Evaluation of Deep Brain Stimulation (DBS) of the Right Operculum 3 (OP3) in Permanent Non-pulsatile Disabling Tinnitus (TINNOP3-DBS)

Study Overview
=================
Brief Summary
-----------------
This pilot study aims at evaluating the effectiveness of the treatment of unilateral or bilateral, non-pulsatile, disabling, tinnitus, without vestibular dysfunction, using Deep Brain Stimulation (DBS) of the parieto-insular right operculum 3 (OP3) in a cross-over, double study design.

Detailed Description
-----------------
Subjective, non-pulsatile, permanent, severe, tinnitus, refractory to all treatment are very disabling. They can lead to serious depression and suicidal behavior, which justifies the development of innovative therapeutic options. Current management is essentially based on psychological therapy and / or prosthetic, to improve for hearing loss that can be frequently associated. In fact, the main objective is habituation for these patients, but when the tinnitus is too intense, it is impossible. Three recent publications in functional magnetic resonance imaging (fMRI) have reported a novel physiopathological hypothesis to explain the appearance of subjective tinnitus. They highlight the prominent role of the right operculum 3 (OP3), a deep opercular region (parieto-insular junction) in the emergence of this symptom. The investigators hypothesize that inhibition of this region using high frequency stimulation could, significantly improve the intensity of the symptom and consequently their quality of life in this selected population.

Official Title
-----------------
Evaluation of Deep Brain Stimulation (DBS) of the Right Operculum 3 (OP3) in Permanent Non-pulsatile Disabling Tinnitus (TINNOP3-DBS)

Conditions
-----------------
Severe Permanent Uni or Bilateral Non-pulsatile Tinnitus, Without Associated Vestibular Pathology, Resistant to Therapeutic Failure, With or Without Hearing Loss

Intervention / Treatment
-----------------
* Device: DBS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Between 18 and 75 years old, Uni or bilateral permanent non-pulsatile tinnitus, without associated vestibular pathology, with or without hearing loss, Severe tinnitus resistant to treatment failure, Tinnitus intensity on the Visual Analog Scale (VAS) ≥ 7, Presenting a quality of life score on the Tinnitus Handicap Inventory (THI) questionnaire> 76 (= grade 5), Social security affiliates or beneficiaries of such a scheme Informed and written consent signed by the patient. Exclusion Criteria: Vestibular dysfunction (balance disorder), Epilepsy, Intercurrent serious pathology, Brain tumor, Contraindication to surgery or anesthesia, History of cerebral infection with herpesvirus, With a contraindication to the practice of MRI, MEG, Computerized Tomography (CT) scan, Under anticoagulants and antiaggregants (Anti vitamin K, low molecular weight heparin, aspirin and derivatives, clopidogrel antiplatelet agents and assimilated, new oral anticoagulants (NACO)) for which a therapeutic window can not be opened within 3 months before and after the surgery, Included in another therapeutic protocol, Progressive dementia or psychiatric illness, Presenting a suicidal risk deemed important for less than 3 months (Montgomery and Asberg depression scale (MADRS): suicidality item (item 10) score> 2), Enforced hospitalisation, Pregnant, parturient or breastfeeding, lack of contraception in patients with the capacity to procreate, Subject to a legal protection measure, Deprived of liberty by judicial or administrative decision, Isolated patient without any contact in case of emergency.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Deep Brain Stimulation (DBS) of the parieto-insular region at the level of the right operculum 3 (OP3)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deep Brain Stimulation (DBS) activated<br>Patients with severe permanent non-pulsatile tinnitus treated by Deep Brain Stimulation (DBS) in position ON | Device: DBS<br>* Deep Brain Stimulation (DBS) of the parieto-insular region at the level of the right operculum 3 (OP3)<br>|
| Other: Deep Brain Stimulation (DBS) non-activated<br>Patients with severe permanent non-pulsatile tinnitus treated by Deep Brain Stimulation (DBS) in position OFF | Device: DBS<br>* Deep Brain Stimulation (DBS) of the parieto-insular region at the level of the right operculum 3 (OP3)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness of the treatment using Deep Brain Stimulation (DBS) of the right operculum 3 (OP3). | Difference in intensity of tinnitus Visual Analog Scale (VAS) [0/10 : higher scores mean better outcome] between the end and the beginning of each of the two periods of the crossover. | 2.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DBS Treatment on Emergent Adverse Events (Tolerance) after surgical intervention and stimulation following the implantation of the DBS medical device. | Emergent Adverse events (partial or general epileptic seizures, worsening of tinnitus, surgical complications, ...): 1) post-operative computed tomography (CT); 2) Clinical evaluation. | 15 months | 
| Evaluation of the subjective effect of stimulation on quality of life. | Scores on the Tinnitus Handicap Inventory (THI) questionnaire [0/100 : higher scores mean worse outcome] at 6 months (early phase) and at 15 months compared to the preoperative THI of the same patient. | 15 months | 
| Evaluation of the subjective effect of stimulation on anxiety / depression. | Scores on the Hospital Anxiety and Depression Scale (HAD) [0/21 : higher scores mean worse outcome] at 6 months (early phase) and at 15 months compared to preoperative HAD of the same patient. | 15 months | 
| Changes comparison of the connectivity of OP3 explored by functional Magnetic Resonance Imaging (fMRI) at 1.5 T. | Functional Magnetic Resonance Imaging records (fMRI 1.5 T) performed preoperatively and at 15 months postoperatively. | 15 months | 
| Connectivities changes of the right OP3 measured by magnetoencephalography (MEG) at baseline 'preoperatively) and the post op (within 1 week) and at long term follow up (15 months) with active stimulation (ON) and inactive (OFF) during MEG recording. | Magnetoencephalography (MEG) records at baseline (preoperatively) and the post op (within 1 week) and at long term follow up (15 months) with active stimulation (ON) and inactive (OFF) during MEG recording. | 15 months | 
| Characterization of the Local Field Potential (LFP) recorded and correlations with tinnitus features perceived by the patient, based on their intensity and characteristic. | Local Field Potential (LFP) records on the electrode when the patient perceives tinnitus features 1) intraoperatively 2) before the implantation of the stimulator. | One week | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tinnitus, Deep Brain Stimulation (DBS), Right operculum 3 (OP3), Functional Magnetic Resonance Imaging (fMRI), Magnetoencephalography (MEG), Local Field Potential (LFP), Visual Analog Scale (VAS), Tinnitus Handicap Inventory (THI) questionnaire, Hospital Anxiety and Depression Scale (HAD), Cross-over study, Double blind design