- Email: [email protected]
Auditory Neuroscience: How to Stop Tinnitus by Buzzing the Vagus
Dispatch R263
It is hypothesized that structural changes within the kinetochore complex impact microtubuleattachment stability and SAC function (reviewed by [12]). Specifically, an increase in the distance between the inner and outer kinetochore, deemed intrakinetochore stretch, occurs upon binding to dynamic microtubules [13,14]. Introduction of intrakinetochore stretch correlates with inactivation of the wait-anaphase signal and is postulated to promote a higher affinity interaction between the outer kinetochore and microtubules by regulating phosphorylation of the KMN complex. At the time this Dispatch was being prepared, no known compliant or ‘stretchable’ component(s) between the inner and outer kinetochore had been characterized. With help from Przewloka et al. [2] and Screpanti et al. [3] we now know that CENP-C is in the right place; the next question is whether it (or perhaps CENP-Cassociated chromatin) is being stretched. The ability of the amino terminus of CENP-C to contact the Mis12 complex is clearly conserved between Drosophila and humans. However, what is happening outside the amino terminus of the molecule is murky. For example, in chicken cells, immunoprecipitated CENP-C exclusively interacted with histone-H3containing chromatin [15]; however, human CENP-C was found to directly interact with CENP-A-containing nucleosomes but not H3 nucleosomes in vitro [5]. Thus, it has been proposed, and is reiterated by Screpanti et al. [3], that CENP-C could interact with both CENP-A and H3 nucleosomes, thereby crosslinking distinct blocks of centromeric chromatin [16]. Obviously this issue remains to be resolved. Even the role of CENP-C as a bridge between the inner and outer kinetochore is not entirely conserved. Recent work in budding yeast found that the Mis12 complex did not interact with CENP-C but rather with another CCAN complex that is generally conserved from yeast to man but has not been identified in either Drosophila or Caenorhabditis elegans [17]. It is exciting to imagine that there are additional, and potentially novel, molecular connections between the inner and outer kinetochore that remain to be characterized. After all, what’s great about missing links is that there
are always more out there just waiting to be found.
12.
References 1. Cheeseman, I.M., and Desai, A. (2008). Molecular architecture of the kinetochore-microtubule interface. Nat. Rev. Mol. Cell Biol. 9, 33–46. 2. Przewloka, M.R., Zsolt, V., BolanosGarcia, V.M., Debski, J., Dadlez, M., and Glover, D.M. (2011). CENP-C is a structural platform for kinetochore assembly. Curr. Biol. 21, 399–405. 3. Screpanti, E., De Antoni, A., Alushin, G.M., Petrovic, A., Melis, T., Nogales, E., and Musacchio, A. (2011). Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. Curr. Biol. 21, 391–398. 4. Saitoh, H., Tomkiel, J., Cooke, C.A., Ratrie, H., 3rd, Maurer, M., Rothfield, N.F., and Earnshaw, W.C. (1992). CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate. Cell 70, 115–125. 5. Carroll, C.W., Milks, K.J., and Straight, A.F. (2010). Dual recognition of CENP-A nucleosomes is required for centromere assembly. J. Cell Biol. 189, 1143–1155. 6. Milks, K.J., Moree, B., and Straight, A.F. (2009). Dissection of CENP-C-directed centromere and kinetochore assembly. Mol. Biol. Cell 20, 4246–4255. 7. Yang, C.H., Tomkiel, J., Saitoh, H., Johnson, D.H., and Earnshaw, W.C. (1996). Identification of overlapping DNA-binding and centromere-targeting domains in the human kinetochore protein CENP-C. Mol. Cell Biol. 16, 3576–3586. 8. Petrovic, A., Pasqualato, S., Dube, P., Krenn, V., Santaguida, S., Cittaro, D., Monzani, S., Massimiliano, L., Keller, J., Tarricone, A., et al. (2010). The MIS12 complex is a protein interaction hub for outer kinetochore assembly. J. Cell Biol. 190, 835–852. 9. Musacchio, A., and Salmon, E.D. (2007). The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8, 379–393. 10. DeLuca, J.G., Howell, B.J., Canman, J.C., Hickey, J.M., Fang, G., and Salmon, E.D. (2003). Nuf2 and Hec1 are required for retention of the checkpoint proteins Mad1 and Mad2 to kinetochores. Curr. Biol. 13, 2103–2109. 11. Kiyomitsu, T., Obuse, C., and Yanagida, M. (2007). Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic
13.
14.
15.
16.
17.
18.
19.
