Experimental Brain Research

, Volume 237, Issue 4, pp 883–896 | Cite as

Low-intensity repetitive transcranial magnetic stimulation over prefrontal cortex in an animal model alters activity in the auditory thalamus but does not affect behavioural measures of tinnitus

  • Wilhelmina H. A. M. MuldersEmail author
  • K. Leggett
  • V. Mendis
  • H. Tarawneh
  • J. K. Wong
  • J. Rodger
Research Article


Tinnitus, a phantom auditory percept, is strongly associated with cochlear trauma. The latter leads to central changes in auditory pathways such as increased spontaneous activity and this may be involved in tinnitus generation. As not all people with cochlear trauma develop tinnitus, recent studies argue that non-auditory structures, such as prefrontal cortex (PFC), play an important role in tinnitus development. As part of sensory gating circuitry, PFC may modify activity in auditory thalamus and consequently in auditory cortex. Human studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive tool for neurostimulation, can alter tinnitus perception. This study used a guinea pig model of hearing loss and tinnitus to investigate effects of low-intensity rTMS (LI-rTMS) over PFC on tinnitus and spontaneous activity in auditory thalamus. In addition, immunohistochemistry for calbindin and parvalbumin in PFC was used to investigate the possible mechanism of action of LI-rTMS. Three treatment groups were compared: sham treatment, LI, low frequency (1 Hz) or LI, high frequency (10 Hz) rTMS (10 min/day, 2 weeks, weekdays only). None of the treatments affected the behavioural measures of tinnitus but spontaneous activity was significantly increased in auditory thalamus after 1 Hz and 10 Hz treatment. Immunostaining showed significant effects of rTMS on the density of calcium-binding protein expressing neurons in the dorsal regions of the PFC suggesting that rTMS treatment evoked plasticity in cortex. In addition, calbindin-positive neuron density in the superficial region of PFC was negatively correlated with spontaneous activity in auditory thalamus suggesting a possible mechanism for change in activity observed.


Tinnitus Compound action potential Gap prepulse inhibition Guinea pig Audiogram 



Compound action potential




Gap prepulse inhibition of acoustic startle






Low intensity


Medial geniculate nucleus


Phosphate buffer


Prefrontal cortex


Prepulse inhibition


Repetitive transcranial magnetic stimulation




Sound pressure level



This work was supported by grants from the Medical Health and Research Infrastructure Fund and funds provided by the School of Human Sciences UWA. JR is funded by a fellowship from MSWA (Multiple Sclerosis Western Australia) and the Perron Institute for Neurological and Translational Science. The authors would like to thank Ms. Marissa Penrose-Menz for her help in creating Fig. 1.


