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Abstract

The majority of tinnitus cases are related to cochlear dysfunction, leading to altered peripheral input to the central auditory system [1]. These alterations are believed to increase the basic level of neural activity during off-conditions of sound and to diminish the increase in neural activity when sound is presented [2]. As a compensatory means the affected region of primary auditory cortex tries to maximize the difference between basic level activity and sound-induced activity by adapting inhibitory and excitatory influences towards less GABAergic inhibition. This adaptation in turn triggers unmasking of dormant synapses and creation of new connections through axonal sprouting and finally results in a reorganization of tonotopic receptive fields and the manifestation of tinnitus [3]. To further investigate the processes involved in tinnitus manifestation we used neuroConstruct [4] to implement a simulation of the primary auditory cortex. It consists of two groups of different types of neurons, excitatory regular spiking pyramidal cells and inhibitory fast spiking basket cells with a group size of ? and ?, respectively. Its organization is based on experimental data from animal studies. Neurons were modeled as conductance-based multi-compartment neurons having numerous ionic conductances to achieve the desired firing properties. Model neurons posses glutamate- (AMPA and NMDA) and GABA-sensitive synaptic receptors. Afferent input from the auditory pathway was modeled as trains of spikes. Their frequency depended on the strength of the input whereas their target site depended on the frequency of the input. Additionally, synaptic background noise was introduced to the system as Gaussian noise. Excitatory cells made connections to other excitatory in their 1st, 2nd and 3rd surrounding ring and to inhibitory cells in their 3rd, 4th and 5th surrounding ring with decreasing probabilities (1.0, 0.8, 0.6 respectively). Inhibitory cells made connections with excitatory cells in their 1st, 2nd, 3rd and 4th surrounding ring allso with decreasing probability (1.0, 0.8, 0.6, 0.5 respectively). This connectivity pattern results in a tonotopic organization of the auditory cortex layer. The simulation also exhibits spontaneous and spike driven firing rates comparable with experimental data [5]. Increasing the background noise and simultaneously decreasing the afferent input to one tonotopic region creates a state that may correspond to the early stage of tinnitus manifestation after cochlear damage. This state also shows an increased basic level of activity in the absence of input and furthermore, a diminished increase of activity during sound presentation. Moreover, a change of the ratio between excitatory and inhibitory weights towards more excitation and less inhibition results in a normal increase of activity during sound presentation. This suggests that the auditory cortex might react upon this diminished ability to detect sound in the damaged frequency region by increasing excitation and decreasing inhibition. The presented simulation constitutes an excellent starting point for a deeper investigation of the early phases in the generation of tinnitus. We are currently extending the simulation to include more structures of the classical pathway and to incorporate synaptic plasticity. Acknowledgments This work was partially supported by the Graduate School for Computing in Medicine and Life Sciences funded by Germany's Excellence Initiative [DFG GSC 235/1]. References Jastreboff PJ: Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci Res 1990, 8(4):221-254. Melcher JR, Sigalovsky IS, Guinan JJ Jr., Levine RA: Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 2000, 83(2):1058-1072. Bartels H, Staal MJ, Albers FWJ: Tinnitus and neural plasticity of the brain. Otology&Neurotology 2007, 28(2):178-184. Gleeson P, Steuber V, Silver RA: neuroConstruct: A tool for modeling networks of neurons in 3D space. Neuron 2007, 54(2):219-235. Wang J, McFadden SL, Caspary D, Salvi R: Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons. Brain Research 2002, 944:219-231.
P O S T E R P R E S E N T A T I O N Open Access
Early signs of tinnitus in a simulation of the
mammalian primary auditory cortex
Christoph Metzner
1,2*
, Melea Menzinger
1
, Achim Schweikard
1
, Bartosz Zurowski
3
From Twentieth Annual Computational Neuroscience Meeting: CNS*2011
Stockholm, Sweden. 23-28 July 2011
The majority of tinnitus cases are related to cochlear
dysfunction, leading to altered peripheral input to the
central auditory system [1]. These alterations are
believed to increase the basic level of neural activity
during off-conditions of sound and to diminish the
increase in neural activity when sound is presented [2].
As a compensatory means the affected region of primary
auditory cortex tries to maximize the difference between
basic level activity and sound-induced activity by adapt-
ing inhibitory and excitatory influences towards less
GABAergic inhibition. This adaptation in turn triggers
unmasking of dormant synapses and creation of new
connections through axonal sprouting and finally results
in a reorganization of tonotopic receptive fields and the
manifestation of tinnitus [3].
