Edited by: Jonathan E. Peelle, Washington University in St. Louis, USA
Reviewed by: Leonard M. Kitzes, University of California, Irvine, USA; Martin Pienkowski, Salus University, USA
*Correspondence: Andrej Kral, Institute of Audioneurotechnology, Hannover School of Medicine, Feodor-Lynen-Str. 35, D-30625 Hannover, Germany e-mail:
This article was submitted to the journal Frontiers in Systems Neuroscience.
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The present study investigates the hemispheric contributions of neuronal reorganization following early single-sided hearing (unilateral deafness). The experiments were performed on ten cats from our colony of deaf white cats. Two were identified in early hearing screening as unilaterally congenitally deaf. The remaining eight were bilaterally congenitally deaf, unilaterally implanted at different ages with a cochlear implant. Implanted animals were chronically stimulated using a single-channel portable signal processor for two to five months. Microelectrode recordings were performed at the primary auditory cortex under stimulation at the hearing and deaf ear with bilateral cochlear implants. Local field potentials (LFPs) were compared at the cortex ipsilateral and contralateral to the hearing ear. The focus of the study was on the morphology and the onset latency of the LFPs. With respect to morphology of LFPs, pronounced hemisphere-specific effects were observed. Morphology of amplitude-normalized LFPs for stimulation of the deaf and the hearing ear was similar for responses recorded at the same hemisphere. However, when comparisons were performed between the hemispheres, the morphology was more dissimilar even though the same ear was stimulated. This demonstrates hemispheric specificity of some cortical adaptations irrespective of the ear stimulated. The results suggest a specific adaptation process at the hemisphere ipsilateral to the hearing ear, involving specific (down-regulated inhibitory) mechanisms not found in the contralateral hemisphere. Finally, onset latencies revealed that the sensitive period for the cortex ipsilateral to the hearing ear is shorter than that for the contralateral cortex. Unilateral hearing experience leads to a functionally-asymmetric brain with different neuronal reorganizations and different sensitive periods involved.
In developmental manipulations of the symmetry of auditory input, as occurs with unilateral deafness (Reale et al.,
The primary auditory cortex contains mainly binaural neurons—neurons responsive to stimulation of only one ear are virtually absent (Zhang et al.,
Recently, effects of unilateral deafness have attracted clinical interest owing to the predominantly monaural therapy of prelingual deafness with one cochlear implant (Graham et al.,
Many previous studies have investigated the plasticity of the brain following cochlear implantation and have described, both in humans and in an animal model, sensitive developmental periods for plasticity (review in Kral and Sharma,
The present study directly compares the hemispheric effects of unilateral hearing. Congenitally deaf (white) cats were selected from a colony of deaf white cats using an early hearing screening procedure described earlier (Heid et al.,
The present study demonstrates that reorganizations following unilateral hearing (deafness) show a specificity for the hemisphere. The cortex ipsilateral to the hearing ear demonstrates a functional shift toward the hearing ear (Kral et al.,
The present experiments complement a previous study and the methods are described in detail there (Kral et al.,
Experiments were performed on 10 cats. In all animals, hearing was strongly asymmetric (Table
1 | Congenital | >12 | • | |
2 | Congenital | >12 | • | • |
3 | 2.5 | 4.5 | • | • |
4 | 3.5 | 9 | • | • |
5 | 3.5 | 6.5 | • | |
6 | 3.5 | 5.5 | • | |
7 | 4.2 | 9.2 | • | |
8 | 5.0 | 10 | • | • |
9 | 6.0 | 11 | • | • |
10 | 6.0 | 8 | • | • |
All animals obtained from our colony of deaf white cats underwent hearing screening within the fourth week of life. The screening procedure was based on a longitudinal study of hearing in deaf white cats recorded every two days after birth and is described in detail elsewhere (Heid et al.,
All experiments were approved by the local state authorities and were performed in compliance with the guidelines of the European Community for the care and use of laboratory animals (EU VD 86/609/EEC) and the German Animal Welfare Act (TierSchG).