  1. Aazh H, Moore BCJ (2018) Thoughts about suicide and self-harm in patients with tinnitus and hyperacusis. J Am Acad Audiol 29:255–261. CrossRefGoogle Scholar
  2. Adler LE, Olincy A, Waldo M et al (1998) Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull 24:189–202CrossRefGoogle Scholar
  3. Atallah BV, Bruns W, Carandini M, Scanziani M (2012) Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. Neuron 73:159–170. CrossRefGoogle Scholar
  4. Axelsson A, Ringdahl A (1989) Tinnitus—a study of its prevalence and characteristics. Br J Audiol 23:53–62. CrossRefGoogle Scholar
  5. Baguley D, McFerran D, Hall D (2013) Tinnitus. Lancet 382:1600–1607. CrossRefGoogle Scholar
  6. Barbas H, Zikopoulos B (2007) The prefrontal cortex and flexible behavior. Neuroscientist 13:532–545. CrossRefGoogle Scholar
  7. Barbas H, Zikopoulos B, Timbie C (2011) Sensory pathways and emotional context for action in primate prefrontal cortex. Biol Psychiatry 69:1133–1139. CrossRefGoogle Scholar
  8. Barry KM, Robertson D, Mulders W (2017) Medial geniculate neurons show diverse effects in response to electrical stimulation of prefrontal cortex. Hear Res 353:204–212. CrossRefGoogle Scholar
  9. Basura GJ, Koehler SD, Shore SE (2015) Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus. J Neurophysiol 114:3064–3075. CrossRefGoogle Scholar
  10. Bauer CA, Brozoski TJ (2006) Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope 116:675–681CrossRefGoogle Scholar
  11. Benali A, Trippe J, Weiler E et al (2011) Theta-burst transcranial magnetic stimulation alters cortical inhibition. J Neurosci 31:1193–1203. CrossRefGoogle Scholar
  12. Bhatt JM, Lin HW, Bhattacharyya N (2016) Prevalence, severity, exposures, and treatment patterns of tinnitus in the United States. JAMA Otolaryngol Head Neck Surg 142:959–965. CrossRefGoogle Scholar
  13. Bhatt JM, Bhattacharyya N, Lin HW (2017) Relationships between tinnitus and the prevalence of anxiety and depression. Laryngoscope 127:466–469. CrossRefGoogle Scholar
  14. Brozoski TJ, Ciobanu L, Bauer CA (2007a) Central neural activity in rats with tinnitus evaluated with manganese-enhanced magnetic resonance imaging (MEMRI). Hear Res 228:168–179CrossRefGoogle Scholar
  15. Brozoski TJ, Spires TJ, Bauer CA (2007b) Vigabatrin, a GABA transaminase inhibitor, reversibly eliminates tinnitus in an animal model. J Assoc Res Otolaryngol 8:105–118CrossRefGoogle Scholar
  16. Cai R, Caspary DM (2015) GABAergic inhibition shapes SAM responses in rat auditory thalamus. Neuroscience 299:146–155. CrossRefGoogle Scholar
  17. Capone F, Dileone M, Profice P et al (2009) Does exposure to extremely low frequency magnetic fields produce functional changes in human brain? J Neural Transm (Vienna) 116:257–265. CrossRefGoogle Scholar
  18. Castillo-Padilla DV, Funke K (2016) Effects of chronic iTBS-rTMS and enriched environment on visual cortex early critical period and visual pattern discrimination in dark-reared rats. Dev Neurobiol 76:19–33. CrossRefGoogle Scholar
  19. De Ridder D, Song JJ, Vanneste S (2013) Frontal cortex TMS for tinnitus. Brain Stimul 6:355–362. CrossRefGoogle Scholar
  20. De Ridder D, Vanneste S, Weisz N, Londero A, Schlee W, Elgoyhen AB, Langguth B (2014) An integrative model of auditory phantom perception: tinnitus as a unified percept of interacting separable subnetworks. Neurosci Biobehav Rev 44:16–32. CrossRefGoogle Scholar
  21. De Ridder D, Vanneste S, Langguth B, Llinas R (2015) thalamocortical dysrhythmia: a theoretical update in tinnitus. Front Neurol 6:124. CrossRefGoogle Scholar
  22. Dehmel S, Eisinger D, Shore SE (2012) Gap prepulse inhibition and auditory brainstem-evoked potentials as objective measures for tinnitus in guinea pigs. Front Syst Neurosci 6:42. CrossRefGoogle Scholar
  23. Eggermont JJ, Roberts LE (2004) The neuroscience of tinnitus. Trends Neurosci 27:676–682CrossRefGoogle Scholar
