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

This study is a randomized controlled clinical trial investigating the therapeutic effects and neural mechanisms of individualized neuromodulation combined with autobiographical Think/No-Think (TNT) thought suppression training in individuals with internalizing disorders, including anxiety disorders, depressive disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and complex PTSD (cPTSD). A total of 150 participants with internalizing disorders will be recruited and randomly assigned into five parallel intervention groups. The intervention period consists of six consecutive treatment days, with one session administered daily. Each session lasts approximately one hour and includes the assigned neuromodulation procedure and/or autobiographical TNT thought suppression training according to the assigned condition. The study investigates whether individualized neuromodulation targeting neural systems involved in cognitive control and memory regulation can enhance the ability to suppress unwanted thoughts and memories and improve clinical symptoms. The study also examines whether combining neuromodulation with targeted thought suppression training produces additional effects compared with neuromodulation alone or behavioral training with sham stimulation. Autobiographical Think/No-Think Training The behavioral intervention is based on an autobiographical TNT paradigm adapted for individuals with internalizing disorders. Before intervention, participants will identify personally relevant negative memories, intrusive thoughts, worries, or symptom-related mental contents under the guidance of trained researchers. For participants with trauma-related symptoms, selected materials will be related to their individual traumatic experiences or trauma-associated memories while following appropriate ethical and safety procedures. Each selected memory or thought will be paired with a neutral cue word to create individualized cue-target associations. The selected materials will be evaluated according to subjective characteristics, including emotional intensity, vividness, distress level, and personal relevance. During Think trials, participants will be instructed to intentionally retrieve and elaborate the associated autobiographical memory or thought when the cue appears. During No-Think trials, participants will be instructed to actively prevent the associated unwanted memory or thought from entering conscious awareness. Participants will be specifically instructed not to replace the unwanted thought with another deliberate thought or distraction strategy, but instead to practice intentional suppression of the original mental content. Repeated TNT training sessions will be conducted throughout the intervention period. Behavioral performance, including memory accessibility, subjective emotional responses, and suppression-related changes, will be evaluated before and after training. Individualized Neuromodulation Intervention Participants will receive one of five intervention conditions according to randomized assignment. The individualized tACS intervention targets the right anterior dorsolateral prefrontal cortex (aDLPFC), a region involved in executive control and intentional regulation of internally generated information. The stimulation frequency will be determined based on each participant's individual beta-band characteristics derived from resting-state EEG analysis. The individualized TIS intervention targets deep neural networks involved in memory retrieval and emotional regulation, with a focus on hippocampal-related neural systems. Individual stimulation parameters will be determined according to participant-specific neurophysiological characteristics, including individualized theta-band features obtained from multimodal assessment. In combined intervention conditions, neuromodulation will be delivered during autobiographical TNT training to investigate whether modulation of cognitive-control or memory-related neural systems can enhance thought suppression training effects. The tACS-only and TIS-only groups will receive the corresponding individualized neuromodulation intervention without TNT training, allowing examination of the independent effects of neuromodulation. The sham stimulation combined with TNT group will receive identical TNT training procedures with sham stimulation to control for behavioral training effects, expectancy effects, and nonspecific stimulation-related effects. Clinical and Behavioral Assessments Clinical assessments will be conducted before and after the intervention, with follow-up evaluations performed after treatment to examine the persistence of intervention-related changes. The assessment battery includes measures of anxiety symptoms, depressive symptoms, sleep quality, worry, rumination, thought suppression ability, intrusive thoughts, obsessive-compulsive symptoms, and trauma-related symptoms. Clinical measures include: Hamilton Anxiety Rating Scale (HAMA) for anxiety symptoms; Hamilton Depression Rating Scale (HAMD) for depressive symptoms; Pittsburgh Sleep Quality Index (PSQI) for sleep quality; Penn State Worry Questionnaire (PSWQ) for pathological worry; Ruminative Response Scale (RRS) for rumination tendency; Thought Control Ability Questionnaire (TCAQ) for perceived ability to control thoughts; White Bear Suppression Inventory (WBSI) for habitual thought suppression tendency; Perseverative Thinking Questionnaire (PTQ) for repetitive negative thinking; Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and Obsessive-Compulsive Inventory-Revised (OCI-R) for obsessive-compulsive symptoms; PTSD-related clinical assessments for trauma-related symptoms when applicable. Behavioral assessments include autobiographical TNT performance measures, including suppression-related memory accessibility, subjective distress, emotional intensity, and changes in control over unwanted mental content. EEG and MRI Assessment Resting-state EEG and resting-state functional MRI (rs-fMRI) assessments will be conducted before and after intervention to investigate neurophysiological and functional network changes associated with treatment. Resting-state EEG will be used to characterize individual neural oscillatory features, including theta- and beta-band activity. EEG analyses will examine changes in oscillatory power, frequency characteristics, and functional connectivity related to cognitive control and thought suppression. Resting-state MRI will be used to examine functional connectivity changes within neural networks associated with executive control, memory retrieval, and emotional regulation. Particular attention will be given to interactions among prefrontal regions and hippocampal-related networks. Multimodal analyses integrating EEG, MRI, behavioral performance, and clinical measures will be conducted to investigate neural mechanisms associated with intervention response. Data Analysis Clinical and behavioral outcomes will be analyzed using repeated-measures statistical models to examine changes from baseline to post-intervention and follow-up assessments. Between-group comparisons will evaluate differences among the five intervention conditions. Associations between changes in clinical symptoms, TNT performance, EEG characteristics, and MRI-based functional connectivity will be examined to identify neural correlates of treatment response. EEG analyses will evaluate intervention-related changes in oscillatory activity, including individualized beta and theta characteristics, resting-state spectral features, and functional connectivity measures. MRI analyses will examine changes in resting-state functional connectivity within cognitive-control and memory-related networks. Multimodal statistical approaches will be used to explore relationships among baseline neural characteristics, stimulation parameters, neural changes, and clinical outcomes. Multiple comparison correction procedures will be applied where appropriate, and effect sizes and confidence intervals will be reported. This study aims to investigate whether individualized neuromodulation combined with autobiographical thought suppression training can modify neural systems involved in cognitive control and memory regulation and improve symptoms associated with internalizing disorders.