Leitthema HNO 2015 · 63:298–301 DOI 10.1007/s00106-014-2980-8 Published online: 10. April 2015 © Springer-Verlag Berlin Heidelberg 2015
J.J. Eggermont Departments of Physiology and Pharmacology, and Psychology, University of Calgary, Calgary, Alberta
Neural substrates of tinnitus in animal and human cortex Cortical correlates of tinnitus
Introduction Approximately two decades ago, research on tinnitus was focused on animal models; however, since then, the increasing use of neuroimaging techniques has resulted in a surge in human studies. Not only functional magnetic resonance imaging (fMRI), but also electroencephalography (EEG) and magnetoencephalography (MEG) based studies in tinnitus patients have increased dramatically. The outcome of some of these studies could be related to those of the animal models, since they focused on the auditory system, particularly the auditory cortex, with an emphasis on spontaneous activity, neural synchrony and tonotopic mapping [18]. Animal models of tinnitus are currently at a crossroads; although clinical interest is in patients’ suffering, alleviation of this suffering does not abolish tinnitus. Animal data so far are not fully compatible with the majority of human data, which increasingly focus on the role of brain rhythms and brain network connectivity. The present article describes the changes in tonotopic maps, spontaneous firing rate (SFR), and changes in pair-wise neural cross-correlation induced by noise exposure at levels that: (1) do not cause hearing loss, (2) only cause a temporary threshold shift (TTS), or (3) cause permanent hearing loss. Several neuroimaging findings in humans with tinnitus, in so far as they relate to animal models, will then be reviewed.
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Effects of noise exposure in animal auditory cortex Traumatic noise exposure in humans typically results in tinnitus, either transient or chronic. Our studies on the effects of both non-traumatic and traumatic noise have demonstrated that similar changes to SFR, neural synchrony and tonotopic maps occur regardless of the exposure level.
Non-traumatic noise exposure Noreña et al. [15] reported that ≥4 months of exposure in adult cats to a 4–20 kHz multi-frequency stimulus ensemble presented at 80 dB sound pressure level (SPL), referred to as enhanced acoustic environment (EAE), decreased the responsiveness of the primary auditory cortex (AI) to the frequencies in the EAE and increased at the outer edges of the band. Immediately after exposure, auditory brainstem response (ABR) pure-tone thresholds were normal. Recordings of SFR in controls and EAE cats were compared according to the location of the recording electrodes corresponding to regions in the control cats with carrier frequencies (CFs) 20 kHz, respectively. The SFRs were not significantly different between controls and EAE cats for recordings in locations with CFs normally corresponding to the EAE spectrum. On the other hand, SFRs were significantly increased for recordings normally corresponding to characteristic frequencies be-
low 4 kHz and above 20 kHz. We also recorded the spontaneous spike firing from pairs of electrodes and calculated the neural synchrony (expressed as a peak crosscorrelation coefficient between the SFR of pairs of neurons; [3]) between them. Only recordings stationary over a 15-min period were used. Synchrony was significantly higher in EAE cats compared with control cats across the entire CF range. Even the local neural synchrony (that is, for electrode distances ≤1 mm) was significantly increased in EAE cats compared to control cats. We found no significant difference in neural synchrony across CF for control cats. However, in EAE cats, the neural synchrony was significantly enhanced in the ≤4 kHz and ≥20 kHz regions of AI compared to the 4–20 kHz region. Pienkowski and Eggermont [17] subsequently demonstrated qualitatively similar plastic changes for a 6-week period of EAE exposure at a level of only 68 dB SPL. Again ABR thresholds were normal, and the resulting reorganization of the AI tonotopic map occurring mostly during the 8–12 week recovery period (and much less during exposure itself) resembled that following noise-induced hearing loss. Most EAE exposure-induced effects were likely present in the thalamus, as deduced from changes in short-latency sound-evoked local field potentials (LFPs), but were further modified in AI. Compared to controls, the SFR was significantly enhanced in the non-EAE frequency ranges compared to controls in
the same frequency range. The SFR in the EAE region was also significantly lower compared to the non-EAE range in exposed cats. Correlations in spike firing in the absence of sound stimulation were computed between neurons recorded on separate electrodes in AI. There was a decrease in the synchrony of spontaneous firing with increasing inter-electrode distance in all three groups. In the shortest distance bin (0.25–0.35 mm), corresponding to the distance between nearest neighbors on the electrode arrays, the synchrony measured in both the no-recovery and the 8- to 2-week-recovery groups was approximately double that measured in controls. However, increased synchrony was observed only in the outside-EAE regions up to distances of about 2 mm in both exposed groups. Importantly, the increase in synchrony showed no sign of reverting to normal 12 weeks after the cessation of exposure in either the EAE- and outside-EAE regions, thereby following the same trend as the changes in the tonotopic maps. If one considers increased SFR and neural synchrony as substrates of tinnitus, one cannot escape the notion that longterm exposure to non-traumatic sound may cause tinnitus.