To further investigate the processes involved in tinnitus
manifestation we used neuroConstruct [4] to implement
a simulation of the primary auditory cortex. It consists of
two groups of different types of neurons, excitatory regu-
lar spiking pyramidal cells and inhibitory fast spiking bas-
ket cells with a group size of ? and ?, respectively. Its
organization is based on experimental data from animal
studies. Neurons were modeled as conductance-based
multi-compartment neurons having numerous ionic con-
ductances to achieve the desired firing properties. Model
neurons posses glutamate- (AMPA and NMDA) and
GABA-sensitive synaptic receptors.
Afferent input from the auditory pathway was modeled
as trains of spikes. Their frequency depended on the
strength of the input whereas their target site depended
on the frequency of the input. Additionally, synaptic back-
ground noise was introduced to the system as Gaussian
noise. Excitatory cells made connections to other
excitatory in their 1st, 2nd and 3rd surrounding ring and
to inhibitory cells in their 3rd, 4th and 5th surrounding
ring with decreasing probabilities (1.0, 0.8, 0.6 respec-
tively). Inhibitory cells made connections with excitatory
cells in their 1st, 2nd, 3rd and 4th surrounding ring allso
with decreasing probability (1.0, 0.8, 0.6, 0.5 respectively).
This connectivity pattern results in a tonotopic organiza-
tion of the auditory cortex layer. The simulation also exhi-
bits spontaneous and spike driven firing rates comparable
with experimental data [5].
Increasing the background noise and simultaneously
decreasing the afferent input to one tonotopic region cre-
ates a state that may correspond to the early stage of tinni-
tus manifestation after cochlear damage. This state also
shows an increased basic level of activity in the absence of
input and furthermore, a diminished increase of activity
during sound presentation. Moreover, a change of the
ratio between excitatory and inhibitory weights towards
more excitation and less inhibition results in a normal
increase of activity during sound presentation. This sug-
gests that the auditory cortex might react upon this dimin-
ished ability to detect sound in the damaged frequency
region by increasing excitation and decreasing inhibition.
The presented simulation constitutes an excellent start-
ing point for a deeper investigation of the early phases in
the generation of tinnitus. We are currently extending the
simulation to include more structures of the classical path-
way and to incorporate synaptic plasticity.
Acknowledgments
This work was partially supported by the Graduate School for Computing in
Medicine and Life Sciences funded by Germanys Excellence Initiative [DFG
GSC 235/1].
Author details
1
Institute for Robotics and Cognitive Systems, University of Luebeck, 23538
Luebeck, Germany.
2
Graduate School for Computing in Medicine and Life
Sciences, University of Luebeck, 23538 Luebeck, Germany.
3
Department of
Psychiatry, University Clinics Schleswig-Holstein, 23538 Luebeck, Germany.
* Correspondence: metzner@rob.uni-luebeck.de
1
Institute for Robotics and Cognitive Systems, University of Luebeck, 23538
Luebeck, Germany
Full list of author information is available at the end of the article
Metzner et al.BMC Neuroscience 2011, 12(Suppl 1):P383
http://www.biomedcentral.com/1471-2202/12/S1/P383
© 2011 Metzner et al; licensee BioMed Central Lt d. This is an open access article distributed under the terms of th e Creative Commons
Attribution L icense (http: //creativec ommons.org/ licenses/by/ 2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Published: 18 July 2011
References
1. Jastreboff PJ: Phantom auditory perception (tinnitus): mechanisms of
generation and perception. Neurosci Res 1990, 8(4):221-254.
2. Melcher JR, Sigalovsky IS, Guinan JJ Jr., Levine RA: Lateralized tinnitus
studied with functional magnetic resonance imaging: abnormal inferior
colliculus activation. J Neurophysiol 2000, 83(2):1058-1072.
3. Bartels H, Staal MJ, Albers FWJ: Tinnitus and neural plasticity of the brain.
Otology&Neurotology 2007, 28(2):178-184.
4. Gleeson P, Steuber V, Silver RA: neuroConstruct: A tool for modeling
networks of neurons in 3D space. Neuron 2007, 54(2):219-235.
