Prefrontal Oscillations in Social Anxiety Disorder (POSAD)

Not Applicable

Recruiting

• Conditions: Anxiety; Anxiety and Fear; Anxiety Disorders
• Interventions: Behavioral: In vivo social exposure; Behavioral: Social exposure in a virtual reality setting; Other: EEG recording; Diagnostic Test: Psychometric evaluation; Diagnostic Test: Visual Analogue Scale of anxiety

• Registration Number: NCT03821779
• Lead Sponsor: Institut National de la Santé Et de la Recherche Médicale, France

Brief Summary

Experimental fear in rodents is correlated with slow oscillations in electrical recordings of prefrontal cortex activities. The present study aims to test whether slow prefrontal oscillations is a biomarker of pathological anxiety in human subjects.

Detailed Description

Fear and anxiety are adaptive responses that may become excessive or inappropriate in pathological conditions, as defined as anxiety disorders in DSM-5. These disorders, including phobic disorders such as social anxiety disorder, are frequent and impairing in the general population, with an estimated lifetime prevalence of 28% and significant consequences on quality of life. Direct and indirect medical costs related to these conditions amount to 74.4 billion €/year in Europe. Despite their prevalence, debilitating nature and chronicity, the pathophysiology of anxiety disorders is poorly understood and neurobiological treatments, including pharmacotherapy, are lacking efficacy. A better understanding of the neuronal mechanisms implicated in anxiety is necessary for the conception of new approaches to treat pathological anxiety.

Anxiety is commonly modeled in animals using fear conditioning, which consists in associating a neutral stimulus (eg: a sound) with a mild electrical foot-shock. As a result of the association between sound and shock, sound presentation in isolation induces a set of conditioned behavioral responses, such as an immobilization ("freezing"). Previous studies have shown that the expression of fear responses, measured on the basis of freezing, is associated with the emergence of slow oscillations (2-6Hz) in medial prefrontal cortex (mPFC) of mice. Moreover, emergence of these oscillations in mPFC is predictive of the occurrence of freezing, and the artificial induction of 4 Hz oscillations in mPFC with optogenetics induces freezing. Finally, inhibiting neurons in mPFC during the ascending phase of this slow mPFC oscillation at the time of conditioned sound presentation is sufficient to significantly reduce fear.

Interestingly, these results obtained in mice seem to find their prolongation in humans. Recent studies using fear conditioning in human subjects have also reported the emergence of prefrontal slow oscillations between 2-6 Hz during expression of conditioned fear responses. These results suggests that common mechanisms underlie the expression of fear in humans and rodents. However, whether similar neuronal circuits and mechanisms are implicated in human anxiety disorders remains unknown.

This study aims at assessing the presence of slow mPFC oscillations during expression of anxiety in patients suffering from anxiety disorders. Beyond understanding of the neuronal mechanisms underlying anxiety expression, this study could provide a biomarker of anxiety with diagnostic and therapeutic implications.

Study Timeline

• Study First Submitted: 2018-11-29
• Study First Submitted QC: 2019-01-25
• Study First Posted: 2019-01-30
• Study Start: 2019-11-12
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-21
• Last Update Posted: 2025-01-23
• Primary Completion: 2026-05-09
• Study Completion: 2026-05-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Social anxiety disorder as defined in DSM-5
• Full understanding of the protocol
• Obtaining informed consent from study subjects before or at inclusion at the latest
• Being registered in the french national health insurance service (Sécurité Sociale) (or equivalent)

Exclusion Criteria

• Active medical co-morbidity including severe hypertension, cardiac insufficiency, Raynaud syndrome, diabetes mellitus, renal insufficiency, adrenal insufficiency, Cushing syndrome and epilepsy

• Severe neurological co-morbidity, including but not limited to Parkinson's disease and multiple sclerosis

• Long-term corticotherapy

• History of significant head injury, defined by loss of consciousness

• Being diagnosed with another major psychiatric condition (DSM5) including bipolar disorder and schizophrenia or substance/alcohol use disorder; with the exception of major depressive disorder and nicotine use disorder

• Suicidal risk evaluated as moderate to high in the MINI questionnaire

• initiation of a psychotropic treatment or change in the dose of ongoing psychotropic treatment within 3 days prior to each visit and including:

  1. antidepressant treatments with selective serotonin recapture inhibitors, serotonin and norepinephrine inhibitors, alpha2-presynaptic adrenoreceptors (mirtazapine, mianserin), tricyclic
  2. anxiolytic drugs including benzodiazepines and anti-histamine
  3. antipsychotic drugs

• Acute alcohol intake 2 days prior to each visit (inclusion, experimental sessions)

• Pregnancy or breastfeeding.