Acute effects of traumatic noise With the recording multi-electrode arrays in place in AI, and pre-trauma responses recorded for units with CFs between ~3 and 30 kHz, Noreña et al. [16] exposed ketamine-anesthetized cats to 5–6 kHz, presented at 115–120 dB SPL for 1 h, and then continued recording the activity from the same recording sites for various times after the trauma. The results showed a loss of sensitivity, with the highest increase in threshold around 8–10 kHz; these thresholds improved over the following 6 h of recording from the same sites. It was interesting that neurons with a pre-trauma CF of around 10 kHz had a CF close to 5 kHz after the trauma, a frequency that they did not respond to before the trauma. This effect was immediate and was attributed to the loss of activity in the 10-kHz region that normally would inhibit inputs to the cortex in the 5–6 kHz area. This disinhibition unmasks previously silent excitatory inputs and shifts the tuning curve dramat-
ically to lower CFs. This is likely a precursor to subsequent changes in the tonotopic map that take place only several weeks after the trauma. Within 15 min after the trauma [12, 13], there was a slight decrease in SFR, regardless of the CF of the neuron. It took approximately 2 h before the SFR had increased (on average about two-fold compared with controls) in neurons with CFs below the trauma tone frequency and those with CFs more than one octave above the trauma tone frequency. In stark contrast to the delayed SFR change, neural synchrony was significantly increased immediately after the trauma. Since tinnitus tends to develop immediately after noise trauma (but may disappear again later), this suggests that a putative neural correlate, at least for transient tinnitus, is not increased SFR but increased neural synchrony.
Chronic effects of traumatic noise To produce a permanent threshold shift, exposures with a 5-kHz tone for 2–4 h at 115–120 dB SPL were used [12, 13, 14]. Recordings were performed at least 4 weeks after the exposure following recovery of the cats in a quiet room with their littermates. Non-exposed littermates and other normal hearing cats were used as agematched controls. There was a two-part hearing loss: a 10- to 45-dB (mean 25) dip around 4 kHz and a sloping loss for frequencies >10 kHz. Tonotopic maps in AI were reorganized in such a way that the area normally tuned to frequencies of 10– 40 kHz was now entirely tuned to 10 kHz. SFRs were significantly higher in reorganized areas than in non-affected areas and control cats. For the frequency range in which map reorganization was found, the neural synchrony in reorganized cortex was significantly higher than in control cats. This suggested a potential correlation between cortical tonotopic map reorganization, increased SFR and neuronal synchrony that might be related to chronic tinnitus found in high-frequency hearing loss induced by acoustic trauma.
