Functional Near-infrared Spectroscopy for Anxiety Monitoring and Neurofeedback.

Study Overview
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Brief Summary
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The objective of this subproject is to validate the efficacy of the fNIRS real-time anxiety monitoring and neurofeedback system. In the first year, the cerebral hemodynamics measured by commercial fNIRS during resting state and cognitive tasks from 60 generalized anxiety disorder (GAD) patients and 30 healthy subjects will be processed and analyzed using AI algorithms. The novel anxiety fNIRS biomarker will be identified and correlated to clinical anxiety scales (such as HARS and STAI). In the second year, the reliability, validity, and responsiveness of the AI-fNIRS biomarker will be validated. The accuracy of using AI-fNIRS biomarker to predict the diagnosis of GAD (according to DSM-5) and anxiety rating scales will be calculated from 60 GAD patients and 30 healthy subjects. In the third year, a neurofeedback method using AI-fNIRS biomarkers to guide digital cognitive behavior therapy (dCBT) through visual/audio cues will be developed. A pilot study with 12 GAD patients will be performed to test the feasibility of mindfulness training during AI-fNIRS neurofeedback. In the fourth year, a large scale RCT will be performed to validate the therapeutic efficacy of AI-fNIRS neurofeedback dCBT in 40 patients with GAD. The protocol of using real-time AI-fNIRS biomarkers as a neurofeedback to augment mindfulness training will be optimized according to previous year.

Official Title
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Clinical Evaluation of Functional Near-infrared Spectroscopy for Anxiety Monitoring and Neurofeedback.

Conditions
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Anxiety Disorders

Intervention / Treatment
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* Device: AI-fNIRS neurofeedback device
* Device: AI-fNIRS neurofeedback device with sham signals


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Being diagnosed with generalized anxiety disorder (GAD) by psychiatrists based on DSM-V. Native Chinese speakers. Right-handers. Normal vision without or after correction. Normal hearing and verbal expression. Regular returns of medical or psychological intervention during participation. Exclusion Criteria: Being diagnosed with other major neurological or mental disorders.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GAD Patients with Intervention<br>The feedback group will get real neurofeedback about changes in anxiety-related cerebral hemodynamics. AI-fNIRS neurofeedback will be provided 3 times a week, for a total of 4 weeks. | Device: AI-fNIRS neurofeedback device<br>* The device, with AI-fNIRS signals serving as brain monitor to indicate the level of anxiety, provides mindfulness training through visual and auditory cues to help participants modulate their brain activity, and thus alleviates anxious states.<br>|
| Sham Comparator: GAD Patients with Sham Controls<br>The sham group will be shown playbacks of someone's real feedback sessions. Sham AI-fNIRS neurofeedback will be provided 3 times a week, for a total of 4 weeks. | Device: AI-fNIRS neurofeedback device with sham signals<br>* The sham control consists of playbacks of someone else's real AI-fNIRS neurofeedback and will be provided 3 times a week, for a total of 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebral hemodynamics from functional near-infrared spectroscopy (fNIRS) | fNIRS is an optical brain monitoring technique. It serves as an ideal tool to record brain activities based on hemodynamics during various cognitive or motor tasks. The regions of interest are bihemispheric prefrontal cortices. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in severity of physiological and psychological anxious symptoms as assessed by Hamilton Anxiety Rating Scale (HARS) | Hamilton Anxiety Rating Scale (HARS) is a frequently-used scale in clinical psychiatric fields to assess the severity of anxious symptoms. Conducted by well-trained clinicians, HARS consists of 14 items and can be classified into 2 domains: physiological and psychological anxious symptoms. The minimum and maximum values are 0 and 56 respectively, with higher scores represent worse outcomes. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in temporary and long-term anxiety levels as assessed by State-Trait Anxiety Inventory (STAI) | State-Trait Anxiety Inventory (STAI) is a self-report measure of subjective feelings of anxiety. It consists of 2 subscales: state and trait anxiety, with the former characteristic of temporary states of emotion and the latter dealing with the frequency of anxiety and other related emotion in general conditions. The minimum and maximum values of each subscale are 20 and 80 respectively. The higher the score, the higher the level of anxiety. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in anxiety level as reported in Visual Analog Scale (VAS) | VAS is a self-report measure. Participants are required to draw a 10 cm line representing their anxiety spectrum, and mark their subjective feelings of anxiety level on it, with the highest on the right end. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in physiological anxious symptoms indicated by Heart Rate Variability (HRV) | Measured with Apple Watch, HRV serves as a physiological index of anxiety. Subjects with anxiety will show lower HRV than healthy individuals. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in performance on Emotional Stroop Task | Sixty words related to either positive, neutral or negative emotion are displayed in various colors in the emotional Stroop task. Participants are required to read out the color of each word as accurately and quickly as possible. The differences in reaction rate between negative emotion and the two other conditions indicate to what extent participants are affected by emotion. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in performance on Dot-Probe Task | Two images are first displayed on the left and right sides respectively and randomly, with one related to negative emotion and another related to neutral emotion. After the images disappear, a dot pops up on either side at random. Participants are required to indicate the direction where the dot showing up by pressing the button as soon as possible. The difference in reaction rate between the negative and neutral emotional images represents the extent to which the participants are influenced by emotion. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in Pittsburgh Sleep Quality Index (PSQI) | PSQI is a self-report measure of sleep quality. It consists of 9 items and is related to 7 dimensions of sleep. The higher the score is, the worse the quality of sleep. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in concentration of brain-derived neurotrophic factor (BDNF) | BDNF, a protein of the highest content in the brain, promotes neuron growth and synapse formation. Its secretion is inhibited under stress or depression; accordingly, BDNF serves as a biological index of aforementioned conditions. | Baseline, 4-week intervention, and 2 months after 4-week intervention. | 
| Change in concentration of Interleukin-6 (IL-6) | IL-6 is a proinflammatory cytokine and capable of modulating immune and inflammatory response. The level of IL-6 is elevated under stress, depression, etc. and hence serves as an indicator of such conditions. | Baseline, 4-week intervention, and 2 months after 4-week intervention. |