Brain Reactivity to Nitrous Oxyde in Depression : an MRI and Ultrasound Study (PROTOBRAIN Pilote)

Study Overview
=================
Brief Summary
-----------------
Recent evidence suggest that Nitrous Oxyde (N2O) could exhibit antidepressant effect in treatment-resistant depression (TRD). However, the pathophysiology of this effect remains unclear and could include glutamatergic activity but also cerebrovascular effects and changes in brain connectivity. The goal of our study is to characterize brain reactivity to N2O in TRD patients, as assessed with Ultrasound Tissue Pulsatility Imaging (TPI) and Magnetic Resonance Imaging (MRI) (including Arterial Spin Labeling - ASL - for brain perfusion and Blood-Oxygen-Level Dependent - BOLD - for brain connectivity and pulsatility). Ultrasound and MRI Neuroimaging will be measured before, during and after a single one-hour exposure of a 50%N20/50%O2 mixture, in depressed individuals (n=20) and healthy volunteers (n=10). We make the hypothesis that brain reactivity will be lower in depressed individuals nonresponders to N2O compared to responders and healthy controls. This study would provide further characterisation of the pathophysiology of the antidepressant response to N2O, as well as providing potential biomakers (Ultrasound and MRI) for treatment response to N2O in TRD.

Detailed Description
-----------------
Neuroimaging examinations will include: Ultrasound Tissue Pulsatility Imaging for assessment of Brain Tissue Pulsatility (BTP) which reflects reactivity in brain movements and mechanical brain properties MRI with structural and functional assessments, namely brain volumes, white matter lesions, ASL for brain perfusion and BOLD for resting-state connectivity and brain pulsatility MRI will be performed before and after a single one-hour exposure of 50%N2O/50%O2 mixture. Ultrasound will be performed before, after and also during gas exposure. Changes in these neuroimaging parameters will constitute the primary assessment of the study. Psychometric and safety assessements will complete the neuroimaging outcomes. Follow-up will includes 1) a baseline visit for baseline MRI and Psychometric assessements, 2) a second visit for gas exposure and neuroimaging assessements, 3) a third and fourth visits for psychometric and safety assessements, respectively 24 hours and one week after gas exposure.

Official Title
-----------------
Cerebrovascular Reactivity to Nitrous Oxyde in Resistant Depression: the PROTOBRAIN Pilote Study

Conditions
-----------------
Treatment Resistant Depression, Nitrous Oxyde

Intervention / Treatment
-----------------
* Drug: Nitrous Oxide-Oxygen
* Device: Tissue Pulsatility Imaging - TPI
* Device: Magnetic Resonance Imaging - MRI


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Inclusion criteria common to all participants Female between 25 and 50 years of age A person who can undergo N2O diffusion via a facial mask. A person who has signed an informed consent. Person affiliated with a social security scheme. Inclusion Criteria for Depressive Patients Major Depressive Episode according to DSM-5 criteria, confirmed by the MINI - International Neuropsychiatric Interview. Patients with an MADRS score greater than 20 (Montgomery Asberg Depression Rating Scale). Patients resistant to at least one well-conducted antidepressant treatment, as documented by the MGH-ATRQ scale. Absence of: bipolar disorder, schizophrenic disorder, neurodegenerative disease, schizophrenic disorder, neurodegenerative disease, addiction to one or more toxics documented by the MINI. Inclusion criteria for healthy voluntary controls Absence of: bipolar disorder, schizophrenic disorder, neurodegenerative disease, schizophrenic disorder, neurodegenerative disease, addiction to one or more toxics documented by the MINI, current or past. Exclusion Criteria: Unstable somatic pathology (including unstable neurological or cardiological pathologies at risk of interfering with N2O diffusion) Presence of active and significant psychotic symptoms, at investigator's discretion Contraindications to mixture 50%N2O/ 50%O2: intracranial hypertension, altered state of consciousness, head trauma, pneumothorax, emphysema bubbles, abdominal gaseous distension, administration of less than 3 months of ophthalmic gas (SF6, C3F8,C2F6) used in eye surgery, known and unsubstituted deficiency in vitamin B12 or folic acid, recent and unexplained neurological abnormalities. Contraindications to MRI, including claustrophobia. Female who is pregnant or breastfeeding or able to procreate without an effective contraceptive method Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, purpose or consequences of the study (including major under legal protection). A person participating in a drug clinical trial or during a period of exclusion from any clinical study due to previous involvement.

