Translational Auditory Neuroscience
Hearing deficits are expected to affect 900 million individuals world- wide in 2025, and has recently ranked 4th in the leading causes of years lived with disability (WHO).
One of the most prevalent and distressing condition associated with hearing loss is tinnitus, or ringing in the ears, which is defined by the perception of sounds in spite of their physical absence. This neurological disorder affects 10-15% of the population and is predicted to double in Europe by 2050. In 1 out of ten, severe tinnitus distracts sufferers from work, interferes with concentration and sleep, increases the risk of disability pension and can be so severe as to trigger suicide. Both patients and therapists are highly unsatisfied by the available therapeutic options, and ENTs most often recommend patients to “live with it”. This is in part due to the lack of fundamental knowledge on the mechanisms causing tinnitus, and those making it persistent and severe.
The goal of the laboratory is to increase the understanding of the mechanisms underlying hearing loss and the maladaptive plasticity occurring during tinnitus with hopes to develop new treatments and drugs to improve hearing function and silence tinnitus.
Our ultimate goal is the prevention and cure of hearing loss and tinnitus. For this purpose, we have established collaborations with both clinical researchers and the industry to facilitate the translation of our findings into cures. The laboratory focuses on i) the molecular mechanisms that regulate synaptic uncoupling in the ear, ii) the mechanisms that govern homeostatic plasticity in the brain during tinnitus, iii) the causative relationship between peripheral damage and phantom sound generation. We have a dual approach using animal models of hearing loss and tinnitus to decipher the signaling pathways disrupted in the ear and/or in the brain but also using genetics in multi-case families with history of tinnitus and/or hearing loss, having in aim the identification and validation of new targets for drug development.
To address this challenge, we use a battery of techniques including behavior, neuroimaging, auditory electrophysiology, molecular biology, synaptic histology, cell culture, cytometry, mouse and human genetics and epidemiology.
Former group members
Corstiaen Versteegh – Post-Doc
Rocio Paublete – Post Doc
Kim Vikhe Patil (2016) – Masters student
Rotation and internships
Daniele Scarcella (2019) – AMGEN summer student
Andra Lazar (2019) – visiting Medical doctor
Valeria Valieva (2019) – visiting Nurse
Petra Brüggemann (2019) – visiting Post-Doc
Alessandra Lugo (2019) – visiting Post-Doc
Eleni Genistarditi (2018) – visiting PhD student
Edis Gunan (2018) – Summer Research School student
Matilda Prada Hellberg (2018) - Summer Research School student
Lucy Yeung (2015) – visiting student
Xi Liu (2014) – trainee
Role of glutamate transporters in noise and drug-induced hearing loss and tinnitus
Using mouse genetics, we identified a role for glutamate transporters in regulating tinnitus. We are now characterizing the mechanisms by which disruption in glutamate homeostasis causes a phantom sound percept.
The main aim is to characterize the functional and molecular consequences of glutamate-mediated de-afferentation in the cochlea. Our working hypothesis is that excess glutamate release in the cochlea causes overexcitation of the auditory neurons, hyperactivate auditory relays, reorganize the auditory cortex and subsequent tinnitus.
The ultimate goal is to provide a better understanding of the ear to brain interactions. These results may have a broad clinical application, contributing to the detailed understanding of normal auditory physiology, as well as the origins of tinnitus resulting from subtle auditory dysfunctions.
Auditory synaptopathy in mice lacking the glutamate transporter GLAST and its impact on brain activity.
Tserga E, Damberg P, Canlon B, Cederroth CR
Prog Brain Res 2021 ;262():245-261
Circadian vulnerability of cisplatin-induced ototoxicity in the cochlea.
Tserga E, Moreno-Paublete R, Sarlus H, Björn E, Guimaraes E, Göritz C, et al
FASEB J 2020 Aug;():
GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus.
Yu H, Vikhe Patil K, Han C, Fabella B, Canlon B, Someya S, et al
Front Behav Neurosci 2016 ;10():158
Circadian rhythms in the auditory system
In collaboration with Prof. Barbara Canlon, we are investigating how circadian rhythms impact on auditory function.
The aim of this project is to better understand the mechanisms underlying differences in noise sensitivity throughout the day, in order to improve treatment efficacy using chronopharmacology.
Department of Defense, NIDCD.
Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids.
Cederroth CR, Park JS, Basinou V, Weger BD, Tserga E, Sarlus H, et al
Curr. Biol. 2019 Aug;29(15):2477-2487.e6
Differential Phase Arrangement of Cellular Clocks along the Tonotopic Axis of the Mouse Cochlea Ex Vivo.