To investigate developmental plasticity in animals with unilateral hearing, chronic stimulation by a cochlear implant was initiated at two different ages, reflecting the results of previous studies (Figure
Implantations were performed under sterile conditions in anesthetized animals as described previously (Kral et al.,
Chronic stimulation was performed using single-channel portable processors with a compressed analogue coding strategy in monopolar stimulation. Stimulation was applied continuously without interruption (on a 24/7 basis; for details see supplementary material in Kral et al.,
For acute experiments, all animals were premedicated with 0.25 mg atropine i.p. and initially anaesthetized with ketamin hydrochloride (24.5 mg/kg Ketavet, Parker-Davis, Germany) and propionylpromazine phosphate (2.1 mg/kg Combelen, Bayer, Germany) or xylazine hydrochloride (1 mg/kg, Bayer, Germany). The animals were then tracheotomized and artificially ventilated with 50% O2 and 50% N2O, with a 0.2–1.5% concentration of isoflurane (Lilly, Germany) added to maintain a controlled depth of anesthesia (Kral et al.,
The animal's head was fixed in a stereotactic holder (Horsley-Clarke). Both bullae and ear canals were exposed. In order to record evoked auditory brainstem responses, a small trephination was drilled at the vertex and a silver-ball electrode (diameter 1 mm) was attached epidurally. Hearing status was tested at the beginning of the experiments. So as to prevent electrophonic responses, the hair cells in normal-hearing ears were destroyed by intracochlear instillation of 300 μl 2.5% neomycine sulphate solution over a 5 min. period and subsequent rinsing using Ringer's solution. The absence of hearing was subsequently confirmed by the absence of brainstem-evoked responses.
Stimulation in the final acute experiments was performed using cochlear implants inserted bilaterally into the cochleae. In chronically electrically stimulated animals, the chronic implant was used for stimulation at the “hearing” ear. The stimulus was a biphasic pulse (200 μs/phase) applied through the apicalmost electrode contact at 10 dB above the lowest cortical threshold (see Kral et al.,
For recording, a trephination above the auditory cortex was performed and the dura was opened. First, within a grid of 3 × 3 positions, LFPs were recorded using low-impedance electrodes to determine the lowest cortical threshold for stimulation with a biphasic pulse (200 μs/phase) applied through the apicalmost electrode of the implant. Mapping of cortical responses was performed using glass microelectrodes (
From the more than 100 recordings at the cortical surface within field A1 and adjacent fields, cortical activation maps were constructed (Figure
The electrical artifacts from the stimulation occurred between 0.0 and 0.6 ms post-stimulus and did not influence the response (latency > 7 ms). The signal before the response (500 ms duration in each animal) was characterized by computing its mean and standard deviation. The threshold of mean ± 4*standard deviation was then used for detecting neuronal responses. The threshold attained absolute values of 10–20 μV.
Using this measure, onset latencies were detected for the first positive response (
Peak amplitudes of
Some analyses were performed exclusively from six positions within the area with the largest responses (the “hot-spot,” Kral et al.,
The comparison of the morphology of mean LFP was assessed using the dissimilarity index (DI, Kral et al.,
This index considers the morphology of the LFPs irrespective of the amplitude. A dissimilarity index can reach values between 0 and 1, whereas 0 represents identical LFPs. Identical but time-reversed signals yield a high dissimilarity index due to the sample-by-sample comparison.
The present comparisons concentrated on LFP morphology and onset latency. First, the response maps and morphology of the LFPs are described, followed by onset latency comparisons.
In the present paper, the terms
On the other hand, the term “
Thus, if the left ear was the hearing ear, and a probe stimulus was presented at the right (i.e., the deaf) ear, the crossed response refers to the response recorded at the left cortex and the uncrossed response refers to that at the right cortex. In this case, the ipsilateral cortex is then the left one and the contralateral cortex is the right one.
Crossed and uncrossed responses compared at the same cortex tend to result in different LFPs in normal hearing animals, with crossed responses showing larger amplitudes and shorter latencies (Kral et al.,
To minimize the effect of different spatial position when comparing responses at the contralateral and the ipsilateral cortex, further analysis was concentrated on hot spots: the areas of largest responses. These were considered as being the cortical representation of the stimulated region in the cochlea and were therefore considered the functionally corresponding sites in the cortex. From a total area of 1.5 mm2 within the hot spot, all LFPs were averaged (~6 recording positions; Figure
First, the effect of stimulation duration was compared in early-implanted animals (Figure
Crossed responses to stimulation of the deaf ear and to stimulation of the hearing ear were compared next (Figure
At the ipsilateral hemisphere early-implanted animals had uncrossed responses larger than crossed ones (Figure
To quantify this observation, dissimilarity index for
A previous study demonstrated high plasticity of LFP onset latency and its sensitivity to developmental modifications (Kral et al.,
First, the effect of stimulation duration and implantation age on onset latencies of crossed responses was determined at the contralateral hemisphere for stimulation of the hearing ear (Figure
Next, onset latencies of crossed responses were compared between hemispheres in four animals with a stimulation duration of 5 months (Figure
Finally, the onset latencies for the responses to the stimulated (hearing) ear were compared between the cortices (Figure
To verify this outcome, the difference in medians of uncrossed and crossed responses to the hearing ear was compared between early and late onset of asymmetric hearing (Figure
The present manuscript describes hemispheric specificity of effects of unilateral hearing following congenital deafness. It demonstrates that in early-onset unilateral hearing, both the ipsilateral and the contralateral hemisphere reorganize and strengthen the responses to stimulation of the hearing ear, giving it an advantage over the deaf ear. In the early-onset animals, the ipsilateral hemisphere responded more strongly to stimulation of the hearing ear. The morphology of the LFPs demonstrated that the reorganizations following unilateral deafness were hemisphere-specific (Figure
The uncrossed pathway appeared more susceptible to developmental alteration of hearing balance than the crossed pathway, although both the crossed and uncrossed responses to the hearing ear were changed by the stimulation. In late implantations, the uncrossed response did not show similar reorganization, and it was largely the crossed pathway of the hearing ear that still benefited from stimulation, although less than in early implanted animals (Figures
The present study compared the effects of stimulation at both hemispheres. There are several limitations to the present approach that merit discussion. First of all, comparisons between hemispheres preclude pairwise testing. Although the present study used an approach validated by several previous studies performing interindividual comparisons (Klinke et al.,
Degeneration of spiral ganglion cells is unlikely to have contributed to the findings here, as there was no significant spiral ganglion cell loss in the implanted (basal) region of the cochlea within the first 2 years of life in congenitally deaf cats, and even at an older age there was less degeneration in the basal cochlea (Heid et al.,
Finally, age at final experiment did not significantly contribute to the present findings. The cortical developmental sequence in deaf and hearing cats with respect to electrically evoked responses terminates at ~6 months (Kral et al.,
Finally, it has to be considered that the effects measured at the ipsilateral cortex need not necessarily arise in the ipsilateral hemisphere, but may have an origin in the contralateral hemisphere before pathway crossing. For the sake of simplicity, however, we will not complicate the considerations below by including this aspect.
The present study is well in agreement with previous investigations on the subject. The notion of auditory sensitive periods in neuronal plasticity (review in Kral,
Early neonatal unilateral ablation studies suggested a reorganization of the auditory brain toward the hearing ear (Nordeen et al.,
The reorganization reported here and in previous studies is in accord with results from cochlear-implanted children (Peters et al.,
Importantly, the outcome shows specificity for the ear that has received input (Figures
Subcortical reorganization with deafness and cochlear implants has been described before (Snyder et al.,
The uncrossed response latency for stimulation of the hearing ear became smaller than the crossed response latency, so that the difference in medians was negative, but only in the early-implanted animals (Figures
Inhibitory synaptic transmission matures later than excitation (review in Kral et al.,
Stimulation of the hearing ear generates strong responses both at the ipsilateral and the contralateral hemisphere (for human data, see Bilecen et al.,
The present study supports the concept of several sensitive developmental periods by demonstrating a shorter sensitive period for reorganization at the ipsilateral hemisphere as compared with the contralateral hemisphere. It shows more extensive changes in uncrossed responses than in the crossed responses in early-onset animals. Furthermore, it shows that unilateral deafness results in an asymmetric brain, with different hemispheres showing differential responses for both the deaf and the hearing ear. The hemisphere ipsilateral to the hearing ear most likely downregulates inhibition, by that specifically decreasing onset latency of the response to the hearing ear. This effect is not found in the contralateral hemisphere.
The deaf ear is, however, not completely ‘disconnected’ from the cortex following single-sided deafness. The hemisphere ipsilateral to the hearing ear preserves responsiveness to the deaf ear, although with a preference for the hearing ear. Finally, the present results support a greater ‘separation’ of the ears in early onset unilateral hearing.
Dr. Jochen Tillein works also for MedEl Company, Innsbruck. His obligations in the company had no interference with the work nor is there any direct financial interaction between MedEl and the research performed in this study. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The study was supported by the German Research Foundation (DFG; Cluster of Excellence Hearing4all and DFG Grant Kr 3370/1-3). The authors want to thank Peter Baumhoff, MSc., for designing Figure