Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Reversing pathological neural activity using targeted plasticity


Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus1,2,3. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively1,4. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations5. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: VNS–tone pairing causes map plasticity.
Figure 2: VNS/multiple tone pairing eliminates the behavioural correlate of tinnitus.
Figure 3: VNS/multiple tone pairing reverses map distortion.
Figure 4: Neurophysiological properties of naive, sham and therapy rats.


  1. Flor, H. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 375, 482–484 (1995)

    Article  ADS  CAS  Google Scholar 

  2. Eggermont, J. J. & Roberts, L. E. The neuroscience of tinnitus. Trends Neurosci. 27, 676–682 (2004)

    Article  CAS  Google Scholar 

  3. Møller, A. R. Tinnitus and pain. Prog. Brain Res. 166, 47–53 (2007)

    Article  ADS  Google Scholar 

  4. Mühlnickel, W., Elbert, T., Taub, E. & Flor, H. Reorganization of auditory cortex in tinnitus. Proc. Natl Acad. Sci. USA 95, 10340–10343 (1998)

    Article  ADS  Google Scholar 

  5. De Ridder, D., De Mulder, D., Menovsky, T., Sunaert, S. & Kovacs, S. Electrical stimulation of auditory and somatosensory cortices for treatment of tinnitus and pain. Prog. Brain Res. 166, 377–388 (2007)

    Article  CAS  Google Scholar 

  6. Okamoto, H., Stracke, H., Stoll, W. & Pantev, C. Listening to tailor-made notched music reduces tinnitus loudness and tinnitus-related auditory cortex activity. Proc. Natl Acad. Sci. USA 107, 1207–1210 (2010)

    Article  ADS  CAS  Google Scholar 

  7. Flor, H., Denke, C., Schaefer, M. & Grüsser, S. Effect of sensory discrimination training on cortical reorganization and phantom limb pain. Lancet 357, 1763–1764 (2001)

    Article  CAS  Google Scholar 

  8. Kilgard, M. P. & Merzenich, M. M. Cortical map reorganization enabled by nucleus basalis activity. Science 279, 1714–1718 (1998)

    Article  ADS  CAS  Google Scholar 

  9. Dorr, A. E. & Debonnel, G. Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. J. Pharmacol. Exp. Ther. 318, 890–898 (2006)

    Article  CAS  Google Scholar 

  10. Clark, K. B., Naritoku, D. K., Smith, D. C., Browning, R. A. & Jensen, R. A. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neurosci. 2, 94–98 (1999)

    Article  CAS  Google Scholar 

  11. Bao, S., Chan, V. T. & Merzenich, N. M. Cortical remodelling induced by activity of ventral tegmental dopamine neurons. Nature 412, 79–83 (2001)

    Article  ADS  CAS  Google Scholar 

  12. Bollinger, J. J. Adult Auditory Cortical Plasticity Modulated by Locus Coeruleus Activity. PhD thesis, Univ. California San Francisco. (2006)

  13. Ben-Menachem, E. Vagus nerve stimulation, side effects, and long-term safety. J. Clin. Neurophysiol. 18, 415–418 (2001)

    Article  CAS  Google Scholar 

  14. Noreña, A. J., Tomita, M. & Eggermont, J. J. Neural changes in cat auditory cortex after a transient pure-tone trauma. J. Neurophysiol. 90, 2387–2401 (2003)

    Article  Google Scholar 

  15. Salvi, R. J., Wang, J. & Ding, D. Auditory plasticity and hyperactivity following cochlear damage. Hear. Res. 147, 261–274 (2000)

    Article  CAS  Google Scholar 

  16. Eggermont, J. in Tinnitus: Pathophysiology and Treatment (eds Langguth, B., Hajak, G., Kleinjung, T., Cacace, A., & Møller, A. R. ) 19–35 (Prog. Brain Res. 166, Elsevier, 2007)

    Book  Google Scholar 

  17. Turner, J. G. et al. Gap detection deficits in rats with tinnitus: a potential novel screening tool. Behav. Neurosci. 120, 188–195 (2006)

    Article  Google Scholar 

  18. Murphy, W. J. & van Campen, L. E. Temporary threshold shift in ABRs and DPOAEs following noise exposure in Long–Evans rats. J. Acoust. Soc. Am. 109, 2373 (2001)

    Article  ADS  Google Scholar 

  19. Bauer, C. A., Turner, J. G., Caspary, D. M., Myers, K. S. & Brozoski, T. J. Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. J. Neurosci. Res. 86, 2564–2578 (2008)

    Article  CAS  Google Scholar 

  20. Bauer, C. A. & Brozoski, T. J. Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model. J. Assoc. Res. Otolaryngol. 2, 54–64 (2001)

