Does insular cortex lesion cause tinnitus in rats?

Document Type : Original Article


1 Department of Audiology, School of Rehabilitation, Tehran University of Medical Science, Tehran, Iran

2 Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

3 Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

4 Department of Physiotherapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran

5 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

6 Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran


Objective(s): Tinnitus is defined as ringing of the ears that is experienced when there is no external sound source, and is an auditory phantom sensation. The insula as a multimodal cortex has been shown to be involved in the processing of auditory stimuli rather than other sensory and motor processing and reported to correlate with some aspects of tinnitus. However, its exact role is not clear. The present study aimed to investigate the effect of excitotoxic lesions limited to the insular cortex on the ability to detect a gap in background noise.
Materials and Methods: Gap detection test and prepulse inhibition, two objective measurements of auditory startle response, were measured, in 33 male Wistar rats, before and up to four weeks after insular lesion in three experimental groups (sham, control, and lesion). 
Results:  The ability to detect the gap interposed between 60dB background noise was impaired at weeks 2, 3, and 4 following insular lesion, while prepulse inhibition remained intact up to four weeks after surgery.
Conclusion: These findings indicated that excitotoxic lesions of the insular cortex may produce a tinnitus-like phenomenon in rats while sparing the hearing sensitivity; suggesting that the insular cortex may have a role in the development of tinnitus.


