Psychotherapy of Anxiety Disorders With Noninvasive Brain Stimulation - Using Virtual Reality

Study Overview
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Brief Summary
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The aim of the study is to transfer the rTMS stimulation protocol by Raij et al. (2018) into a therapeutic setting to improve exposure therapy in acrophobic patients. The quasi-randomized, placebo-controlled and double-blinded study will include 88 patients with height phobia (according to DSM 5). All participants will perform two exposure sessions in virtual reality (VR). Before exposure therapy, one group will receive verum rTMS of the left frontal cortex, which is indirectly functionally linked to the ventromedial prefrontal cortex (Raij et al., 2018). The control group will receive sham stimulation. A structural MRI and a TMS navigation system will be used for precise localization of the left FC. Anxiety symptoms will be measured using subjective ratings (e.g. Acrophobia Questionnaire) and the behavioural approach task (BAT) in VR and in real life before and after the treatment, and at 6 months follow-up. Furthermore, blood samples will be collected before rTMS and after exposure treatment to assess epigenetic and gene expression based changes.

Detailed Description
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The following hypotheses are derived: Patients with acrophobia, who receive an active rTMS of the left FC before VRET, show a significantly stronger reduction of phobic symptoms immediately after exposure therapy, compared to the sham stimulation group. Patients with acrophobia, who receive an active rTMS of the left FC before VRET, show a significantly greater increase in approach behavior and significantly less distress during the BAT immediately after exposure therapy, compared to the sham stimulation group. The postulated differences in hypotheses 1 and 2 are still detectable at follow-up after 6 months.

Official Title
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Nicht-invasive Hirnstimulation in Der Psychotherapie Von Angsterkrankungen

Conditions
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Phobia

Intervention / Treatment
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* Device: Verum TMS
* Device: Sham TMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acrophobia (according to DSM-5) Right handed German native speaker Written informed consent Exclusion Criteria: Neurological and/or severe physical illnesses Comorbid Axis I disorder (other than phobias) Pretreated phobia of heights Use of tricyclic antidepressants, antipsychotics, or other substances that increase cerebral seizure susceptibility Craniocerebral injuries, head surgery Epileptic seizures, or family history of epilepsy Metal parts in the head area Cardiac pacemakers Infusion pumps Heart diseases Increased intracranial pressure Pregnancy Cochlear implants Tattoos (done before the year 2000) Piercings (if not completely removable) Permanent make-up Nicotine or pain patches other MRI contraindications

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verum TMS<br>ITBS (intermittent Theta Burst Stimulation) over left frontal cortex | Device: Verum TMS<br>* Intensity of 100% of the resting motor threshold with iTBS. 600 stimuli applied in bursts of three pulses at 50 Hz given every 200 ms. iTBS will be applied 20 times for 2 s every 10 s.<br>* Other names: Cool-B70 A/P, MagPro X100, MagVenture®, Denmark;|
| Sham Comparator: Sham TMS<br>Sham TMS over left frontal cortex | Device: Sham TMS<br>* Sham stimulation with same protocol, but without magnetic stimulation<br>* Other names: Cool-B70 A/P, MagPro X100,, MagVenture®, Denmark;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective anxiety symptoms | Acrophobia Questionnaire (Cohen, 1977) with two subscales: 1) degree of anxiety (ACRO) and 2) degree of avoidance (AVOI) in height-related situations. | change from T1 (baseline /study start) to T4 (immediately after treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective anxiety in behavioral approach tests (BAT) | anxiety measurement by a behavioral approach test (BAT) in virtual reality (glass elevator on the outside of an high-rise building, height up to 150m) and in real life (open stairwell height up to 11,6m). | change from T1 (baseline /study start) to T4 (immediately after treatment) | 
| Subjective anxiety symptoms (Follow-Up) | Acrophobia Questionnaire (Cohen, 1977) with two subscales: 1) degree of anxiety (ACRO) and 2) degree of avoidance (AVOI) in height-related situations. | change from T1 (baseline/ study start) to T28 (6 months follow-up) | 
| Subjective anxiety in behavioral approach tests (BAT) (Follow-Up) | anxiety measurement by a behavioral approach test (BAT) in virtual reality (glass elevator on the outside of an high-rise building, height up to 150m) and in real life (open stairwell height up to 11,6m). | change from T1 (baseline /study start) to T28 (6 months follow-up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VR, Exposure therapy, Acrophobia, rTMS, PFC