Anxiety Disorders, Anxiety, Anxiety and Fear
Conditions
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.
Interventions
BEHAVIORALIn vivo social exposure
Subjects will be invited to give a 5 minutes oral presentation on the topic of their choice to five examiners displaying no facial emotional reaction, after a 5 minutes period of silent waiting in front of the examiners. This waiting period is prompt to elicit anticipation-type of social anxiety.
BEHAVIORALSocial exposure in a virtual reality setting
Subjects will give a 5 minutes oral presentation on the subject of their choice to a virtual reality panel composed of 5 examiners displaying no facial emotional reaction, after a 5 minutes period of silent waiting in front of the examiners. This waiting period is expected to elicit anticipation-type of social anxiety.
OTHEREEG recording
EEG will be recorded with a standard 16-electrodes cap. Recordings will start before the 5 minutes waiting period and continue throughout oral presentation and recovery. The recovery period will be used as a baseline control
DIAGNOSTIC_TESTPsychometric evaluation
Subjects will be evaluated prior to inclusion using the following assessment tools * Anamnestic Association for Methodology and Documentation in Psychiatry (AMDP) questionnaire * Mini International Neuropsychiatric Interview (MINI 6.0, for psychiatric diagnoses) * Liebowitz Social Anxiety Scale (LSAS) * Montgomery Asberg Depression Rating Scale (MADRS) * Brief Anxiety Scale of Tyrer (BAS) * State-Trait Anxiety Inventory (STAI A-B) * Global Assessment of Functioning (GAF)
DIAGNOSTIC_TESTVisual Analogue Scale of anxiety
Subjects will be asked to rate their anxiety levels * immediately before (5 minutes of silent waiting), * during * and after the 5-minute oral presentation (recovery)
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
First phase (go-no-go) with 10 subjects in 1 arm Second phase with 20 subjets (2 arms) in a cross-over design.
Eligibility
Sex/Gender
ALL
Age
20 Years to 50 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
France
Contacts
PRINCIPAL_INVESTIGATOROlivier Doumy, MD
Centre Hospitalier Charles Perrens, Bordeaux; INRA NutriNeuro, Bordeaux; Université de Bordeaux, France
PRINCIPAL_INVESTIGATORAlexandra Bouvard, MD
Centre Hospitalier Charles Perrens, Bordeaux; Université de Bordeaux, France
STUDY_DIRECTORCyril Herry, PhD
Neurocentre Magendie, Inserm U1215, Bordeaux, France
PRINCIPAL_INVESTIGATORCyril Dejean, PhD
Neurocentre Magendie, Inserm U1215, Bordeaux, France
PRINCIPAL_INVESTIGATORThomas Bienvenu, PhD
Centre Hospitalier Charles Perrens, Bordeaux; Neurocentre Magendie, Inserm U1215, Bordeaux, France
PRINCIPAL_INVESTIGATORJacques Taillard, MS
GENPHASS, CHU de Bordeaux
STUDY_CHAIRBruno Aouizerate, MD-PhD
Centre Hospitalier Charles Perrens, Bordeaux; INRA NutriNeuro, Bordeaux; Université de Bordeaux, France
Outcome results
None listed