5. Wang J, McFadden SL, Caspary D, Salvi R: Gamma-aminobutyric acid
circuits shape response properties of auditory cortex neurons. Brain
Research 2002, 944:219-231.
doi:10.1186/1471-2202-12-S1-P383
Cite this article as: Metzner et al.: Early signs of tinnitus in a simulation
of the mammalian primary auditory cortex. BMC Neuroscience 2011 12
(Suppl 1):P383.
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Metzner et al.BMC Neuroscience 2011, 12(Suppl 1):P383
http://www.biomedcentral.com/1471-2202/12/S1/P383
Page 2 of 2
Conference Paper
Full-text available
The majority of tinnitus cases are related to cochlear dysfunction, leading to altered peripheral input to the central auditory system [1]. These alterations are believed to diminish the difference in activation during on- and off-conditions of sound [2]. As a compensatory means the affected region of primary auditory cortex tries to maximize the difference between basic level activity and sound-induced activity by changing the excitatory /inhibitory balance. In a previous model comprising ~3000 multi-compartment Hodgkin-Huxley-type neurons [3], we have shown that solely an increase of excitatory influences may be sufficient to achieve these maximization [3]. This previous Hodgkin-Huxley-type model [3] did not take into account synaptic plasticity, however. Therefore we developed a simplified version where we could efficiently implement models of short-term and long-term synaptic plasticity. The structure and organization of the simulation was adopted from the Hodgkin-Huxley-type model [3], i.e. it consists of two groups of neurons, excitatory pyramidal cells and inhibitory basket cells in a 4:1 ratio, but with 71.875 neurons in total . The multi-compartment Hodgkin-Huxley-type model neurons were replaced by the simple neuron model proposed by Izhikevich [4]. Pyramidal cells were tuned to have a firing behaviour ranging from regular spiking to chattering, with a bias towards regular spiking, and basket cells were tuned to have fast spiking properties [5]. The neurons are equipped with glutamate- (AMPA and NMDA) and GABA-sensitive synaptic receptors having first-order linear kinetics [5]. Furthermore, we incorporated models of short-term depression (STD) and facilitation (STF) [6] as well as long-term synaptic plasticity [5]. The network consists of 8 clusters each of them coding a specific frequency, with one cluster resembling tinnitus-associated changes regarding noise and afferent input (TC, tinnitus cluster). Importantly, the model largely showed the same results as the previous model, when we switched off all short- and long-term plasticity mechanisms. The tinnitus cluster shows an increased basic level of activity in the absence of input and, moreover, a diminished increase of activity during sound presentation of this particular frequency. Again a change of the ratio between excitatory and inhibitory weights towards more excitation and less inhibition in the TC results in a normal increase of activity during sound presentation. Including the plasticity mechanisms results in an increase of excitatory weights over time in the TC. This results in a higher firing rate in TC and the tinnitus cluster shows an even higher basic level of activity during absence of sound which almost reaches the activity level during sound presentation before plastic changes. Furthermore, the 'pathological region' shows a dramatically increased synchronicity in firing behaviour which is also associated with tinnitus manifestation [1]. Further simulations showed that the long-term synaptic plasticity is the main driving force of these changes. The presented simulation shows that synaptic plasticity facilitates processes that are believed to constitute the beginning of tinnitus manifestation. Our neurobiologically plausible simulation is an encouraging starting point for further modeling of the development of tinnitus, particularly due to its flexibility and computational efficiency. Acknowledgments This work was partially supported by the Graduate School for Computing in Medicine and Life Sciences funded by Germany's Excellence Initiative [DFG GSC 235/1]. References Bartels H, Staal MJ, Albers FWJ: Tinnitus and neural plasticity of the brain. Otology&Neurotology 2007, 28(2):178-184. Melcher JR, Sigalovsky IS, Guinan JJ Jr., Levine RA: Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 2000, 83(2):1058-1072. Metzner C, Menzinger M, Schweikard A, Zurowski B: Early signs of tinnitus in a simulation of the mammalian primary auditory cortex. BMC Neuroscience 2011, 12(Suppl. 1):P383. Izhikevich EM: Simple model of spiking neurons. IEEE Transact. On Neur. Netw 2003, 14:1569-1572. Izhikevich EM, Gally JA, Edelmann GM: Spike-timing dynamics of neuronal groups. Cerebral Cortex 2004, 14:933-944. Markram H, Wang Y, Tsodyks M: Differential signaling via the same axon of neocortical pyramidal neurons. Proc Natl Acad Sci USA 1998, 95:5323-5328.
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This paper presents an approach for using functional magnetic resonance imaging (fMRI) to investigate the physiology of tinnitus and demonstrates that the approach is effective in revealing tinnitus-related abnormalities in brain function. Our approach as applied here included 1) using a masking noise stimulus to change tinnitus loudness and examining the inferior colliculus (IC) for corresponding changes in activity, 2) separately considering subpopulations with particular tinnitus characteristics, in this case tinnitus lateralized to one ear, 3) controlling for intersubject differences in hearing loss by considering only subjects with normal or near-normal audiograms, and 4) tailoring the experimental design to the characteristics of the tinnitus subpopulation under study. For lateralized tinnitus subjects, we hypothesized that soundevoked activation would be abnormally asymmetric because of the asymmetry of the tinnitus percept. This was tested using two reference groups for comparison: nontinnitus subjects and nonlateralized tinnitus subjects. Binaural noise produced abnormally asymmetric IC activation in every lateralized tinnitus subject (n 5 4). In reference subjects (n 5 9), activation (i.e., percent change in image signal) in the right versus left IC did not differ significantly. Compared with reference subjects, lateralized tinnitus subjects showed abnormally low percent signal change in the IC contralateral, but not ipsilateral, to the tinnitus percept. Consequently, activation asymmetry (i.e., the ratio of percent signal change in the IC ipsilateral versus contralateral to the tinnitus percept) was significantly greater in lateralized tinnitus subjects as compared with reference subjects. Monaural noise also produced abnormally asymmetric IC activation in la...
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Neurons containing gamma aminobutyric acid (GABA) are widely distributed throughout the primary auditory cortex (AI). We investigated the effects of endogenous GABA by comparing response properties of 110 neurons in chinchilla AI before and after iontophoresis of bicuculline, a GABA(A) receptor antagonist, and/or CGP35348, a GABA(B) receptor antagonist. GABA(A) receptor blockade significantly increased spontaneous and driven discharge rates, dramatically decreased the thresholds of many neurons, and constricted the range of thresholds across the neural population. Some neurons with 'non-onset' temporal discharge patterns developed an onset pattern that was followed by a long pause. Interestingly, the excitatory response area typically expanded on both sides of the characteristic frequency; this expansion exceeded one octave in a third of the sample. Although GABA(B) receptor blockade had little effect alone, the combination of CGP35348 and bicuculline produced greater increases in driven rate and expansion of the frequency response area than GABA(A) receptor blockade alone, suggesting a modulatory role of local GABA(B) receptors. The results suggest that local GABA inhibition contributes significantly to intensity and frequency coding by controlling the range of intensities over which cortical neurons operate and the range of frequencies to which they respond. The inhibitory circuits that generate nonmonotonic rate-level functions are separate from those that influence other response properties of AI neurons.
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To describe the current ideas about the manifestations of neural plasticity in generating tinnitus. Recently published source articles were identified using MEDLINE, PubMed, and Cochrane Library according to the key words mentioned below. Review articles and controlled trials were particularly selected. Data were selected systematically, scaled on validity and comparability. An altered afferent input to the auditory pathway may be the initiator of a complex sequence of events, finally resulting in the generation of tinnitus at the central level of the auditory nervous system. The effects of neural plasticity can generally be divided into early modifications and modifications with a later onset. The unmasking of dormant synapses, diminishing of (surround) inhibition and initiation of generation of new connections through axonal sprouting are early manifestations of neural plasticity, resulting in lateral spread of neural activity and development of hyperexcitability regions in the central nervous system. The remodeling process of tonotopic receptive fields within auditory pathway structures (dorsal cochlear nucleus, inferior colliculus, and the auditory cortex) are late manifestations of neural plasticity. The modulation of tinnitus by stimulating somatosensory or visual systems in some people with tinnitus might be explained via the generation of tinnitus following the nonclassical pathway. The similarities between the pathophysiological processes of phantom pain sensations and tinnitus have stimulated the theory that chronic tinnitus is an auditory phantom perception.
1186/1471-2202-12-S1-P383 Cite this article as: Metzner et al.: Early signs of tinnitus in a simulation of the mammalian primary auditory cortex
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doi:10.1186/1471-2202-12-S1-P383 Cite this article as: Metzner et al.: Early signs of tinnitus in a simulation of the mammalian primary auditory cortex. BMC Neuroscience 2011 12 (Suppl 1):P383