20.
checkpoint through direct interaction with Bub1 and BubR1. Dev. Cell 13, 663–676. Maresca, T.J., and Salmon, E.D. (2010). Welcome to a new kind of tension: translating kinetochore mechanics into a wait-anaphase signal. J. Cell Sci. 123, 825–835. Maresca, T.J., and Salmon, E.D. (2009). Intrakinetochore stretch is associated with changes in kinetochore phosphorylation and spindle assembly checkpoint activity. J. Cell Biol. 184, 373–381. Uchida, K.S., Takagaki, K., Kumada, K., Hirayama, Y., Noda, T., and Hirota, T. (2009). Kinetochore stretching inactivates the spindle assembly checkpoint. J. Cell Biol. 184, 383–390. Hori, T., Amano, M., Suzuki, A., Backer, C.B., Welburn, J.P., Dong, Y., McEwen, B.F., Shang, W.H., Suzuki, E., Okawa, K., et al. (2008). CCAN makes multiple contacts with centromeric DNA to provide distinct pathways to the outer kinetochore. Cell 135, 1039–1052. Ribeiro, S.A., Vagnarelli, P., Dong, Y., Hori, T., McEwen, B.F., Fukagawa, T., Flors, C., and Earnshaw, W.C. (2010). A super-resolution map of the vertebrate kinetochore. Proc. Natl. Acad. Sci. USA 107, 10484–10489. Hornung, P., Maier, M., Alushin, G.M., Lander, G.C., Nogales, E., and Westermann, S. (2011). Molecular architecture and connectivity of the budding yeast Mtw1 kinetochore complex. J. Mol. Biol. 405, 548–559. Maskell, D.P., Hu, X.W., and Singleton, M.R. (2010). Molecular architecture and assembly of the yeast kinetochore MIND complex. J. Cell Biol. 190, 823–834. Schittenhelm, R.B., Heeger, S., Althoff, F., Walter, A., Heidmann, S., Mechtler, K., and Lehner, C.F. (2007). Spatial organization of a ubiquitous eukaryotic kinetochore protein network in Drosophila chromosomes. Chromosoma 116, 385–402. Wan, X., O’Quinn, R.P., Pierce, H.L., Joglekar, A.P., Gall, W.E., DeLuca, J.G., Carroll, C.W., Liu, S.T., Yen, T.J., McEwen, B.F., et al. (2009). Protein architecture of the human kinetochore microtubule attachment site. Cell 137, 672–684.
Biology Department, University of Massachusetts Amherst, Amherst, MA 01003, USA. E-mail: [email protected]
DOI: 10.1016/j.cub.2011.02.026
Auditory Neuroscience: How to Stop Tinnitus by Buzzing the Vagus Recent observations linking the vagus nerve to plasticity in the central nervous system could pave the way to new treatments for one of the most common and intractable disorders of the auditory system. Jan Schnupp Many millions of people (an estimated 14% of the population) suffer from persistent tinnitus, a constant ‘ringing in their ears’, and about 2% find their tinnitus very disruptive, as it interferes with their ability to follow conversations, to concentrate, or to enjoy beautiful music or a quiet
night’s sleep. Tinnitus is therefore a major public health issue, but treatment options remain limited. While the causes and symptoms of tinnitus may be quite diverse, tinnitus often arises when the central auditory pathway struggles to adapt to focal damage to the sensory structures of the cochlea, typically by excessive noise exposure.
Current Biology Vol 21 No 7 R264
A Normal
B Lesioned
Current Biology
Figure 1. Reorganization of the auditory pathway after focal damage. (A) Highly schematic representation of the ascending auditory pathway. Neurons tuned to varying frequencies are tonotopically arranged from low (blue) to high (red), and connected through feed-forward and lateral connections. (B) Noise trauma can cause focal damage to the input layer (the cochlea). The network responds by changing its connectivity so as to compensate for the lost input. This leads to an overrepresentation of the frequencies at the lesion edges (shown here as more low (blue) and high (red) frequency bands to compensate for the loss of mid (green and yellow) frequencies). These changes also heighten overall excitability, and increase spontaneous activity and firing synchrony among neighboring cells.