    Article  CAS  Google Scholar 

  21. Lobarinas, E., Sun, W., Cushing, R. & Salvi, R. A novel behavioral paradigm for assessing tinnitus using schedule-induced polydipsia avoidance conditioning (SIP-AC). Hear. Res. 190, 109–114 (2004)

    Article  Google Scholar 

  22. Moore, B. C. & Sandhya, V. The relationship between tinnitus pitch and the edge frequency of the audiogram in individuals with hearing impairment and tonal tinnitus. Hear. Res. 261, 51–56 (2010)

    Article  Google Scholar 

  23. Yang, G. et al. Salicylate induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats. Hear. Res. 226, 244–253 (2007)

    Article  CAS  Google Scholar 

  24. Noreña, A. J. & Eggermont, J. J. Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization. J. Neurosci. 25, 699–705 (2005)

    Article  Google Scholar 

  25. Kilgard, M. P., Vazquez, J. L., Engineer, N. D. & Pandya, P. K. Experience dependent plasticity alters cortical synchronization. Hear. Res. 229, 171–79 (2007)

    Article  CAS  Google Scholar 

  26. Dietrich, V., Nieschalk, M., Stoll, W., Rajan, R. & Pantev, C. Cortical reorganization in patients with high frequency cochlear hearing loss. Hear. Res. 158, 95–101 (2001)

    Article  CAS  Google Scholar 

  27. Dauman, R. & Cazals, Y. Auditory frequency selectivity and tinnitus. Arch. Otorhinolaryngol. 246, 252–255 (1989)

    Article  CAS  Google Scholar 

  28. Kaltenbach, J. A. & Afman, C. E. 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, 165–172 (2000)

    Article  CAS  Google Scholar 

  29. Diesch, E., Andermann, M., Flor, H. & Rupp, A. Interaction among the components of multiple auditory steady-state responses: enhancement in tinnitus patients, inhibition in controls. Neuroscience 167, 540–553 (2010)

    Article  CAS  Google Scholar 

  30. Bauer, C. A., Brozoski, T. J. & Myers, K. Primary afferent dendrite degeneration as a cause of tinnitus. J. Neurosci. Res. 85, 1489–1498 (2007)

    Article  CAS  Google Scholar 

  31. König, O., Schaette, R., Kempter, R. & Gross, M. Course of hearing loss and occurrence of tinnitus. Hear. Res. 221, 59–64 (2006)

    Article  Google Scholar 

  32. Burns, E. M. A comparison of variability among measurements of subjective tinnitus and objective stimuli. Audiology 23, 426–440 (1984)

    Article  CAS  Google Scholar 

  33. Ochi, K., Ohashi, T. & Kenmochi, M. Hearing impairment and tinnitus pitch in patients with unilateral tinnitus: comparison of sudden hearing loss and chronic tinnitus. Laryngoscope 113, 427–431 (2003)

    Article  Google Scholar 

  34. Engineer, N. D. et al. Environmental enrichment improves response strength, threshold, selectivity, and latency of auditory cortex neurons. J. Neurophysiol. 92, 73–82 (2004)

    Article  Google Scholar 

Download references


We would like to thank A. Kuzu, J. Omana, D. Vuppala, H. Rasul, M. Fink, E. Hanacik, R. Miller and C. Walker for help with rat behavioural training. We would also like to thank J. Eggermont, A. Møller, C. Bauer, J. Fritz, H. Reed, C. Engineer, A. Reed, M. Brosch, R. Rennaker, R. Beitel, V. Miller, C. McIntyre, G. White, P. Pandya, R. Tyler and D. deRidder for suggestions about earlier versions of the manuscript. This work was supported by the James S. McDonnell Foundation, the Texas Advanced Research Program, the National Institute for Deafness and other Communication Disorders, and MicroTransponder Inc.

Author information

Authors and Affiliations



N.D.E., J.R.R., J.D.S., S.P.S. and M.S.B. did the behaviour training sessions, noise exposure and auditory brainstem response recordings. N.D.E., J.R.R., J.D.S., W.A.V. and J.A.S. did cortical microelectrode mappings. J.A.S. did the A1 mapping surgeries. S.P.S. and N.D.E. did all the VNS implant surgeries. M.P.K. and N.D.E. designed the experiments, wrote the manuscript and performed data analysis. All authors discussed the paper and commented on the manuscript.

Corresponding author

Correspondence to Navzer D. Engineer.

Ethics declarations

Competing interests

N.D.E. is a full-time employee of MicroTransponder Inc (Austin, Texas), which develops therapies using neurostimulation. M.P.K. is a consultant and shareholder of MicroTransponder Inc.

Supplementary information

Supplementary Information

The file contains a Supplementary Discussion, additional references and Supplementary Figures 1-17 with legends. (PDF 1768 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Engineer, N., Riley, J., Seale, J. et al. Reversing pathological neural activity using targeted plasticity. Nature 470, 101–104 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing