to each subsequent assessment at which the scale is administered.

Post-traumatic stress symptoms will be assessed using the 20-item PTSD Checklist for DSM-5 (PCL-5) in participants for whom this assessment is applicable. Each item is rated on a 5-point Likert scale (0-4), yielding a total score of 0-80. Higher scores indicate greater PTSD symptom severity (worse outcome). The outcome will be the change in total PCL-5 score from baseline to each subsequent assessment at which the scale is administered.

Resting-state electroencephalography (EEG) will be used to quantify theta-band (4-8 Hz) power spectral density (PSD) at baseline and immediately after the six-day intervention. PSD will be estimated from resting-state EEG recordings using the prespecified spectral estimation procedure. Theta-band PSD will be calculated as the mean PSD across frequencies from 4 to 8 Hz within the prespecified EEG electrodes or regions of interest. The outcome will be the change in mean theta-band PSD from baseline to post-intervention, expressed in microvolts squared per hertz (µV²/Hz). Higher values indicate greater theta-band spectral power density.

Resting-state EEG will be used to quantify beta-band (13-30 Hz) power spectral density (PSD) at baseline and immediately after the six-day intervention. PSD will be estimated from resting-state EEG recordings using the prespecified spectral estimation procedure. Beta-band PSD will be calculated as the mean PSD across frequencies from 13 to 30 Hz within the prespecified EEG electrodes or regions of interest. The outcome will be the change in mean beta-band PSD from baseline to post-intervention, expressed in microvolts squared per hertz (µV²/Hz). Higher values indicate greater beta-band spectral power density.

Resting-state functional magnetic resonance imaging (rs-fMRI) will be used to quantify functional connectivity between the prespecified hippocampal seed region and prefrontal cortical target region at baseline and immediately after the six-day intervention. For each participant, the blood-oxygen-level-dependent (BOLD) time series will be extracted from the hippocampal seed and the prespecified prefrontal target region. Functional connectivity will be calculated as the Pearson correlation coefficient between the two regional time series and transformed using Fisher's r-to-z transformation. The outcome will be the change in the Fisher z-transformed functional connectivity value from baseline to post-intervention. Higher values indicate stronger positive functional connectivity between the specified regions.

Longitudinal changes in clinical and behavioral questionnaire scores will be analyzed using linear mixed-effects models (LMMs). Fixed effects will include intervention group, assessment time, and the group-by-time interaction. A participant-level random intercept will be included to account for within-participant correlation across repeated assessments. The primary group comparisons will focus on differences in change over time between the five randomized intervention groups. Model estimates, effect sizes, and 95% confidence intervals will be reported. Model assumptions and the handling of missing data will be evaluated according to the prespecified statistical analysis plan.