Neurons in the central auditory pathway are thought to respond to such a loss of sensitivity at the periphery by changing their connectivity. Figure 1 provides a simplified illustration of this process, and shows how changes in the strength of lateral connectivity may compensate for the loss of a subset of input channels. However, the auditory pathway also comprises a wealth of inhibitory connections and feedback loops, and these may also change after noise damage and play a role in tinnitus. At the level of auditory cortex, these changes lead to broader tuning curves, increases in spontaneous firing, a greater synchronization of neural activity, and a ‘sensitization’ such that cortical neurons fire more vigorously to sounds of modest intensity. Furthermore, the normal cortical tonotopic mapping is distorted so that frequencies
adjacent to the ‘deaf spot’ become overrepresented [1,2]. These changes may be partly adaptive, making the most of the remaining inputs, but they also seem to favor the generation of tinnitus as a sort of auditory phantom sensation. Indeed, phantom limb sensations following amputation and tinnitus following focal cochlear damage may come about in a similar manner [3,4]. None of this paints a very encouraging picture for tinnitus sufferers. Too many details of the disease process remain unknown, and few of the prevalent ideas and theories suggest any obvious targets for therapy. However, it would be wrong to think that there is no hope of progress. Now, recent research carried out by Navzer Engineer and colleagues in the laboratory of Mike Kilgard [5] offers some exciting new perspectives. To understand their contribution, we must bear in mind that current theories of tinnitus stem from animal experiments, predominantly on rats. Documenting physiological changes in a rat’s central auditory system after noise trauma is not too difficult, but how do we know whether the rats experience tinnitus? We can’t easily ask them. To diagnose tinnitus in animals, researchers often use a trick which exploits the animals’ natural startle reflex [6]. Most animals startle in response to an unexpected, loud ‘bang’, and, if the animals happen to sit on a platform fitted with accelerometers when they perform the little ‘jump’ associated with the startle reflex, then the amplitude of their startle can be measured. Unsurprisingly, the startle reflex amplitude is much smaller if the animals are able to anticipate the bang, and this can be exploited to test animals for tinnitus. If there is a continuous, fairly quiet ‘narrowband’ background noise (a bit like a faint noisy whistling), and this is interrupted by brief silent periods only just before each loud ‘bang’, then normal animals quickly learn to recognize the silent gap as warning, and their startle response is suppressed. However, if an animal suffers from tinnitus which covers the silent periods, then it will miss the silent gap, fail to anticipate the impending ‘bang’, and startle strongly. A lack of startle suppression is therefore often used as a measure of tinnitus. Engineer et al. [5] used this startle paradigm in a study aiming not just to clarify the physiology of tinnitus, but
also to treat it. As we had seen above, noise trauma triggers a number of physiological changes in the cortex, but which, if any, of these changes is causally related to tinnitus is unclear. By studying individual variations across a cohort of noise-exposed rats, Engineer and colleagues [5] were able to observe that large map distortion, broadening of tuning curves and increased evoked responses all correlated highly with poor startle suppression responses (and therefore presumably pronounced tinnitus), but increases in spontaneous activity and synchronized firing did not. This seems to argue against increased spontaneous or synchronized activity playing a key role in tinnitus generation, which is somewhat counter-intuitive, as one might expect ongoing spontaneous activity to be at the heart of phantom sensations that occur in the absence of external sounds. Engineer and colleagues [5] then set about trying to reverse the physiological changes, as well as the tinnitus, by stimulating the vagus nerve (10th cranial). At first sight, the vagus may seem an unlikely candidate for this purpose. It derives its name from the latin word for ‘wanderer’, as it roams along a complicated branching path through our necks and much of our bodies, where it subserves a wide range of functions, including the control of our heart rate, activity of the digestive system, gag and cough reflexes, or the delivery of taste information from the back of the throat to the brain, but it does not normally mediate or modulate auditory sensations. The idea that the vagus may nevertheless play a useful role in tinnitus therapy stemmed from clinical observations that electrical vagal nerve stimulation (VNS) can alleviate epilepsy [7] and depression [8]. Of course, direct electrical stimulation of the vagus can have all manner of unpleasant side effects, including causing gagging or coughing fits, and driving the heart rate and blood pressure down to the point of unconsciousness. To avoid this, therapeutic VNS targets the cervical branch of the left vagus nerve, which is not strongly connected to the heart, and the electrical stimulation is kept quite gentle. VNS probably works by activating the brain’s neuromodulator systems.
Dispatch R265