Neuroimaging studies of tinnitus in humans Animal studies of tinnitus measure singleand multi-unit neural activity, as well as LFPs with precise temporal and anatomical resolution, but are limited by the necessity to infer the presence or absence of tinnitus and/or hyperacusis from indirect behavioral methods. In contrast, imaging methods in humans provide either poorer spatial (MEG, EEG) or temporal (PET, fMRI) resolution compared to physiological experiments in animals. However, human studies benefit from knowledge of the presence or absence of tinnitus and hyperacusis based on verbal reports from the participants. This article will limit itself here to those studies that can be related to findings in animal models, thereby excluding changes in brain rhythms and long-distance cortical connectivity. In recent fMRI mapping studies in humans with tinnitus and clinically normal hearing (i.e., ≤20 dB hearing loss) for frequencies ≤8 kHz Langers et al. [8] could not show tonotopic map changes. It is possible that more detailed analysis of human tonotopic maps may have revealed map reorganization, but that has not been done so far. It should be noted that cats with only mild noise-induced hearing loss (8 kHz was negatively correlated with modulated GM probability in ventral posterior cingulate cortex, dorsomedial prefrontal cortex and a subcallosal region that included ventromedial prefrontal cortex. Boyen et al. [2] also used VBM to compare GM volume between three groups: hearing-impaired individuals with tinnitus, hearing-impaired individuals without tinnitus, and normalhearing controls, with each group of sim-
ilar ages. In agreement with Melcher et al. [10], no significant GM differences were found between the two patient groups. Subsequent region-of-interest analyses of all cortical areas, the cerebellum, and the subcortical auditory nuclei showed a GM increase in the left primary auditory cortex in tinnitus patients compared to hearing-impaired individuals without tinnitus and control groups. These results suggested a specific role of the left primary auditory cortex and the additional involvement of various nonauditory brain structures in tinnitus. The combined results support the notion that structural changes in the brain are not specific to tinnitus, but rather result from auditory deafferentation.
Outlook Here we have reviewed findings from animal models of tinnitus and from human tinnitus studies regarding the cortical activity that underlies this disorder. Animal studies concur that, following noise exposure, neural gain is increased in the auditory cortex, as expressed by increased driven neural responses in these structures. Increases in SFR are also observed after noise trauma. In this regard, computational models suggest that changes in central gain may be sufficient to increase SFR in central auditory pathways, which could be the neural basis for tinnitus. However, caution is needed, since changes in SFR and central gain are inconsistently correlated in the animal data. Other neural mechanisms that may underlie tinnitus, such as increased neural synchrony and tonotopic map reorganization due to deafferentation, need more investigation in animal studies. A challenge in animal models is to rule out impaired temporal processing or hyperacusis as the source of neural and behavioral changes seen in these studies, separately from tinnitus. Within the limits of this challenge, animal studies have revealed neuroplastic mechanisms that may contribute to the development of tinnitus percepts.
Corresponding address J.J. Eggermont Departments of Physiology and Pharmacology, and Psychology, University of Calgary T2N 2V1 Calgary, Alberta Canada [email protected]
Acknowledgments. This research was supported by Alberta Innovates-Health Solutions, the Natural Sciences and Engineering Research Council of Canada, and the Campbell McLaurin Chair for Hearing Deficiencies.
Compliance with ethical guidelines Conflict of interest. J.J. Eggermont states that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies. All national guidelines on the care and use of laboratory animals have been followed and the necessary approval was obtained from the relevant authorities.
