The goal of this clinical trial is to explore the flexibility of threat control and underlying neural mechanism based on the threat reversal paradigm (a highly validated new paradigm where threat learning and inhibition are required) in patients with anxiety disorders (mainly generalized anxiety disorder). The hypotheses are:

1. Threat reversal abilities are hypothesized to be impaired in patients with anxiety disorders compared to healthy normal subjects, which are assumed to be associated with anxiety symptoms.
2. The neural mechanism underlying threat reversal abnormalities in patients with anxiety disorders is hypothesized to involve the prefrontal cortex, amygdala, and hippocampus.
3. The repetitive stimulation to the core brain regions of threat reversal is assumed to improve threat reversal abilities and anxiety symptoms of patients.

In this study, there are three sub-trials in combination with skin conductance response (SCR), functional magnetic resonance imaging (fMRI), and non-invasive neuromodulation techniques to uncover the abnormal threat reversal in anxiety disorder at behavioral and neural levels.

Participants in the first trial will learn the threat of emotional faces based on the Pavlovian conditioned fear learning paradigm; their neural activities in the hypothesized brain regions will be obtained via brain imaging equipment. The researchers will compare the differences among three groups (one patient group, two healthy control groups with different anxiety level) on performance in the threat reversal task, and their neural activities and brain functional connectivity characteristics, in order to reveal the potential behavioral threat reversal abnormalities and core associated brain regions underlying threat reversal.

Participants in the second trial will be given the same learning paradigm and brain imaging equipment as in the first, but with repetitive stimulation intervention on the core brain regions determined in study 1. Using a double-blind randomized controlled experiment, the participants will be divided into three groups (active stimulation + patient, sham stimulation + patient, and sham stimulation + healthy control). The researchers will compare the behavioral differences in the threat reversal task after active and sham stimulation.

Participants in the third trial will be given the same study design and intervention as the second trial, but for eight weeks. Finally, the researchers will retest and compare the improvement in threat reversal abilities and anxiety symptoms to see the long-term clinical effects of the intervention.

Inclusion Criteria for patient participants:

Clinical diagnosis of anxiety disorders (by psychiatrists using the structured clinical interview for DSM-IV-TR (SCID) with reference to the diagnostic criteria for GAD according to the ICD-10)

Exclusion Criteria for patient participants:

1. A history of serious cardiovascular, cerebrovascular diseases, stroke, or other neurological disorders, a history of gastrointestinal diseases.
2. Severe hearing or vision impairments.
3. Metallic implants in the body, such as non-removable dentures, stents, metal plates, joint metal replacements, etc.
4. Claustrophobia.
5. Acute or chronic diseases or infections.
6. Pregnancy or breastfeeding.
7. Smoking or drinking alcohol within 24 hours before the experiment.
8. Previous participation in similar experiments conducted by this institution.

Inclusion Criteria for healthy control participants:

1. No physical diseases or mental disorders.
2. No claustrophobia.
3. No hereditary diseases.
4. No medication history or smoking history.
5. Females not pregnant and not in their menstrual period.
6. Normal vision or corrected vision, no smoking, drinking alcohol, or taking medication within 24 hours prior to the experiment.
7. No previous participation in similar experiments.

We will share our data on the Open Science Framework after data collection

The information will be shared after the related paper is published and will be available for at least one year.

The information will be shared on the Open Science Framework for the public.