Most vagal sensory afferents terminate in the so-called nucleus of the solitary tract, which in turn projects to the raphe nucleus and the locus coeruleus. These send diffuse serotonergic and noradrenergic projections through much of the forebrain, and also activate neurons in the nucleus basalis, the command centre of cholinergic neuromodulation. Thus, VNS may trigger increases in serotonin, noradrenaline and acetylcholine levels throughout much of the brain and this may have therapeutic benefit, not just because abnormally low levels of these neuromodulators may be directly implicated in some neurological disorders, but also because these neuromodulators can facilitate changes in synaptic connections [9,10], which may make the brain ‘‘malleable’’, so that connectivity patterns can be ‘relearned’. Engineer and colleagues [5] now observed that pairing the representation of particular tones with VNS can either distort a frequency map in a normal animal, or, more importantly, redress the over-representation of putative tinnitus frequencies after noise trauma. More importantly, this form of VNS therapy enabled the treated animals to regain normal startle suppression, suggesting that they may have been cured of tinnitus. Normal startle suppression re-emerged after 10 days of VNS sessions and persisted until the end of the experiment, 3 weeks later. Control animals, in which tones were paired with stimulation of the trigeminal (5th cranial) nerve instead of the vagus, showed no return to normal startle suppression, and therefore presumably no relief from tinnitus. Interestingly, even though VNS therapy did prove effective in the behavioral tests, it did not reverse all of the physiological changes in auditory cortex. Map distortion was reversed, as was the broadening of tuning curves, but spontaneous activity remained elevated in the VNS-treated rats. This again argues against spontaneous activity levels playing a major role in tinnitus. Of course these results must be interpreted with caution. While it is plausible to assume that startle suppression can serve as a measure of tinnitus in rats, it is nevertheless an assumption. Nor do these results prove conclusively that distorted frequency mapping in the primary auditory cortex
is a root cause of tinnitus. But even though these results are ‘strongly suggestive’ rather than definitive, they nevertheless represent an exciting advance, and are already inspiring new therapeutic approaches. Transferring the methods used by Engineer and colleagues [5] from rats to humans does, however, presuppose that the patients have cuff electrodes surgically implanted around their vagus, which makes this method, as it stands, rather too invasive for the large majority of tinnitus sufferers. However, there are currently about 50,000 individuals worldwide who carry such electrode implants to treat epilepsy or depression, and some of those implanted patients also suffer from tinnitus. The first trials on a small number of such patients are currently underway. If the treatment proves as effective as one would hope, then it would be highly desirable to find a less invasive alternative to surgical implantation of cuff electrodes. Most branches of the vagus are not easily accessible, with the sole exception of the auricular branch, which carries touch information from the outer ear and ear canal to the brainstem. It should therefore, in principle, be possible to achieve a form of ‘VNS’ without surgery, simply by delivering mild electric shocks to the skin of the outer ear. That would be much easier and safer, but may also prove less effective. Unlike visceral afferents of the vagus, which terminate predominantly in the nucleus of the solitary tract, fibers from the auricular branch target mostly the trigeminal nucleus and may therefore be less able to activate the brain’s neuromodulatory centers. That said, it is not uncommon for people to exhibit ‘viscerally vagal’ side effects in response to mechanical stimulation of their outer ears. For example, around 2.5% of people cough reflexively when someone touches their ear canal [11], and some rare individuals are even at risk of ‘auricular syncope’ — they faint due to a rapid blood pressure drop when someone sticks a finger in their ear [12]. While such cases are somewhat exceptional, they nevertheless demonstrate that the auricular branch of the vagus does sometimes ‘cross-talk’ with visceral aspects of vagal function and may therefore perhaps also activate the nucleus of the solitary tract, and
through it the brain’s neuromodulatory centers. So perhaps it is not too far-fetched to imagine that the recent observations by Engineer and colleagues [5] could inspire the development of modified in-ear headphones, which would treat tinnitus by delivering suitably chosen auditory stimuli together with an electrical stimulation of the auricular branch of the vagus through the skin of the ear canal. Prototyping and testing such devices would be comparatively cheap and safe and may prove worthwhile, even if such devices turned out to be effective only in a minority of patients, given that there are currently tens of millions of chronic tinnitus sufferers desperately waiting for a cure. References 1. Norena, A.J., and Eggermont, J.J. (2003). Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus. Hear. Res. 183, 137–153. 2. Eggermont, J.J. (2006). Cortical tonotopic map reorganization and its implications for treatment of tinnitus. Acta Otolaryngol. Suppl. 556, 9–12. 3. Muhlnickel, W., Elbert, T., Taub, E., and Flor, H. (1998). Reorganization of auditory cortex in tinnitus. Proc. Natl. Acad. Sci. USA 95, 10340–10343. 4. Eggermont, J.J. (2003). Central tinnitus. Auris Nasus Larynx Suppl. 30, S7–S12. 5. Engineer, N.D., Riley, J.R., Seale, J.D., Vrana, W.A., Shetake, J.A., Sudanagunta, S.P., Borland, M.S., and Kilgard, M.P. (2011). Reversing pathological neural activity using targeted plasticity. Nature 470, 101–104. 6. Turner, J.G., Brozoski, T.J., Bauer, C.A., Parrish, J.L., Myers, K., Hughes, L.F., and Caspary, D.M. (2006). Gap detection deficits in rats with tinnitus: a potential novel screening tool. Behav. Neurosci. 120, 188–195. 7. Ben-Menachem, E. (2002). Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 1, 477–482. 8. Cristancho, P., Cristancho, M.A., Baltuch, G.H., Thase, M.E., and O’Reardon, J.P. (2011). Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J. Clin. Psych., epub ahead of print. 9. Hasselmo, M.E. (2006). The role of acetylcholine in learning and memory. Curr. Opin. Neurobiol. 16, 710–715. 10. Izumi, Y., and Zorumski, C.F. (1999). Norepinephrine promotes long-term potentiation in the adult rat hippocampus in vitro. Synapse 31, 196–202. 11. Tekdemir, I., Aslan, A., and Elhan, A. (1998). A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold’s ear-cough reflex. Surg. Radiol. Anat. 20, 253–257. 12. Thakar, A., Deepak, K.K., and Kumar, S.S. (2008). Auricular syncope. J. Laryngol. Otol. 122, 1115–1117.
