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Reversing pathological neural activity using targeted plasticity

Nature volume 470, pages 101–104 (2011)Cite this article

Abstract

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.

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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.

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References

  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 

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Acknowledgements

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.

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Authors and Affiliations

  1. Cortical Plasticity Laboratory, Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, 75080, Texas, USA

    Navzer D. Engineer, Jonathan R. Riley, Jonathan D. Seale, Will A. Vrana, Jai A. Shetake, Sindhu P. Sudanagunta, Michael S. Borland & Michael P. Kilgard

  2. MicroTransponder Inc., 2802 Flintrock Trace, Suite 225, Austin, Texas 78738, USA ,

    Navzer D. Engineer

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  1. Navzer D. Engineer
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Contributions

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.

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Correspondence to Navzer D. Engineer.

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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.

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Engineer, N., Riley, J., Seale, J. et al. Reversing pathological neural activity using targeted plasticity. Nature 470, 101–104 (2011). https://doi.org/10.1038/nature09656

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