1. Tunkel DE, Bauer CA, Sun GH, Rosenfeld RM, Chandrasekhar SS, Cunningham Jr ER, et al. Clinical practice guideline: Tinnitus. Otolaryngol Head Neck Surg 2014; 151:S1-S40.
2. Newman CW, Sandridge SA, Snow J. Tinnitus questionnaires. Tinnitus: Theory and Management 2004:237-254.
3. McCormack A, Edmondson-Jones M, Somerset S, Hall D. A systematic review of the reporting of tinnitus prevalence and severity. Hear Res 2016; 337:70-79.
4. Axelsson A, Ringdahl A. Tinnitus—a study of its prevalence and characteristics. Br J Audiol 1989; 23:53-62.
5. Moazami-Goudarzi M, Michels L, Weisz N, Jeanmonod D. Temporo-insular enhancement of EEG low and high frequencies in patients with chronic tinnitus. QEEG study of chronic tinnitus patients. BMC Neurosci 2010; 11:40-51.
6. Weisz N, Dohrmann K, Elbert T. The relevance of spontaneous activity for the coding of the tinnitus sensation. Prog Brain Res 2007; 166:61-70.
7. Weisz N, Müller S, Schlee W, Dohrmann K, Hartmann T, Elbert T. The neural code of auditory phantom perception. J Neurosci 2007; 27:1479-1484.
8. Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, et al. Reversing pathological neural activity using targeted plasticity. Nature 2011; 470:101.
9. Basura GJ, Koehler SD, Shore SE. Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus. J Neurophysiol  2015; 114:3064-3075.
10. Wunderlich AP, Schönfeldt-Lecuona C, Wolf RC, Dorn K, Bachor E, Freund W. Cortical activation during a pitch discrimination task in tinnitus patients and controls–an fMRI study. Audiol Neurootol 2010; 15:137-148.
11. Rauschecker JP, Leaver AM, Mühlau M. Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 2010; 66:819-826.
12. De Ridder D, Elgoyhen AB, Romo R, Langguth B. Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proc Natl Acad Sci U S A 2011; 108:8075-8080.
13. Vanneste S, De Ridder D. The auditory and non-auditory brain areas involved in tinnitus. An emergent property of multiple parallel overlapping subnetworks. Front Syst Neurosci 2012; 6:31-39.
14. De Ridder D, Vanneste S, Congedo M. The distressed brain: A group blind source separation analysis on tinnitus. PloS one 2011; 6:e24273.
15. Brodmann K. Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues: Barth; 1909.
16. Boucher O, Rouleau I, Lassonde M, Lepore F, Nguyen D, Uddin L. Neuropsychological deficits following damage to the insular cortex: a clinical review.  Insula: neuroanatomy, functions, and clinical disorders: Nova Publishers, Palo Alto; 2014. p. 119-160.
17. Isnard J, Guénot M, Sindou M, Mauguière F. Clinical manifestations of insular lobe seizures: a stereo‐electroencephalographic study. Epilepsia 2004; 45:1079-1090.
18. Bamiou D-E, Musiek FE, Luxon LM. The insula (Island of Reil) and its role in auditory processing: literature review. Brain Res Rev 2003; 42:143-154.
19. SPREEN O, BENTON AL, FINCHAM RW. Auditory agnosia without aphasia. Arch Neurol 1965; 13:84-92.
20. Engelien A, Sibersweig D, Stern E, Huber W, Döring w, Frith C, et al. The functional anatomy of recovery from auditory agnosia: A PET study of sound categorization in a neurological patient and normal controls. Brain 1995; 118:1395-1409.
21. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev 1996; 22:229-244.
22. Ghaziri J, Tucholka A, Nguyen D. The connectivity of the human insular cortex: a review. Insula: Neuroanatomy, Functions and Clinical Disorders ed New York: Nova Scien 2014:31-66.
23. Bieser A, Müller-Preuss P. Auditory responsive cortex in the squirrel monkey: neural responses to amplitude-modulated sounds. Exp Brain Res 1996; 108:273-284.
24. Bieser A. Processing of twitter-call fundamental frequencies in insula and auditory cortex of squirrel monkeys. Exp Brain Res 1998; 122:139-148.
25. Afif A, Minotti L, Kahane P, Hoffmann D. Anatomofunctional organization of the insular cortex: a study using intracerebral electrical stimulation in epileptic patients. Epilepsia2010. p. 2305-2315.
26. Lenhardt ML, Shulman A, Goldstein BA. The role of the insula cortex in the final common pathway for tinnitus: experience using ultra-high-frequency therapy. Int Tinnitus J 2008; 14:13.
27. Husain FT. Neural networks of tinnitus in humans: elucidating severity and habituation. Hear Res 2016; 334:37-48.
28. Haller S, Birbaumer N, Veit R. Real-time fMRI feedback training may improve chronic tinnitus. Eur Radiol 2010; 20:696-703.
29. De Ridder D. A heuristic pathophysiological model of tinnitus.  Textbook of Tinnitus: Springer; 2011. p. 171-197.
30. Landgrebe M, Barta W, Rosengarth K, Frick U, Hauser S, Langguth B, et al. Neuronal correlates of symptom formation in functional somatic syndromes: a fMRI study. Neuroimage 2008; 41:1336-1344.
31. Schecklmann M, Lehner A, Poeppl TB, Kreuzer PM, Rupprecht R, Rackl J, et al. Auditory cortex is implicated in tinnitus distress: a voxel-based morphometry study. Brain Struct Funct 2013; 218:1061-1070.