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK. E-mail: [email protected] DOI: 10.1016/j.cub.2011.02.021
It is hypothesized that structural changes within the kinetochore complex impact microtubuleattachment stability and SAC function (reviewed by [12]). Specifically, an increase in the distance between the inner and outer kinetochore, deemed intrakinetochore stretch, occurs upon binding to dynamic microtubules [13,14]. Introduction of intrakinetochore stretch correlates with inactivation of the wait-anaphase signal and is postulated to promote a higher affinity interaction between the outer kinetochore and microtubules by regulating phosphorylation of the KMN complex. At the time this Dispatch was being prepared, no known compliant or ‘stretchable’ component(s) between the inner and outer kinetochore had been characterized. With help from Przewloka et al. [2] and Screpanti et al. [3] we now know that CENP-C is in the right place; the next question is whether it (or perhaps CENP-Cassociated chromatin) is being stretched. The ability of the amino terminus of CENP-C to contact the Mis12 complex is clearly conserved between Drosophila and humans. However, what is happening outside the amino terminus of the molecule is murky. For example, in chicken cells, immunoprecipitated CENP-C exclusively interacted with histone-H3containing chromatin [15]; however, human CENP-C was found to directly interact with CENP-A-containing nucleosomes but not H3 nucleosomes in vitro [5]. Thus, it has been proposed, and is reiterated by Screpanti et al. [3], that CENP-C could interact with both CENP-A and H3 nucleosomes, thereby crosslinking distinct blocks of centromeric chromatin [16]. Obviously this issue remains to be resolved. Even the role of CENP-C as a bridge between the inner and outer kinetochore is not entirely conserved. Recent work in budding yeast found that the Mis12 complex did not interact with CENP-C but rather with another CCAN complex that is generally conserved from yeast to man but has not been identified in either Drosophila or Caenorhabditis elegans [17]. It is exciting to imagine that there are additional, and potentially novel, molecular connections between the inner and outer kinetochore that remain to be characterized. After all, what’s great about missing links is that there
are always more out there just waiting to be found.
12.
References 1. Cheeseman, I.M., and Desai, A. (2008). Molecular architecture of the kinetochore-microtubule interface. Nat. Rev. Mol. Cell Biol. 9, 33–46. 2. Przewloka, M.R., Zsolt, V., BolanosGarcia, V.M., Debski, J., Dadlez, M., and Glover, D.M. (2011). CENP-C is a structural platform for kinetochore assembly. Curr. Biol. 21, 399–405. 3. Screpanti, E., De Antoni, A., Alushin, G.M., Petrovic, A., Melis, T., Nogales, E., and Musacchio, A. (2011). Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. Curr. Biol. 21, 391–398. 4. Saitoh, H., Tomkiel, J., Cooke, C.A., Ratrie, H., 3rd, Maurer, M., Rothfield, N.F., and Earnshaw, W.C. (1992). CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate. Cell 70, 115–125. 5. Carroll, C.W., Milks, K.J., and Straight, A.F. (2010). Dual recognition of CENP-A nucleosomes is required for centromere assembly. J. Cell Biol. 189, 1143–1155. 6. Milks, K.J., Moree, B., and Straight, A.F. (2009). Dissection of CENP-C-directed centromere and kinetochore assembly. Mol. Biol. Cell 20, 4246–4255. 7. Yang, C.H., Tomkiel, J., Saitoh, H., Johnson, D.H., and Earnshaw, W.C. (1996). Identification of overlapping DNA-binding and centromere-targeting domains in the human kinetochore protein CENP-C. Mol. Cell Biol. 16, 3576–3586. 8. Petrovic, A., Pasqualato, S., Dube, P., Krenn, V., Santaguida, S., Cittaro, D., Monzani, S., Massimiliano, L., Keller, J., Tarricone, A., et al. (2010). The MIS12 complex is a protein interaction hub for outer kinetochore assembly. J. Cell Biol. 190, 835–852. 9. Musacchio, A., and Salmon, E.D. (2007). The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8, 379–393. 10. DeLuca, J.G., Howell, B.J., Canman, J.C., Hickey, J.M., Fang, G., and Salmon, E.D. (2003). Nuf2 and Hec1 are required for retention of the checkpoint proteins Mad1 and Mad2 to kinetochores. Curr. Biol. 13, 2103–2109. 11. Kiyomitsu, T., Obuse, C., and Yanagida, M. (2007). Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic
13.
14.
15.
16.
17.
18.
19.
20.
checkpoint through direct interaction with Bub1 and BubR1. Dev. Cell 13, 663–676. Maresca, T.J., and Salmon, E.D. (2010). Welcome to a new kind of tension: translating kinetochore mechanics into a wait-anaphase signal. J. Cell Sci. 123, 825–835. Maresca, T.J., and Salmon, E.D. (2009). Intrakinetochore stretch is associated with changes in kinetochore phosphorylation and spindle assembly checkpoint activity. J. Cell Biol. 184, 373–381. Uchida, K.S., Takagaki, K., Kumada, K., Hirayama, Y., Noda, T., and Hirota, T. (2009). Kinetochore stretching inactivates the spindle assembly checkpoint. J. Cell Biol. 184, 383–390. Hori, T., Amano, M., Suzuki, A., Backer, C.B., Welburn, J.P., Dong, Y., McEwen, B.F., Shang, W.H., Suzuki, E., Okawa, K., et al. (2008). CCAN makes multiple contacts with centromeric DNA to provide distinct pathways to the outer kinetochore. Cell 135, 1039–1052. Ribeiro, S.A., Vagnarelli, P., Dong, Y., Hori, T., McEwen, B.F., Fukagawa, T., Flors, C., and Earnshaw, W.C. (2010). A super-resolution map of the vertebrate kinetochore. Proc. Natl. Acad. Sci. USA 107, 10484–10489. Hornung, P., Maier, M., Alushin, G.M., Lander, G.C., Nogales, E., and Westermann, S. (2011). Molecular architecture and connectivity of the budding yeast Mtw1 kinetochore complex. J. Mol. Biol. 405, 548–559. Maskell, D.P., Hu, X.W., and Singleton, M.R. (2010). Molecular architecture and assembly of the yeast kinetochore MIND complex. J. Cell Biol. 190, 823–834. Schittenhelm, R.B., Heeger, S., Althoff, F., Walter, A., Heidmann, S., Mechtler, K., and Lehner, C.F. (2007). Spatial organization of a ubiquitous eukaryotic kinetochore protein network in Drosophila chromosomes. Chromosoma 116, 385–402. Wan, X., O’Quinn, R.P., Pierce, H.L., Joglekar, A.P., Gall, W.E., DeLuca, J.G., Carroll, C.W., Liu, S.T., Yen, T.J., McEwen, B.F., et al. (2009). Protein architecture of the human kinetochore microtubule attachment site. Cell 137, 672–684.
Biology Department, University of Massachusetts Amherst, Amherst, MA 01003, USA. E-mail: [email protected]
DOI: 10.1016/j.cub.2011.02.026
Auditory Neuroscience: How to Stop Tinnitus by Buzzing the Vagus Recent observations linking the vagus nerve to plasticity in the central nervous system could pave the way to new treatments for one of the most common and intractable disorders of the auditory system. Jan Schnupp Many millions of people (an estimated 14% of the population) suffer from persistent tinnitus, a constant ‘ringing in their ears’, and about 2% find their tinnitus very disruptive, as it interferes with their ability to follow conversations, to concentrate, or to enjoy beautiful music or a quiet
night’s sleep. Tinnitus is therefore a major public health issue, but treatment options remain limited. While the causes and symptoms of tinnitus may be quite diverse, tinnitus often arises when the central auditory pathway struggles to adapt to focal damage to the sensory structures of the cochlea, typically by excessive noise exposure.
Current Biology Vol 21 No 7 R264
A Normal
B Lesioned
Current Biology
Figure 1. Reorganization of the auditory pathway after focal damage. (A) Highly schematic representation of the ascending auditory pathway. Neurons tuned to varying frequencies are tonotopically arranged from low (blue) to high (red), and connected through feed-forward and lateral connections. (B) Noise trauma can cause focal damage to the input layer (the cochlea). The network responds by changing its connectivity so as to compensate for the lost input. This leads to an overrepresentation of the frequencies at the lesion edges (shown here as more low (blue) and high (red) frequency bands to compensate for the loss of mid (green and yellow) frequencies). These changes also heighten overall excitability, and increase spontaneous activity and firing synchrony among neighboring cells.
