DETEC-T – In search of validated markers for drug development in TINNITUS

Tinnitus is the perception of a sound without external stimulation. It is often described as a ringing, buzzing or humming in the ears or the head, and it affects about 10-15 % of the population i.e. millions of people. Usually accompanied by hearing loss, tinnitus has many causes including noise exposure, physical injury such as head trauma or whiplash, ear diseases, muscle spasms, circulatory changes, side effects from medication, nerve pathway irritation and central auditory system changes. Moreover, mimicking this human disorder, tinnitus can be induced in rodents by acoustic trauma and chemical agents as salicylate allowing pre-clinical studies.

However, the determination of physiological markers of tinnitus in humans and rodents remains a challenge. It is a main objective of the research community studying tinnitus because ideally it would provide an objective measure for quantifying acoustic/perceptive features of tinnitus and would allow quantitative assessments of effects of various tinnitus inducing agents and of putative therapeutic trials. In this way, the general aim of DETEC-T research program is to develop understanding and interpretation of physiological measures in rat models of tinnitus in direct collaboration with academic and fundamental research. Our physiological techniques include manganese enhanced MRI (MEMRI), electrophysiological spontaneous and evoked activity and behavioral test of gap-inhibited acoustic startle (GIAS).

Our results using MEMRI imaging showed an increase of auditory brain areas activity following administration of tinnitus-inducing agents (salicylate and acoustic trauma) (Figure 1A, B). In addition, we observed an increase of cortical electrophysiological activity (Figure 1C) and a behavioral deficit of GIAS. Taken together, these preliminary results validate our rat tinnitus-induced models and open the door to the further development of biomarkers and innovative tools for tinnitus assessments.

The successful evolution of DETEC-T program is based upon high quality work of Aurore Marie (Cilcare), Maida Cardoso and Amandine Laboulais (BioNanoNMRI) working in MEMRI imaging and Philippe Larroze-Chicot (Cilcare) and Veronique Baudoux (Cilcare) working in electrophysiology and behavioral tests respectively. This project is in direct collaboration with Dr. Cazals, Dr. Norena (Université Aix Marseille) and Dr. Goze-Bac (BioNanoNMRI, Université Montpellier), Sergio Gonzalez (Cilcare) is the project manager of DETEC-T research program.

We are grateful to the intellectual contribution of Dr. Salvi (State University of New York, USA), permanent member of CILcare’s scientific committee and Dr. Turner (Southern Illinois University, USA), permanent consultant for CILcare for behavioral GIAS, and the technical support of Christophe Coillot, Guillaume Dupont, Pauline de Pellegars and Éric Alibert (BioNanoNMRI).

Acknowledgments : Financial and institutional partners of DETEC-T are University of Montpellier, Inserm, CNRS, La Region Occitanie, Languedoc-Roussillon Incubation, Transfert-LR, BPI France.

Figure 1. Previous results of DETEC-T program. A. Central nervous system auditory pathway. B. MEMRI imaging of control (left panel) and tinnitus-induced model (right panel). Strong brain area activity is label in red (1. Cochlear nerve, 2. Cochlear nucleus, 3. Lateral lemniscus, 4. Trapezoid body, 5. Olive, 6. Inferior colliculus). C. Spontaneous electrophysiological activity of auditory cortex in control and tinnitus induced model.