References 1. Arnold W, Bartenstein P, Oestreicher EWR, Schweiger M (1996) Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: a PET study with [18F]deoxyglucose. ORL J Otorhinolaryngol Relat Spec 58:195–199 2. Boyen K, Langers DRM, Kleine E de, Dijk P van (2013) Gray matter in the brain: differences associated with tinnitus and hearing loss. Hear Res 295:67–78 3. Eggermont JJ (1992) Neural interaction in cat primary auditory cortex. Dependence on recording depth, electrode separation and age. J Neurophysiol 68:1216–1228 4. Eggermont JJ (2013) Hearing loss, hyperacusis, and tinnitus: what is modeled in animal research? Hear Res 295:140–149 5. Geven LI, Kleine E de, Willemsen ATM, Dijk P van (2014) Asymmetry in primary auditory cortex activity in tinnitus patients and controls. Neuroscience 256:117–125 6. Husain FT, Medina RE, Davis CW et al (2011) Neuroanatomical changes due to hearing loss and chronic tinnitus: a combined VBM and DTI study. Brain Res 1369:74–88 7. Landgrebe M, Langguth B, Rosengarth K et al (2009) Structural brain changes in tinnitus: grey matter decrease in auditory and non-auditory brain areas. Neuroimage 46:213–218 8. Langers DM, Kleine E de, Dijk P van (2012) Tinnitus does not require macroscopic tonotopic map reorganization. Front Syst Neurosci 6:2
9. Langguth B, Eichhammer P, Kreutzer A et al (2006) The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus—first results from a PET study. Acta Otolaryngol Suppl 556:84–88 10. Melcher JR, Knudson IM, Levine RA (2013) Subcallosal brain structure: correlation with hearing threshold at supra-clinical frequencies (>8 kHz), but not with tinnitus. Hear Res 295:79–86 11. Muhlau M, Rauschecker JP, Oestreicher E et al (2006) Structural brain changes in tinnitus. Cerebral Cortex 16:1283–1288 12. Noreña AJ, Eggermont JJ (2003) Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus. Hear Res 183:137–153 13. Noreña AJ, Eggermont JJ (2005) Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization. J Neurosci 25:699–705 14. Noreña AJ, Eggermont JJ (2006) Enriched acoustic environment after noise trauma abolishes neural signs of tinnitus. Neuroreport 17:559–563 15. Noreña AJ, Gourévitch B, Aizawa N, Eggermont JJ (2006) Spectrally enhanced acoustic environment disrupts frequency representation in cat auditory cortex. Nat Neurosci 9:932–939 16. Noreña AJ, Tomita M, Eggermont JJ (2003) Neural changes in cat auditory cortex after a transient pure-tone trauma. J Neurophysiol 90:2387–2401 17. Pienkowski M, Eggermont JJ (2009) Recovery from reorganization induced in adult cat primary auditory cortex by a band-limited spectrally enhanced acoustic environment. Hear Res 257:24–40 18. Roberts LE, Eggermont JJ, Caspary DM et al (2010) Ringing ears: the neuroscience of tinnitus. J Neurosci 30:14972–14979 19. Schecklmann M, Lehner A, Poeppl TB et al (2013) Auditory cortex is implicated in tinnitus distress: a voxel-based morphometric study. Brain Struct Funct 218:1061–1070 20. Schneider P, Andermann M, Wengenroth M et al (2009) Reduced volume of Heschl’s gyrus in tinnitus. Neuroimage 45:927–939 21. Seki S, Eggermont JJ (2002) Changes in cat primary auditory cortex after minor -to-moderate puretone induced hearing loss. Hear Res 173:172–186 22. Seki S, Eggermont JJ (2003) Changes in spontaneous firing rate and neural synchrony in cat primary auditory cortex after localized tone-induced hearing loss. Hear Res 180:28–38
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J.J. Eggermont Departments of Physiology and Pharmacology, and Psychology, University of Calgary, Calgary, Alberta
Neural substrates of tinnitus in animal and human cortex Cortical correlates of tinnitus
Introduction Approximately two decades ago, research on tinnitus was focused on animal models; however, since then, the increasing use of neuroimaging techniques has resulted in a surge in human studies. Not only functional magnetic resonance imaging (fMRI), but also electroencephalography (EEG) and magnetoencephalography (MEG) based studies in tinnitus patients have increased dramatically. The outcome of some of these studies could be related to those of the animal models, since they focused on the auditory system, particularly the auditory cortex, with an emphasis on spontaneous activity, neural synchrony and tonotopic mapping [18]. Animal models of tinnitus are currently at a crossroads; although clinical interest is in patients’ suffering, alleviation of this suffering does not abolish tinnitus. Animal data so far are not fully compatible with the majority of human data, which increasingly focus on the role of brain rhythms and brain network connectivity. The present article describes the changes in tonotopic maps, spontaneous firing rate (SFR), and changes in pair-wise neural cross-correlation induced by noise exposure at levels that: (1) do not cause hearing loss, (2) only cause a temporary threshold shift (TTS), or (3) cause permanent hearing loss. Several neuroimaging findings in humans with tinnitus, in so far as they relate to animal models, will then be reviewed.
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Effects of noise exposure in animal auditory cortex Traumatic noise exposure in humans typically results in tinnitus, either transient or chronic. Our studies on the effects of both non-traumatic and traumatic noise have demonstrated that similar changes to SFR, neural synchrony and tonotopic maps occur regardless of the exposure level.