Park JS, Cederroth CR, Basinou V, Sweetapple L, Buijink R, Lundkvist GB, et al
Curr. Biol. 2017 Sep;27(17):2623-2629.e2
TrkB-mediated protection against circadian sensitivity to noise trauma in the murine cochlea.
Meltser I, Cederroth CR, Basinou V, Savelyev S, Lundkvist GS, Canlon B
Curr. Biol. 2014 Mar;24(6):658-63
STOP: Swedish Tinnitus Outreach Project
Tinnitus is a very heterogeneous disorder. Distinct forms of tinnitus cannot respond as well to the same therapeutic intervention.
The goals of this study are to identify determinants of tinnitus, and use a comprehensive approach to classify tinnitus patients according to subtypes by means of questionnaires and auditory assessment in order to evaluate the prevalence of each form of tinnitus.
In a second step, we want to identify homogeneous sub-groups and perform genetic analyses to define new endophenotypes for a more accurate diagnostic of tinnitus patients at the clinic.
See the Swedish Tinnitus Outreach Project (STOP) for more information.
University of Nottingham, University of Bergen, University of Granada, Institute Mario Negri (Milano), Decibel Therapeutics.
Marie Curie ITN (ESIT), GENDER-NET Co-Plus Fund, Decibel Therapeutics.
The spatial percept of tinnitus is associated with hearing asymmetry: Subgroup comparisons.
Genitsaridi E, Kypraios T, Edvall NK, Trpchevska N, Canlon B, Hoare DJ, Cederroth CR, Hall DA
Prog Brain Res 2021 ;263():59-80
Impact of Temporomandibular Joint Complaints on Tinnitus-Related Distress.
Edvall NK, Gunan E, Genitsaridi E, Lazar A, Mehraei G, Billing M, et al
Front Neurosci 2019 ;13():879
Relationship between headaches and tinnitus in a Swedish study.
Lugo A, Edvall NK, Lazar A, Mehraei G, Lopez-Escamez JA, Bulla J, et al
Sci Rep 2020 05;10(1):8494
Association between Hyperacusis and Tinnitus.
Cederroth CR, Lugo A, Edvall NK, Lazar A, Lopez-Escamez JA, Bulla J, et al
J Clin Med 2020 Jul;9(8):
The genetic basis of hearing loss and tinnitus
Tinnitus has always been thought to derive from environmental factors, and evidence of genetic contributions to tinnitus have been lacking. We recently evidenced in twins and adoptees the genetic transmission of tinnitus and have initiated large scale studies using GWAS, WES, and WGS to identify functional variants associated in tinnitus. In parallel, while the monogenic transmission of hearing loss is acknowledged, less is known on the complex genetic architecture that governs hearing problems. The comparison of the genetic landscape between hearing loss and tinnitus will provide insights on the pathways involved specifically in the two auditory disorders.
University of Granada, Decibel Therapeutics.
Marie Curie ITN (ESIT), GENDER-NET Co-Plus Fund, Decibel Therapeutics, Forschung für Leben, Svenska Läkaresällskapet, Lars Hiertas Minne, Tysta Skolan.
Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.
Palviainen T, Pratt S, Quaranta N, Rämö J, Saarentaus E, Sardone R, Satizabal CL, Schweinfurth JM, Seshadri S, Shiroma E, Shulman E, Simonsick E, Spankovich C, Tropitzsch A, Lauschke VM, Sullivan PF, Goedegebure A, Cederroth CR, Williams FMK, Nagtegaal AP et.al
Am J Hum Genet 2022 06;109(6):1077-1091
Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study.
Amanat S, Gallego-Martinez A, Sollini J, Perez-Carpena P, Espinosa-Sanchez JM, Aran I, Soto-Varela A, Batuecas-Caletrio A, Canlon B, May P, Cederroth CR, Lopez-Escamez JA
EBioMedicine 2021 Apr;66():103309
Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus.
Cederroth CR, PirouziFard M, Trpchevska N, Idrizbegovic E, Canlon B, Sundquist J, et al
JAMA Otolaryngol Head Neck Surg 2019 Mar;145(3):222-229
Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort.
Maas IL, Brüggemann P, Requena T, Bulla J, Edvall NK, Hjelmborg JVB, et al
Genet. Med. 2017 09;19(9):1007-1012
The epidemiology of hearing loss and tinnitus
Knowledge on the environmental contributors to tinnitus are poorly known. Our recent systematic review identifies a handful of longitudinal or case-control studies suggesting a causal relationship with the development of hearing loss and tinnitus. Here, we use cross-sectional and longitudinal data from large Swedish cohorts in order to identify exposures that contribute to the development of hearing loss and tinnitus and reversely if both auditory conditions can be used as a predictor of other disorders.
