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

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.

Study Overview

• Status: Recruiting
• 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

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.

• Study Type: Interventional
• Enrollment (Anticipated): 7
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stephan CHABARDES, MD, PhD; Phone Number: 33 (0)4 76 76 93 85; Email: SChabardes@chu-grenoble.fr
• Study Contact Backup: Name: Caroline SANDRE-BALLESTER, PhD; Phone Number: 33 (0)4 38 78 28 51; Email: CSandreballester@chu-grenoble.fr

Study Locations

• France
  • Grenoble, France, 38000
    • Recruiting
    • CLINATEC
    • Contact: Stephan CHABARDES, MD, PhD; Phone Number: 33 (0)4 76 76 93 85; Email: SChabardes@chu-grenoble.fr
    • Contact: Caroline SANDRE-BALLESTER, PhD; Phone Number: 33 (0)4 38 78 28 51; Email: CSandreballester@chu-grenoble.fr
    • Principal Investigator: Eric SEIGNEURET, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Between 18 and 75 years old,
2. Uni or bilateral permanent non-pulsatile tinnitus, without associated vestibular pathology, with or without hearing loss,
3. Severe tinnitus resistant to treatment failure,
4. Tinnitus intensity on the Visual Analog Scale (VAS) ≥ 7,
5. Presenting a quality of life score on the Tinnitus Handicap Inventory (THI) questionnaire> 76 (= grade 5),
6. Social security affiliates or beneficiaries of such a scheme
7. Informed and written consent signed by the patient.

Exclusion Criteria:

1. Vestibular dysfunction (balance disorder),
2. Epilepsy,
3. Intercurrent serious pathology,
4. Brain tumor,
5. Contraindication to surgery or anesthesia,
6. History of cerebral infection with herpesvirus,
7. With a contraindication to the practice of MRI, MEG, Computerized Tomography (CT) scan,
8. 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,
9. Included in another therapeutic protocol,
10. Progressive dementia or psychiatric illness,
11. Presenting a suicidal risk deemed important for less than 3 months (Montgomery and Asberg depression scale (MADRS): suicidality item (item 10) score> 2),
12. Enforced hospitalisation,
13. Pregnant, parturient or breastfeeding, lack of contraception in patients with the capacity to procreate,
14. Subject to a legal protection measure,
15. Deprived of liberty by judicial or administrative decision,
16. Isolated patient without any contact in case of emergency.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Collaborators: Commissariat A L'energie Atomique; Équipe 5 Neuroimagerie et perfusion cérébrale, Grenoble Institut des Neurosciences (GIN)

Publications and helpful links

General Publications

• Job A, Paucod JC, O'Beirne GA, Delon-Martin C. Cortical representation of tympanic membrane movements due to pressure variation: an fMRI study. Hum Brain Mapp. 2011 May;32(5):744-9. doi: 10.1002/hbm.21063.
• Job A, Pons Y, Lamalle L, Jaillard A, Buck K, Segebarth C, Delon-Martin C. Abnormal cortical sensorimotor activity during "Target" sound detection in subjects with acute acoustic trauma sequelae: an fMRI study. Brain Behav. 2012 Mar;2(2):187-99. doi: 10.1002/brb3.21.
• Job A, Jacob R, Pons Y, Raynal M, Kossowski M, Gauthier J, Lombard B, Delon-Martin C. Specific activation of operculum 3 (OP3) brain region during provoked tinnitus-related phantom auditory perceptions in humans. Brain Struct Funct. 2016 Mar;221(2):913-22. doi: 10.1007/s00429-014-0944-0. Epub 2014 Dec 12.
• Eickhoff SB, Grefkes C, Zilles K, Fink GR. The somatotopic organization of cytoarchitectonic areas on the human parietal operculum. Cereb Cortex. 2007 Aug;17(8):1800-11. doi: 10.1093/cercor/bhl090. Epub 2006 Oct 10.
• Maliia MD, Donos C, Barborica A, Popa I, Ciurea J, Cinatti S, Mindruta I. Functional mapping and effective connectivity of the human operculum. Cortex. 2018 Dec;109:303-321. doi: 10.1016/j.cortex.2018.08.024. Epub 2018 Sep 10.

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2021
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): February 1, 2024

Study Registration Dates

• First Submitted: February 24, 2020
• First Submitted That Met QC Criteria: March 2, 2020
• First Posted (Actual): March 5, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Functional Magnetic Resonance Imaging (fMRI); Tinnitus; Cross-over study; Deep Brain Stimulation (DBS); Magnetoencephalography (MEG); Right operculum 3 (OP3); Local Field Potential (LFP); Visual Analog Scale (VAS); Tinnitus Handicap Inventory (THI) questionnaire; Hospital Anxiety and Depression Scale (HAD); Double blind design
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Otorhinolaryngologic Diseases; Ear Diseases; Sensation Disorders; Hearing Disorders; Hearing Loss; Tinnitus
• Other Study ID Numbers: 38RC18.208; 2019-A01562-55 (Other Identifier: ANSM ID RCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No