Non-traumatic noise exposure Noreña et al. [15] reported that ≥4 months of exposure in adult cats to a 4–20 kHz multi-frequency stimulus ensemble presented at 80 dB sound pressure level (SPL), referred to as enhanced acoustic environment (EAE), decreased the responsiveness of the primary auditory cortex (AI) to the frequencies in the EAE and increased at the outer edges of the band. Immediately after exposure, auditory brainstem response (ABR) pure-tone thresholds were normal. Recordings of SFR in controls and EAE cats were compared according to the location of the recording electrodes corresponding to regions in the control cats with carrier frequencies (CFs) 20 kHz, respectively. The SFRs were not significantly different between controls and EAE cats for recordings in locations with CFs normally corresponding to the EAE spectrum. On the other hand, SFRs were significantly increased for recordings normally corresponding to characteristic frequencies be-
low 4 kHz and above 20 kHz. We also recorded the spontaneous spike firing from pairs of electrodes and calculated the neural synchrony (expressed as a peak crosscorrelation coefficient between the SFR of pairs of neurons; [3]) between them. Only recordings stationary over a 15-min period were used. Synchrony was significantly higher in EAE cats compared with control cats across the entire CF range. Even the local neural synchrony (that is, for electrode distances ≤1 mm) was significantly increased in EAE cats compared to control cats. We found no significant difference in neural synchrony across CF for control cats. However, in EAE cats, the neural synchrony was significantly enhanced in the ≤4 kHz and ≥20 kHz regions of AI compared to the 4–20 kHz region. Pienkowski and Eggermont [17] subsequently demonstrated qualitatively similar plastic changes for a 6-week period of EAE exposure at a level of only 68 dB SPL. Again ABR thresholds were normal, and the resulting reorganization of the AI tonotopic map occurring mostly during the 8–12 week recovery period (and much less during exposure itself) resembled that following noise-induced hearing loss. Most EAE exposure-induced effects were likely present in the thalamus, as deduced from changes in short-latency sound-evoked local field potentials (LFPs), but were further modified in AI. Compared to controls, the SFR was significantly enhanced in the non-EAE frequency ranges compared to controls in
the same frequency range. The SFR in the EAE region was also significantly lower compared to the non-EAE range in exposed cats. Correlations in spike firing in the absence of sound stimulation were computed between neurons recorded on separate electrodes in AI. There was a decrease in the synchrony of spontaneous firing with increasing inter-electrode distance in all three groups. In the shortest distance bin (0.25–0.35 mm), corresponding to the distance between nearest neighbors on the electrode arrays, the synchrony measured in both the no-recovery and the 8- to 2-week-recovery groups was approximately double that measured in controls. However, increased synchrony was observed only in the outside-EAE regions up to distances of about 2 mm in both exposed groups. Importantly, the increase in synchrony showed no sign of reverting to normal 12 weeks after the cessation of exposure in either the EAE- and outside-EAE regions, thereby following the same trend as the changes in the tonotopic maps. If one considers increased SFR and neural synchrony as substrates of tinnitus, one cannot escape the notion that longterm exposure to non-traumatic sound may cause tinnitus.
Acute effects of traumatic noise With the recording multi-electrode arrays in place in AI, and pre-trauma responses recorded for units with CFs between ~3 and 30 kHz, Noreña et al. [16] exposed ketamine-anesthetized cats to 5–6 kHz, presented at 115–120 dB SPL for 1 h, and then continued recording the activity from the same recording sites for various times after the trauma. The results showed a loss of sensitivity, with the highest increase in threshold around 8–10 kHz; these thresholds improved over the following 6 h of recording from the same sites. It was interesting that neurons with a pre-trauma CF of around 10 kHz had a CF close to 5 kHz after the trauma, a frequency that they did not respond to before the trauma. This effect was immediate and was attributed to the loss of activity in the 10-kHz region that normally would inhibit inputs to the cortex in the 5–6 kHz area. This disinhibition unmasks previously silent excitatory inputs and shifts the tuning curve dramat-
ically to lower CFs. This is likely a precursor to subsequent changes in the tonotopic map that take place only several weeks after the trauma. Within 15 min after the trauma [12, 13], there was a slight decrease in SFR, regardless of the CF of the neuron. It took approximately 2 h before the SFR had increased (on average about two-fold compared with controls) in neurons with CFs below the trauma tone frequency and those with CFs more than one octave above the trauma tone frequency. In stark contrast to the delayed SFR change, neural synchrony was significantly increased immediately after the trauma. Since tinnitus tends to develop immediately after noise trauma (but may disappear again later), this suggests that a putative neural correlate, at least for transient tinnitus, is not increased SFR but increased neural synchrony.