Neurons in the central auditory pathway are thought to respond to such a loss of sensitivity at the periphery by changing their connectivity. Figure 1 provides a simplified illustration of this process, and shows how changes in the strength of lateral connectivity may compensate for the loss of a subset of input channels. However, the auditory pathway also comprises a wealth of inhibitory connections and feedback loops, and these may also change after noise damage and play a role in tinnitus. At the level of auditory cortex, these changes lead to broader tuning curves, increases in spontaneous firing, a greater synchronization of neural activity, and a ‘sensitization’ such that cortical neurons fire more vigorously to sounds of modest intensity. Furthermore, the normal cortical tonotopic mapping is distorted so that frequencies
adjacent to the ‘deaf spot’ become overrepresented [1,2]. These changes may be partly adaptive, making the most of the remaining inputs, but they also seem to favor the generation of tinnitus as a sort of auditory phantom sensation. Indeed, phantom limb sensations following amputation and tinnitus following focal cochlear damage may come about in a similar manner [3,4]. None of this paints a very encouraging picture for tinnitus sufferers. Too many details of the disease process remain unknown, and few of the prevalent ideas and theories suggest any obvious targets for therapy. However, it would be wrong to think that there is no hope of progress. Now, recent research carried out by Navzer Engineer and colleagues in the laboratory of Mike Kilgard [5] offers some exciting new perspectives. To understand their contribution, we must bear in mind that current theories of tinnitus stem from animal experiments, predominantly on rats. Documenting physiological changes in a rat’s central auditory system after noise trauma is not too difficult, but how do we know whether the rats experience tinnitus? We can’t easily ask them. To diagnose tinnitus in animals, researchers often use a trick which exploits the animals’ natural startle reflex [6]. Most animals startle in response to an unexpected, loud ‘bang’, and, if the animals happen to sit on a platform fitted with accelerometers when they perform the little ‘jump’ associated with the startle reflex, then the amplitude of their startle can be measured. Unsurprisingly, the startle reflex amplitude is much smaller if the animals are able to anticipate the bang, and this can be exploited to test animals for tinnitus. If there is a continuous, fairly quiet ‘narrowband’ background noise (a bit like a faint noisy whistling), and this is interrupted by brief silent periods only just before each loud ‘bang’, then normal animals quickly learn to recognize the silent gap as warning, and their startle response is suppressed. However, if an animal suffers from tinnitus which covers the silent periods, then it will miss the silent gap, fail to anticipate the impending ‘bang’, and startle strongly. A lack of startle suppression is therefore often used as a measure of tinnitus. Engineer et al. [5] used this startle paradigm in a study aiming not just to clarify the physiology of tinnitus, but
also to treat it. As we had seen above, noise trauma triggers a number of physiological changes in the cortex, but which, if any, of these changes is causally related to tinnitus is unclear. By studying individual variations across a cohort of noise-exposed rats, Engineer and colleagues [5] were able to observe that large map distortion, broadening of tuning curves and increased evoked responses all correlated highly with poor startle suppression responses (and therefore presumably pronounced tinnitus), but increases in spontaneous activity and synchronized firing did not. This seems to argue against increased spontaneous or synchronized activity playing a key role in tinnitus generation, which is somewhat counter-intuitive, as one might expect ongoing spontaneous activity to be at the heart of phantom sensations that occur in the absence of external sounds. Engineer and colleagues [5] then set about trying to reverse the physiological changes, as well as the tinnitus, by stimulating the vagus nerve (10th cranial). At first sight, the vagus may seem an unlikely candidate for this purpose. It derives its name from the latin word for ‘wanderer’, as it roams along a complicated branching path through our necks and much of our bodies, where it subserves a wide range of functions, including the control of our heart rate, activity of the digestive system, gag and cough reflexes, or the delivery of taste information from the back of the throat to the brain, but it does not normally mediate or modulate auditory sensations. The idea that the vagus may nevertheless play a useful role in tinnitus therapy stemmed from clinical observations that electrical vagal nerve stimulation (VNS) can alleviate epilepsy [7] and depression [8]. Of course, direct electrical stimulation of the vagus can have all manner of unpleasant side effects, including causing gagging or coughing fits, and driving the heart rate and blood pressure down to the point of unconsciousness. To avoid this, therapeutic VNS targets the cervical branch of the left vagus nerve, which is not strongly connected to the heart, and the electrical stimulation is kept quite gentle. VNS probably works by activating the brain’s neuromodulator systems.