• Ongoing hospitalization without consent (decision of a third-party: medical, justice)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group 1: Go-no-go phase	In vivo social exposure	The presence of significant prefrontal oscillations in the EEG recording 2-6Hz band during in vivo social exposure (oral presentation to examiners) will be assessed in 10 subjects with social anxiety disorder. EEG will be recorded immediately before, during and after oral presentations to examiners. Psychometric evaluation will be performed prior to experimental sessions. Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods (wainting, presentation, recovery). Results of EEG recordings in the first 10 subjects will lead to continuation (presence of significant slow prefrontal oscillations during anxiety) or interruption (absence of signification oscillation) of the study.
Group 1: Go-no-go phase	Visual Analogue Scale of anxiety	The presence of significant prefrontal oscillations in the EEG recording 2-6Hz band during in vivo social exposure (oral presentation to examiners) will be assessed in 10 subjects with social anxiety disorder. EEG will be recorded immediately before, during and after oral presentations to examiners. Psychometric evaluation will be performed prior to experimental sessions. Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods (wainting, presentation, recovery). Results of EEG recordings in the first 10 subjects will lead to continuation (presence of significant slow prefrontal oscillations during anxiety) or interruption (absence of signification oscillation) of the study.
Group 2.1	In vivo social exposure	In group 2.1, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "real exposure": oral presentation to a panel of examiners 2. "virtual reality" : oral presentation to virtual examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.1	Social exposure in a virtual reality setting	In group 2.1, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "real exposure": oral presentation to a panel of examiners 2. "virtual reality" : oral presentation to virtual examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.1	EEG recording	In group 2.1, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "real exposure": oral presentation to a panel of examiners 2. "virtual reality" : oral presentation to virtual examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 1: Go-no-go phase	Psychometric evaluation	The presence of significant prefrontal oscillations in the EEG recording 2-6Hz band during in vivo social exposure (oral presentation to examiners) will be assessed in 10 subjects with social anxiety disorder. EEG will be recorded immediately before, during and after oral presentations to examiners. Psychometric evaluation will be performed prior to experimental sessions. Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods (wainting, presentation, recovery). Results of EEG recordings in the first 10 subjects will lead to continuation (presence of significant slow prefrontal oscillations during anxiety) or interruption (absence of signification oscillation) of the study.
Group 2.2	In vivo social exposure	In group 2.2, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "virtual reality" : oral presentation to virtual examiners 2. "real exposure": oral presentation to a panel of examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.2	EEG recording	In group 2.2, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "virtual reality" : oral presentation to virtual examiners 2. "real exposure": oral presentation to a panel of examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 1: Go-no-go phase	EEG recording	The presence of significant prefrontal oscillations in the EEG recording 2-6Hz band during in vivo social exposure (oral presentation to examiners) will be assessed in 10 subjects with social anxiety disorder. EEG will be recorded immediately before, during and after oral presentations to examiners. Psychometric evaluation will be performed prior to experimental sessions. Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods (wainting, presentation, recovery). Results of EEG recordings in the first 10 subjects will lead to continuation (presence of significant slow prefrontal oscillations during anxiety) or interruption (absence of signification oscillation) of the study.
Group 2.2	Social exposure in a virtual reality setting	In group 2.2, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "virtual reality" : oral presentation to virtual examiners 2. "real exposure": oral presentation to a panel of examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.1	Psychometric evaluation	In group 2.1, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "real exposure": oral presentation to a panel of examiners 2. "virtual reality" : oral presentation to virtual examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.2	Visual Analogue Scale of anxiety	In group 2.2, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "virtual reality" : oral presentation to virtual examiners 2. "real exposure": oral presentation to a panel of examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.1	Visual Analogue Scale of anxiety	In group 2.1, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "real exposure": oral presentation to a panel of examiners 2. "virtual reality" : oral presentation to virtual examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.
Group 2.2	Psychometric evaluation	In group 2.2, 10 subjects will undergo 2 sessions in a cross-over design with EEG recording immediately before, during and after: 1. "virtual reality" : oral presentation to virtual examiners 2. "real exposure": oral presentation to a panel of examiners Rating of anxiety levels will be performed by subjects using a Visual Analogue Scale of anxiety during each of the 3 experimental periods for each session. Psychometric evaluation will be performed prior to experimental sessions.

Primary Outcome Measures

Name	Time	Method
Change in power of slow oscillations in prefrontal EEG recordings during anticipation relative to baseline	During the 5 minutes before oral presentation and during the 1 hour rest period	The change in power of PFC 2-6 Hz oscillations between the 5-minutes waiting period before oral presentation and the recovery period will be computed as a ratio.; Detection of exaggerated 2-6Hz oscillations in prefrontal cortex during anxious anticipation is the primary aim of this study.

Secondary Outcome Measures

Name	Time	Method
Duration of prefrontal slow oscillations epochs during anticipation	During the 5 minutes before oral presentation	Time-frequency analysis will be performed to determine the duration of 2-6Hz prefrontal oscillations epochs and total duration of these oscillations within experimental period. Significant oscillatory epochs will be defined using power ratios. These metrics will be used in order to assess the neurobiological and clinical relevance of this biomarker.

Trial Locations

Locations (1)

GENPHASS, SANPSY, CHU de Bordeaux; 🇫🇷 Bordeaux, France