  24. Eggermont JJ, Roberts LE (2015) Tinnitus: animal models and findings in humans. Cell Tissue Res 361:311–336. CrossRefGoogle Scholar
  25. Fioretti A, Eibenstein A, Fusetti M (2011) New trends in tinnitus management. Open Neurol J 5:12–17. CrossRefGoogle Scholar
  26. Folmer RL, Griest SE, Martin WH (2001) Chronic tinnitus as phantom auditory pain. Otolaryngol Head Neck Surg 124:394–400. CrossRefGoogle Scholar
  27. Fuggetta G, Noh NA (2013) A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders. Exp Neurol 245:87–95. CrossRefGoogle Scholar
  28. Gordon JS, Griest SE, Thielman EJ et al (2016) Audiologic characteristics in a sample of recently-separated military Veterans: the noise outcomes in servicemembers epidemiology study (NOISE study). Hear Res. Google Scholar
  29. Grehl S, Viola HM, Fuller-Carter PI et al (2014) Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies. Brain Stimul. Google Scholar
  30. Grehl S, Viola HM, Fuller-Carter PI et al (2015) Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies. Brain Stimul 8:114–123. CrossRefGoogle Scholar
  31. Gu JW, Halpin CF, Nam EC, Levine RA, Melcher JR (2010) Tinnitus, diminished sound-level tolerance, and elevated auditory activity in humans with clinically normal hearing sensitivity. J Neurophysiol 104:3361–3370. CrossRefGoogle Scholar
  32. Heath A, Lindberg DR, Makowiecki K et al (2018) Medium- and high-intensity rTMS reduces psychomotor agitation with distinct neurobiologic mechanisms. Transl Psychiatry 8:126. CrossRefGoogle Scholar
  33. Hendry SH, Jones EG, Emson PC, Lawson DE, Heizmann CW, Streit P (1989) Two classes of cortical GABA neurons defined by differential calcium binding protein immunoreactivities. Exp Brain Res 76:467–472CrossRefGoogle Scholar
  34. Hinton DE, Chhean D, Pich V, Hofmann SG, Barlow DH (2006) Tinnitus among Cambodian refugees: relationship to PTSD severity. J Trauma Stress 19:541–546. CrossRefGoogle Scholar
  35. Hoffman HJ, Reed GW (2004) Epidemiology of tinnitus. In: Snow JBJ (ed) Tinnitus: theory and management. BC Dekker, Hamilton, pp 16–41Google Scholar
  36. Hoppenrath K, Funke K (2013) Time-course of changes in neuronal activity markers following iTBS-TMS of the rat neocortex. Neurosci Lett 536:19–23. CrossRefGoogle Scholar
  37. Jastreboff PJ (2007) Tinnitus retraining therapy. Prog Brain Res 166:415–423CrossRefGoogle Scholar
  38. John YJ, Zikopoulos B, Bullock D, Barbas H (2016) The emotional gatekeeper: a computational model of attentional selection and suppression through the pathway from the amygdala to the inhibitory thalamic reticular nucleus. PLoS Comput Biol 12:e1004722. CrossRefGoogle Scholar
  39. Kalappa BI, Brozoski TJ, Turner JG, Caspary DM (2014) Single unit hyperactivity and bursting in the auditory thalamus of awake rats directly correlates with behavioural evidence of tinnitus. J Physiol 592:5065–5078. CrossRefGoogle Scholar
  40. Kaltenbach JA, Afman CE (2000) Hyperactivity in the dorsal cochlear nucleus after intense sound exposure and its resemblance to tone-evoked activity: a physiological model for tinnitus. Hear Res 140:165–172CrossRefGoogle Scholar
  41. Kleinjung T, Eichhammer P, Landgrebe M et al (2008) Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study. Otolaryngol Head Neck Surg 138:497–501. CrossRefGoogle Scholar
  42. Labedi A, Benali A, Mix A, Neubacher U, Funke K (2014) Modulation of inhibitory activity markers by intermittent theta-burst stimulation in rat cortex is NMDA-receptor dependent. Brain Stimul 7:394–400. CrossRefGoogle Scholar
  43. Lee JC, Blumberger DM, Fitzgerald PB, Daskalakis ZJ, Levinson AJ (2012) The role of transcranial magnetic stimulation in treatment-resistant depression: a review. Curr Pharm Des 18:5846–5852CrossRefGoogle Scholar