Chronic effects of traumatic noise To produce a permanent threshold shift, exposures with a 5-kHz tone for 2–4 h at 115–120 dB SPL were used [12, 13, 14]. Recordings were performed at least 4 weeks after the exposure following recovery of the cats in a quiet room with their littermates. Non-exposed littermates and other normal hearing cats were used as agematched controls. There was a two-part hearing loss: a 10- to 45-dB (mean 25) dip around 4 kHz and a sloping loss for frequencies >10 kHz. Tonotopic maps in AI were reorganized in such a way that the area normally tuned to frequencies of 10– 40 kHz was now entirely tuned to 10 kHz. SFRs were significantly higher in reorganized areas than in non-affected areas and control cats. For the frequency range in which map reorganization was found, the neural synchrony in reorganized cortex was significantly higher than in control cats. This suggested a potential correlation between cortical tonotopic map reorganization, increased SFR and neuronal synchrony that might be related to chronic tinnitus found in high-frequency hearing loss induced by acoustic trauma.
Neuroimaging studies of tinnitus in humans Animal studies of tinnitus measure singleand multi-unit neural activity, as well as LFPs with precise temporal and anatomical resolution, but are limited by the necessity to infer the presence or absence of tinnitus and/or hyperacusis from indirect behavioral methods. In contrast, imaging methods in humans provide either poorer spatial (MEG, EEG) or temporal (PET, fMRI) resolution compared to physiological experiments in animals. However, human studies benefit from knowledge of the presence or absence of tinnitus and hyperacusis based on verbal reports from the participants. This article will limit itself here to those studies that can be related to findings in animal models, thereby excluding changes in brain rhythms and long-distance cortical connectivity. In recent fMRI mapping studies in humans with tinnitus and clinically normal hearing (i.e., ≤20 dB hearing loss) for frequencies ≤8 kHz Langers et al. [8] could not show tonotopic map changes. It is possible that more detailed analysis of human tonotopic maps may have revealed map reorganization, but that has not been done so far. It should be noted that cats with only mild noise-induced hearing loss (8 kHz was negatively correlated with modulated GM probability in ventral posterior cingulate cortex, dorsomedial prefrontal cortex and a subcallosal region that included ventromedial prefrontal cortex. Boyen et al. [2] also used VBM to compare GM volume between three groups: hearing-impaired individuals with tinnitus, hearing-impaired individuals without tinnitus, and normalhearing controls, with each group of sim-
ilar ages. In agreement with Melcher et al. [10], no significant GM differences were found between the two patient groups. Subsequent region-of-interest analyses of all cortical areas, the cerebellum, and the subcortical auditory nuclei showed a GM increase in the left primary auditory cortex in tinnitus patients compared to hearing-impaired individuals without tinnitus and control groups. These results suggested a specific role of the left primary auditory cortex and the additional involvement of various nonauditory brain structures in tinnitus. The combined results support the notion that structural changes in the brain are not specific to tinnitus, but rather result from auditory deafferentation.
Outlook Here we have reviewed findings from animal models of tinnitus and from human tinnitus studies regarding the cortical activity that underlies this disorder. Animal studies concur that, following noise exposure, neural gain is increased in the auditory cortex, as expressed by increased driven neural responses in these structures. Increases in SFR are also observed after noise trauma. In this regard, computational models suggest that changes in central gain may be sufficient to increase SFR in central auditory pathways, which could be the neural basis for tinnitus. However, caution is needed, since changes in SFR and central gain are inconsistently correlated in the animal data. Other neural mechanisms that may underlie tinnitus, such as increased neural synchrony and tonotopic map reorganization due to deafferentation, need more investigation in animal studies. A challenge in animal models is to rule out impaired temporal processing or hyperacusis as the source of neural and behavioral changes seen in these studies, separately from tinnitus. Within the limits of this challenge, animal studies have revealed neuroplastic mechanisms that may contribute to the development of tinnitus percepts.