Charité Tinnitus Clinic (Berlin), Institute Mario Negri (Milano), Decibel Therapeutics.
GENDER-NET Co-Plus Fund.
Global Prevalence and Incidence of Tinnitus: A Systematic Review and Meta-analysis.
Jarach CM, Lugo A, Scala M, van den Brandt PA, Cederroth CR, Odone A, Garavello W, Schlee W, Langguth B, Gallus S
JAMA Neurol 2022 Aug;():
Gender-Specific Risk Factors and Comorbidities of Bothersome Tinnitus.
Basso L, Boecking B, Brueggemann P, Pedersen NL, Canlon B, Cederroth CR, et al
Front Neurosci 2020 ;14():706
Sex-Specific Association of Tinnitus With Suicide Attempts.
Lugo A, Trpchevska N, Liu X, Biswas R, Magnusson C, Gallus S, et al
JAMA Otolaryngol Head Neck Surg 2019 Jul;145(7):685-687
TODD: Tinnitus Objective Diagnostic Device
An important gap in the care of tinnitus patients is the lack of robust objective methodologies to diagnose tinnitus. This project aims to translate to humans an objective measure of tinnitus developed in animals. Here, we use MEG to investigate cortical evoked responses to specific sequences of stimuli and assess whether the responses are altered in tinnitus subjects.
Alterations in auditory brain stem response distinguish occasional and constant tinnitus.
Edvall NK, Mehraei G, Claeson M, Lazar A, Bulla J, Leineweber C, Uhlén I, Canlon B, Cederroth CR
J Clin Invest 2022 03;132(5):
Differential Neural Responses Underlying the Inhibition of the Startle Response by Pre-Pulses or Gaps in Mice.
Moreno-Paublete R, Canlon B, Cederroth CR
Front Cell Neurosci 2017 ;11():19
Global Burden of Disease study
In view of the recent call for action from the WHO to better understand the impact of auditory disorders on life quality, I joined the GBD study as a collaborator with expertise in the auditory system.
Hearing loss prevalence and years lived with disability, 1990-2019: findings from the Global Burden of Disease Study 2019.
Lancet 2021 03;397(10278):996-1009
Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
Lancet 2020 10;396(10258):1204-1222
- H2020 GENDER-NET Co Plus Fund
- H2020 ITN (ESIT)
- Svenska Läkaresällskapet
- Lars Hiertas Minne
- Magnus Bergvalls Stiftelse
- Loo och Hans Ostermans
- Tysta Skolan
- Karolinska Institutet
- Professor Barbara Canlon, Karolinska Institutet
- Professor Patrick Sullivan, Karolinska Institutet
- Professor Daniel Lundqvist, Karolinska Institutet
- Professor Anna Magnusson, Karolinska Institutet
- Dr. Volker Lauschke, Karolinska Institutet
- Dr. François Lallemend, Karolinska Institutet
- Dr. Inger Uhlén, Karolinska Hospital
- Professor Berthold Langguth, University Hospital of Regensburg, Germany
- Professor David Baguley, University of Nottingham, UK
- Professor Deborah Hall, University of Nottingham, UK
- Professor Birgit Mazurek, Chartié Hospital, Germany
- Dr. Silvano Gallus, Institute of Research Mario Negri, Italy
- Professor Jan Bulla, University of Bergen, Norway
Additional relevant Articles/Publications
Medicine in the Fourth Dimension.
Cederroth CR, Albrecht U, Bass J, Brown SA, Dyhrfjeld-Johnsen J, Gachon F, et al
Cell Metab. 2019 Aug;30(2):238-250
Therapeutic Approaches to the Treatment of Tinnitus.
Langguth B, Elgoyhen AB, Cederroth CR
Annu. Rev. Pharmacol. Toxicol. 2019 Jan;59():291-313
Hearing loss and tinnitus--are funders and industry listening?
Cederroth CR, Canlon B, Langguth B
Nat. Biotechnol. 2013 Nov;31(11):972-4
2019 – Evangelia Tserga, PhD
Title of thesis: Synaptic uncoupling in the mouse cochlea induced by noise or cisplatin and its clinical relevance
Department of Physiology and Pharmacology, Karolinska Institutet
2017 - Vasiliki Basinou, PhD
Title of thesis: Circadian rhythms in the auditory system
Department of Physiology and Pharmacology, Karolinska Institutet
2009 - Christopher R. Cedderroth, PhD
Title of thesis: Endocrine Disruptors and the Fetal Origin of Diseases.
Department of Genetic Medicine and Development, University of Geneva, Switzerland.