  44. Leggett K, Mendis V, Mulders WHAM (2018) Divergent responses in the gap prepulse inhibition of the acoustic startle reflex in two different guinea pig colonies. Int Tinnitus J 22:1–9Google Scholar
  45. Lehner A, Schecklmann M, Kreuzer PM, Poeppl TB, Rupprecht R, Langguth B (2013) Comparing single-site with multisite rTMS for the treatment of chronic tinnitus—clinical effects and neuroscientific insights: study protocol for a randomized controlled trial. Trials 14:269. CrossRefGoogle Scholar
  46. Lensjo KK, Christensen AC, Tennoe S, Fyhn M, Hafting T (2017) Differential expression and cell-type specificity of perineuronal nets in hippocampus, medial entorhinal cortex, and visual cortex examined in the rat and mouse. eNeuro. Google Scholar
  47. Makowiecki K, Garrett A, Harvey AR, Rodger J (2018) Low-intensity repetitive transcranial magnetic stimulation requires concurrent visual system activity to modulate visual evoked potentials in adult mice. Sci Rep 8:5792. CrossRefGoogle Scholar
  48. Melcher JR, Sigalovsky IS, Guinan JJ Jr, Levine RA (2000) Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 83:1058–1072CrossRefGoogle Scholar
  49. Melcher JR, Levine RA, Bergevin C, Norris B (2009) The auditory midbrain of people with tinnitus: abnormal sound-evoked activity revisited. Hear Res 257:63–74. CrossRefGoogle Scholar
  50. Mix A, Benali A, Funke K (2014) Strain differences in the effect of rTMS on cortical expression of calcium-binding proteins in rats. Exp Brain Res 232:435–442. CrossRefGoogle Scholar
  51. Moazami-Goudarzi M, Michels L, Weisz N, Jeanmonod D (2010) Temporo-insular enhancement of EEG low and high frequencies in patients with chronic tinnitus. QEEG study of chronic tinnitus patients. BMC Neurosci 11:40. CrossRefGoogle Scholar
  52. Mulders WH, Robertson D (2009) Hyperactivity in the auditory midbrain after acoustic trauma: dependence on cochlear activity. Neuroscience 164:733–746CrossRefGoogle Scholar
  53. Mulders WH, Robertson D (2011) Progressive centralization of midbrain hyperactivity after acoustic trauma. Neuroscience 192:753–760. CrossRefGoogle Scholar
  54. Mulders WH, Ding D, Salvi R, Robertson D (2011) Relationship between auditory thresholds, central spontaneous activity, and hair cell loss after acoustic trauma. J Comp Neurol 519:2637–2647. CrossRefGoogle Scholar
  55. Mulders WH, Barry KM, Robertson D (2014) Effects of furosemide on cochlear neural activity, central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig. PLoS One 9:e97948. CrossRefGoogle Scholar
  56. Mulders WHAM, Vooys V, Makowiecki K, Tang A, Rodger J (2016) The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus. Sci Rep 6:38234. (2016)CrossRefGoogle Scholar
  57. Pell GS, Roth Y, Zangen A (2011) Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms. Prog Neurobiol 93:59–98. CrossRefGoogle Scholar
  58. Pinault D (2004) The thalamic reticular nucleus: structure, function and concept. Brain Res Brain Res Rev 46:1–31. CrossRefGoogle Scholar
  59. Rapisarda C, Bacchelli B (1977) The brain of the guinea pig in stereotaxic coordinates. Arch Sci Biol (Bologna) 61:1–37Google Scholar
  60. Rauschecker JP, Leaver AM, Muhlau M (2010) Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 66:819–826. CrossRefGoogle Scholar
  61. Rauschecker JP, May ES, Maudoux A, Ploner M (2015) Frontostriatal gating of tinnitus and chronic pain. Trends Cogn Sci 19:567–578. CrossRefGoogle Scholar
  62. Rodger J, Sherrard RM (2015) Optimising repetitive transcranial magnetic stimulation for neural circuit repair following traumatic brain injury. Neural Regen Res 10:357–359. CrossRefGoogle Scholar
  63. Seewoo BJ, Feindel KW, Etherington SJ, Rodger J (2018) Resting-state fMRI study of brain activation using low-intensity repetitive transcranial magnetic stimulation in rats. Sci Rep 8:6706. CrossRefGoogle Scholar