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Most vagal sensory afferents terminate in the so-called nucleus of the solitary tract, which in turn projects to the raphe nucleus and the locus coeruleus. These send diffuse serotonergic and noradrenergic projections through much of the forebrain, and also activate neurons in the nucleus basalis, the command centre of cholinergic neuromodulation. Thus, VNS may trigger increases in serotonin, noradrenaline and acetylcholine levels throughout much of the brain and this may have therapeutic benefit, not just because abnormally low levels of these neuromodulators may be directly implicated in some neurological disorders, but also because these neuromodulators can facilitate changes in synaptic connections [9,10], which may make the brain ‘‘malleable’’, so that connectivity patterns can be ‘relearned’. Engineer and colleagues [5] now observed that pairing the representation of particular tones with VNS can either distort a frequency map in a normal animal, or, more importantly, redress the over-representation of putative tinnitus frequencies after noise trauma. More importantly, this form of VNS therapy enabled the treated animals to regain normal startle suppression, suggesting that they may have been cured of tinnitus. Normal startle suppression re-emerged after 10 days of VNS sessions and persisted until the end of the experiment, 3 weeks later. Control animals, in which tones were paired with stimulation of the trigeminal (5th cranial) nerve instead of the vagus, showed no return to normal startle suppression, and therefore presumably no relief from tinnitus. Interestingly, even though VNS therapy did prove effective in the behavioral tests, it did not reverse all of the physiological changes in auditory cortex. Map distortion was reversed, as was the broadening of tuning curves, but spontaneous activity remained elevated in the VNS-treated rats. This again argues against spontaneous activity levels playing a major role in tinnitus. Of course these results must be interpreted with caution. While it is plausible to assume that startle suppression can serve as a measure of tinnitus in rats, it is nevertheless an assumption. Nor do these results prove conclusively that distorted frequency mapping in the primary auditory cortex
is a root cause of tinnitus. But even though these results are ‘strongly suggestive’ rather than definitive, they nevertheless represent an exciting advance, and are already inspiring new therapeutic approaches. Transferring the methods used by Engineer and colleagues [5] from rats to humans does, however, presuppose that the patients have cuff electrodes surgically implanted around their vagus, which makes this method, as it stands, rather too invasive for the large majority of tinnitus sufferers. However, there are currently about 50,000 individuals worldwide who carry such electrode implants to treat epilepsy or depression, and some of those implanted patients also suffer from tinnitus. The first trials on a small number of such patients are currently underway. If the treatment proves as effective as one would hope, then it would be highly desirable to find a less invasive alternative to surgical implantation of cuff electrodes. Most branches of the vagus are not easily accessible, with the sole exception of the auricular branch, which carries touch information from the outer ear and ear canal to the brainstem. It should therefore, in principle, be possible to achieve a form of ‘VNS’ without surgery, simply by delivering mild electric shocks to the skin of the outer ear. That would be much easier and safer, but may also prove less effective. Unlike visceral afferents of the vagus, which terminate predominantly in the nucleus of the solitary tract, fibers from the auricular branch target mostly the trigeminal nucleus and may therefore be less able to activate the brain’s neuromodulatory centers. That said, it is not uncommon for people to exhibit ‘viscerally vagal’ side effects in response to mechanical stimulation of their outer ears. For example, around 2.5% of people cough reflexively when someone touches their ear canal [11], and some rare individuals are even at risk of ‘auricular syncope’ — they faint due to a rapid blood pressure drop when someone sticks a finger in their ear [12]. While such cases are somewhat exceptional, they nevertheless demonstrate that the auricular branch of the vagus does sometimes ‘cross-talk’ with visceral aspects of vagal function and may therefore perhaps also activate the nucleus of the solitary tract, and
through it the brain’s neuromodulatory centers. So perhaps it is not too far-fetched to imagine that the recent observations by Engineer and colleagues [5] could inspire the development of modified in-ear headphones, which would treat tinnitus by delivering suitably chosen auditory stimuli together with an electrical stimulation of the auricular branch of the vagus through the skin of the ear canal. Prototyping and testing such devices would be comparatively cheap and safe and may prove worthwhile, even if such devices turned out to be effective only in a minority of patients, given that there are currently tens of millions of chronic tinnitus sufferers desperately waiting for a cure. References 1. Norena, A.J., and Eggermont, J.J. (2003). Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus. Hear. Res. 183, 137–153. 2. Eggermont, J.J. (2006). Cortical tonotopic map reorganization and its implications for treatment of tinnitus. Acta Otolaryngol. Suppl. 556, 9–12. 3. Muhlnickel, W., Elbert, T., Taub, E., and Flor, H. (1998). Reorganization of auditory cortex in tinnitus. Proc. Natl. Acad. Sci. USA 95, 10340–10343. 4. Eggermont, J.J. (2003). Central tinnitus. Auris Nasus Larynx Suppl. 30, S7–S12. 5. Engineer, N.D., Riley, J.R., Seale, J.D., Vrana, W.A., Shetake, J.A., Sudanagunta, S.P., Borland, M.S., and Kilgard, M.P. (2011). Reversing pathological neural activity using targeted plasticity. Nature 470, 101–104. 6. Turner, J.G., Brozoski, T.J., Bauer, C.A., Parrish, J.L., Myers, K., Hughes, L.F., and Caspary, D.M. (2006). Gap detection deficits in rats with tinnitus: a potential novel screening tool. Behav. Neurosci. 120, 188–195. 7. Ben-Menachem, E. (2002). Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 1, 477–482. 8. Cristancho, P., Cristancho, M.A., Baltuch, G.H., Thase, M.E., and O’Reardon, J.P. (2011). Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J. Clin. Psych., epub ahead of print. 9. Hasselmo, M.E. (2006). The role of acetylcholine in learning and memory. Curr. Opin. Neurobiol. 16, 710–715. 10. Izumi, Y., and Zorumski, C.F. (1999). Norepinephrine promotes long-term potentiation in the adult rat hippocampus in vitro. Synapse 31, 196–202. 11. Tekdemir, I., Aslan, A., and Elhan, A. (1998). A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold’s ear-cough reflex. Surg. Radiol. Anat. 20, 253–257. 12. Thakar, A., Deepak, K.K., and Kumar, S.S. (2008). Auricular syncope. J. Laryngol. Otol. 122, 1115–1117.
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK. E-mail: [email protected] DOI: 10.1016/j.cub.2011.02.021