32. Leaver AM, Seydell-Greenwald A, Turesky T, Morgan S, Kim HJ, Rauschecker JP. Cortico-limbic morphology separates tinnitus from tinnitus distress. Front Syst Neurosci  2012; 6:21-34.
33. Rauschecker JP, May ES, Maudoux A, Ploner M. Frontostriatal gating of tinnitus and chronic pain. Trends Cogn Sci 2015; 19:567-578.
34. Garcia-Larrea L, Perchet C, Creac’h C, Convers P, Peyron R, Laurent B, et al. Operculo-insular pain (parasylvian pain): a distinct central pain syndrome. Brain 2010; 133:2528-2539.
35. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 2007; 27:2349-2356.
36. Sadaghiani S, Hesselmann G, Kleinschmidt A. Distributed and antagonistic contributions of ongoing activity fluctuations to auditory stimulus detection. J Neurosci 2009; 29:13410-13417.
37. Zobay O, Palmer AR, Hall DA, Sereda M, Adjamian P. Source space estimation of oscillatory power and brain connectivity in tinnitus. PLoS One 2015; 10:e0120123.
38. King CT, Hashimoto K, Blonde GD, Spector AC. Unconditioned oromotor taste reactivity elicited by sucrose and quinine is unaffected by extensive bilateral damage to the gustatory zone of the insular cortex in rats. Brain Res 2015; 1599:9-19.
39. Cosme CV, Gutman AL, LaLumiere RT. The dorsal agranular insular cortex regulates the cued reinstatement of cocaine-seeking, but not food-seeking, behavior in rats. Neuropsychopharmacology 2015; 40: 2425-2433.
40. Schier LA, Blonde GD, Spector AC. Bilateral lesions in a specific subregion of posterior insular cortex impair conditioned taste aversion expression in rats. J Comp Neurol 2016; 524:54-73.
41. Paxinos G, Watson CR, Emson PC. AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods 1980; 3:129-149.
42. Kirby ED, Jensen K, Goosens KA, Kaufer D. Stereotaxic surgery for excitotoxic lesion of specific brain areas in the adult rat. J Vis Exp 2012:e4079.
43. Turner JG, Brozoski TJ, Bauer CA, Parrish JL, Myers K, Hughes LF, et al. Gap detection deficits in rats with tinnitus: a potential novel screening tool. Behav Neurosci 2006; 120:188-195.
44. Mohr D, von Ameln-Mayerhofer A, Fendt M. 5, 7-dihydroxytryptamine injections into the prefrontal cortex and nucleus accumbens differently affect prepulse inhibition and baseline startle magnitude in rats. Behavioural Brain Res 2009; 202:58-63.
45. Longenecker RJ, Alghamdi F, Rosen MJ, Galazyuk AV. Prepulse inhibition of the acoustic startle reflex vs. auditory brainstem response for hearing assessment. Hear Res 2016; 339:80-93.
46. Shadwick K, Sun W. Acoustic startle reflex and pre-pulse inhibition in tinnitus patients. J Otol 2014; 9:141-145.
47. Willott JF. Animal models of presbycusis and the aging auditory system.  Functional Neurobiology of Aging: Elsevier; 2001. p. 605-621.
48. Valsamis B, Schmid S. Habituation and prepulse inhibition of acoustic startle in rodents. J Vis Exp 2011:e3446.
49. Heller AJ. Classification and epidemiology of tinnitus. Otolaryngol Clin North Am 2003; 36:239-248.
50. Boyen K, Başkent D, van Dijk P. The gap detection test: Can it be used to diagnose tinnitus? Ear Hear 2015; 36:e138.
51. Zhang Y, Zhou W, Wang S, Zhou Q, Wang H, Zhang B, et al. The roles of subdivisions of human insula in emotion perception and auditory processing. Cereb Cortex 2018; 29:517-528.
52. Pugnaghi M, Meletti S, Castana L, Francione S, Nobili L, Mai R, et al. Features of somatosensory manifestations induced by intracranial electrical stimulations of the human insula. Clin Neurophysiol 2011; 122:2049-2058.
53. Burton H, Jones E. The posterior thalamic region and its cortical projection in New World and Old World monkeys. J Comp Neurol 1976; 168:249-301.
54. Mesulam MM, Mufson EJ. Insula of the old world monkey. Architectonics in the insulo‐orbito‐temporal component of the paralimbic brain. J Comp Neurol 1982; 212:1-22.
55. Höistad M, Barbas H. Sequence of information processing for emotions through pathways linking temporal and insular cortices with the amygdala. Neuroimage 2008; 40:1016-1033.
56. Pandya DN, Rosene DL. Some observations on trajectories and topography of commissural fibers.  Epilepsy and the Corpus Callosum: Springer; 1985. p. 21-39.
57. Mayer AR, Hanlon FM, Franco AR, Teshiba T, Thoma RJ, Clark VP, et al. The neural networks underlying auditory sensory gating. Neuroimage 2009; 44:182-189.
58. Knott V, Millar A, Fisher D. Sensory gating and source analysis of the auditory P50 in low and high suppressors. Neuroimage 2009; 44:992-1000.
59. Campbell J, Bean C, LaBrec A. Normal hearing young adults with mild tinnitus: Reduced inhibition as measured through sensory gating. Audiol Res 2018; 8:214-220.
60. Perrot X, Ryvlin P, Isnard J, GuÈnot M, Catenoix H, Fischer C, et al. Evidence for corticofugal modulation of peripheral auditory activity in humans. Cereb Cortex 2005; 16:941-948.