Corresponding address J.J. Eggermont Departments of Physiology and Pharmacology, and Psychology, University of Calgary T2N 2V1 Calgary, Alberta Canada [email protected]
Acknowledgments. This research was supported by Alberta Innovates-Health Solutions, the Natural Sciences and Engineering Research Council of Canada, and the Campbell McLaurin Chair for Hearing Deficiencies.
Compliance with ethical guidelines Conflict of interest. J.J. Eggermont states that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies. All national guidelines on the care and use of laboratory animals have been followed and the necessary approval was obtained from the relevant authorities.
References 1. Arnold W, Bartenstein P, Oestreicher EWR, Schweiger M (1996) Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: a PET study with [18F]deoxyglucose. ORL J Otorhinolaryngol Relat Spec 58:195–199 2. Boyen K, Langers DRM, Kleine E de, Dijk P van (2013) Gray matter in the brain: differences associated with tinnitus and hearing loss. Hear Res 295:67–78 3. Eggermont JJ (1992) Neural interaction in cat primary auditory cortex. Dependence on recording depth, electrode separation and age. J Neurophysiol 68:1216–1228 4. Eggermont JJ (2013) Hearing loss, hyperacusis, and tinnitus: what is modeled in animal research? Hear Res 295:140–149 5. Geven LI, Kleine E de, Willemsen ATM, Dijk P van (2014) Asymmetry in primary auditory cortex activity in tinnitus patients and controls. Neuroscience 256:117–125 6. Husain FT, Medina RE, Davis CW et al (2011) Neuroanatomical changes due to hearing loss and chronic tinnitus: a combined VBM and DTI study. Brain Res 1369:74–88 7. Landgrebe M, Langguth B, Rosengarth K et al (2009) Structural brain changes in tinnitus: grey matter decrease in auditory and non-auditory brain areas. Neuroimage 46:213–218 8. Langers DM, Kleine E de, Dijk P van (2012) Tinnitus does not require macroscopic tonotopic map reorganization. Front Syst Neurosci 6:2
9. Langguth B, Eichhammer P, Kreutzer A et al (2006) The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus—first results from a PET study. Acta Otolaryngol Suppl 556:84–88 10. Melcher JR, Knudson IM, Levine RA (2013) Subcallosal brain structure: correlation with hearing threshold at supra-clinical frequencies (>8 kHz), but not with tinnitus. Hear Res 295:79–86 11. Muhlau M, Rauschecker JP, Oestreicher E et al (2006) Structural brain changes in tinnitus. Cerebral Cortex 16:1283–1288 12. Noreña AJ, Eggermont JJ (2003) Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus. Hear Res 183:137–153 13. Noreña AJ, Eggermont JJ (2005) Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization. J Neurosci 25:699–705 14. Noreña AJ, Eggermont JJ (2006) Enriched acoustic environment after noise trauma abolishes neural signs of tinnitus. Neuroreport 17:559–563 15. Noreña AJ, Gourévitch B, Aizawa N, Eggermont JJ (2006) Spectrally enhanced acoustic environment disrupts frequency representation in cat auditory cortex. Nat Neurosci 9:932–939 16. Noreña AJ, Tomita M, Eggermont JJ (2003) Neural changes in cat auditory cortex after a transient pure-tone trauma. J Neurophysiol 90:2387–2401 17. Pienkowski M, Eggermont JJ (2009) Recovery from reorganization induced in adult cat primary auditory cortex by a band-limited spectrally enhanced acoustic environment. Hear Res 257:24–40 18. Roberts LE, Eggermont JJ, Caspary DM et al (2010) Ringing ears: the neuroscience of tinnitus. J Neurosci 30:14972–14979 19. Schecklmann M, Lehner A, Poeppl TB et al (2013) Auditory cortex is implicated in tinnitus distress: a voxel-based morphometric study. Brain Struct Funct 218:1061–1070 20. Schneider P, Andermann M, Wengenroth M et al (2009) Reduced volume of Heschl’s gyrus in tinnitus. Neuroimage 45:927–939 21. Seki S, Eggermont JJ (2002) Changes in cat primary auditory cortex after minor -to-moderate puretone induced hearing loss. Hear Res 173:172–186 22. Seki S, Eggermont JJ (2003) Changes in spontaneous firing rate and neural synchrony in cat primary auditory cortex after localized tone-induced hearing loss. Hear Res 180:28–38
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