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, Longitudinal, Monocentric, Physiological study comparing depressive patients (responders versus non-respondeurs to Nitrous Oxyde) and healthy volunteers
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: healthy voluntary controls<br>A single Non-blinded One-hour administration of 50% Nitrous oxyde (N2O) 50%oxygen (O2) Gas Mixture | Drug: Nitrous Oxide-Oxygen<br>* The medical product used in this study is a gas for common medical use in various domains including anesthesic, consisting in the equimolar mixture of nitrous oxide and oxygen. Subjects will receive a mixture of 50% N2O / 50% O2 for 1 hour.<br>* Other names: KALINOX® 50 %/50 %;Device: Tissue Pulsatility Imaging - TPI<br>* Tissue Pulsatility Imaging (TPI) is a variation of ultrasonic Doppler strain imaging we are developing to measure the local expansion and relaxation of the brain tissue over the cardiac cycle to characterize and image perfusion.<br>Device: Magnetic Resonance Imaging - MRI<br>* Structural and Functionnal (including BOLD and ASL) MRI will be aquired in this study<br>|
| Experimental: Depressive Patients<br>A single Non-blinded One-hour administration of 50% Nitrous oxyde (N2O) 50%oxygen (O2) Gas Mixture | Drug: Nitrous Oxide-Oxygen<br>* The medical product used in this study is a gas for common medical use in various domains including anesthesic, consisting in the equimolar mixture of nitrous oxide and oxygen. Subjects will receive a mixture of 50% N2O / 50% O2 for 1 hour.<br>* Other names: KALINOX® 50 %/50 %;Device: Tissue Pulsatility Imaging - TPI<br>* Tissue Pulsatility Imaging (TPI) is a variation of ultrasonic Doppler strain imaging we are developing to measure the local expansion and relaxation of the brain tissue over the cardiac cycle to characterize and image perfusion.<br>Device: Magnetic Resonance Imaging - MRI<br>* Structural and Functionnal (including BOLD and ASL) MRI will be aquired in this study<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Tissue Pulsatility (BTP) as measured with Ultrasound TPI | BTP will be measured before, during and after N2O exposure | 3 months after LVLS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Volumes (MRI) |  | 6 months after LVLS | 
| White Matter Lesions (MRI) |  | 6 months after LVLS | 
| Resting-State Connectivity (BOLD-MRI) |  | 6 months after LVLS | 
| Brain Pulsatility (BOLD-MRI) |  | 6 months after LVLS | 
| Brain Perfusion in Arterial Spin Labelling (ASL-MRI) |  | 6 months after LVLS | 
| Hamilton scale for depression, 17-items |  | 6 months after LVLS | 
| POMS - Profile of Mood State |  | 6 months after LVLS | 
| QIDS-SR - Quick Inventory of depressive Symptomatology Self Report |  | 6 months after LVLS | 
| CGI - Clinical Global Impressions |  | 6 months after LVLS | 
| STAI-Y-A - State-Trait Anxiety Inventory |  | 6 months after LVLS | 
| subjective VAE- Visual Analog Evaluation |  | 6 months after LVLS | 
| SSI - Scale for Suicidal Ideation |  | 6 months after LVLS | 
| YMRS - Young Mania Rating Scale |  | 6 months after LVLS | 
| CADSS - Clinician administered dissociative States |  | 6 months after LVLS | 
| BPRS - Brief Psychiatric Rating Scale |  | 6 months after LVLS | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Magnetic Resonance Imaging, Ultrasound, Tissue Pulsatility Imaging, Treatment Resistant Depression, Nitrous Oxyde