  64. Tang A, Garrett A, Woodward R et al (2015a) Construction and evaluation of rodent-specific TMS coils. Brain Stimul 2:338CrossRefGoogle Scholar
  65. Tang A, Thickbroom G, Rodger J (2015b) Repetitive transcranial magnetic stimulation of the brain: mechanisms from animal and experimental models. Neuroscientist. Google Scholar
  66. Tang AD, Makowiecki K, Bartlett C, Rodger J (2015c) Low intensity repetitive transcranial magnetic stimulation does not induce cell survival or regeneration in a mouse optic nerve crush model. PLoS One 10:e0126949. CrossRefGoogle Scholar
  67. Tang AD, Hong I, Boddington LJ, Garrett AR, Etherington S, Reynolds JN, Rodger J (2016a) Low-intensity repetitive magnetic stimulation lowers action potential threshold and increases spike firing in layer 5 pyramidal neurons in vitro. Neuroscience 335:64–71. CrossRefGoogle Scholar
  68. Tang AD, Lowe AS, Garrett AR et al (2016b) Construction and evaluation of rodent-specific rTMS coils. Front Neural Circuits. Google Scholar
  69. Thickbroom GW (2007) Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp Brain Res 180:583–593. CrossRefGoogle Scholar
  70. Turner JG, Brozoski TJ, Bauer CA, Parrish JL, Myers K, Hughes LF, Caspary DM (2006) Gap detection deficits in rats with tinnitus: a potential novel screening tool. Behav Neurosci 120:188–195. CrossRefGoogle Scholar
  71. Vanneste S, De Ridder D (2011) Bifrontal transcranial direct current stimulation modulates tinnitus intensity and tinnitus-distress-related brain activity. Eur J Neurosci 34:605–614. CrossRefGoogle Scholar
  72. Vanneste S, Plazier M, Ost J, van der Loo E, Van de Heyning P, De Ridder D (2010) Bilateral dorsolateral prefrontal cortex modulation for tinnitus by transcranial direct current stimulation: a preliminary clinical study. Exp Brain Res 202:779–785. CrossRefGoogle Scholar
  73. Vlachos A, Muller-Dahlhaus F, Rosskopp J, Lenz M, Ziemann U, Deller T (2012) Repetitive magnetic stimulation induces functional and structural plasticity of excitatory postsynapses in mouse organotypic hippocampal slice cultures. J Neurosci 32:17514–17523. CrossRefGoogle Scholar
  74. Vogler DP, Robertson D, Mulders WH (2011) Hyperactivity in the ventral cochlear nucleus after cochlear trauma. J Neurosci 31:6639–6645. CrossRefGoogle Scholar
  75. Wassermann EM, Zimmermann T (2012) Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther 133:98–107. CrossRefGoogle Scholar
  76. Wilson MT, St George L (2016) Repetitive transcranial magnetic stimulation: a call for better data. Front Neural Circuits 10:57. CrossRefGoogle Scholar
  77. Winsky L, Kuznicki J (1996) Antibody recognition of calcium-binding proteins depends on their calcium-binding status. J Neurochem 66:764–771CrossRefGoogle Scholar
  78. Zhang J (2013) Auditory cortex stimulation to suppress tinnitus: mechanisms and strategies. Hear Res 295:38–57. CrossRefGoogle Scholar
  79. Zikopoulos B, Barbas H (2006) Prefrontal projections to the thalamic reticular nucleus form a unique circuit for attentional mechanisms. J Neurosci 26:7348–7361. CrossRefGoogle Scholar
  80. Zikopoulos B, Barbas H (2007) Circuits for multisensory integration and attentional modulation through the prefrontal cortex and the thalamic reticular nucleus in primates. Rev Neurosci 18:417–438CrossRefGoogle Scholar
  81. Zikopoulos B, Barbas H (2012) Pathways for emotions and attention converge on the thalamic reticular nucleus in primates. J Neurosci 32:5338–5350. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Human SciencesUniversity of Western AustraliaCrawleyAustralia
  2. 2.School of Biological SciencesUniversity of Western AustraliaCrawleyAustralia
  3. 3.Ear Science Institute AustraliaSubiacoAustralia
  4. 4.Perron Institute for Neurological and Translational ScienceUniversity of Western AustraliaCrawleyAustralia

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