Screening of deafness-causing DNA variants that are common in patients of European ancestry using a microarray-based approach

by Denise Yan, Guangxin Xiang, Xingping Chai, Jie Qing, Haiqiong Shang, Bing Zou, Rahul Mittal, Jun Shen, Richard J. H. Smith, Yao-Shan Fan, Susan H. Blanton, Mustafa Tekin, Cynthia Morton, Wanli Xing, Jing Cheng, Xue Zhong Liu

The unparalleled heterogeneity in genetic causes of hearing loss along with remarkable differences in prevalence of causative variants among ethnic groups makes single gene tests technically inefficient. Although hundreds of genes have been reported to be associated with nonsyndromic hearing loss (NSHL), GJB2, GJB6, SLC26A4, and mitochondrial (mt) MT-RNR1 and MTTS are the major contributors. In order to provide a faster, more comprehensive and cost effective assay, we constructed a DNA fluidic array, CapitalBioMiamiOtoArray, for the detection of sequence variants in five genes that are common in most populations of European descent. They consist of c.35delG, p.W44C, p.L90P, c.167delT (GJB2); 309kb deletion (GJB6); p.L236P, p.T416P (SLC26A4); and m.1555A>G, m.7444G>A (mtDNA). We have validated our hearing loss array by analyzing a total of 160 DNAs samples. Our results show 100% concordance between the fluidic array biochip-based approach and the established Sanger sequencing method, thus proving its robustness and reliability at a relatively low cost.

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The gap-prepulse inhibition deficit of the cortical N1-P2 complex in patients with tinnitus: The effect of gap duration

Publication date: Available online 7 March 2017
Source:Hearing Research
Author(s): Yunseo Ku, Joong woo Ahn, Chiheon Kwon, Do Youn Kim, Myung-Whan Suh, Moo Kyun Park, Jun Ho Lee, Seung Ha Oh, Hee Chan Kim
The present study aimed to investigate whether gap-prepulse inhibition (GPI) deficit in patients with tinnitus occurred in the N1-P2 complex of the cortical auditory evoked potential. Auditory late responses to the intense sound of the GPI paradigm were obtained from 16 patients with tinnitus and 18 age- and hearing loss-matched controls without tinnitus. The inhibition degrees of the N1-P2 complex were assessed at 100-, 50-, and 20-ms gap durations with tinnitus-pitch-matched and non-matched frequency background noises. At the 20-ms gap condition with the tinnitus-pitch-matched frequency background noise, only the tinnitus group showed an inhibition deficit of the N1-P2 complex. The inhibition deficits were absent in both groups with longer gap durations. These findings suggested that the effect of tinnitus emerged depending on the cue onset timing and duration of the gap-prepulse. Since inhibition deficits were observed in both groups at the same 20-ms gap condition, but with the tinnitus-pitch-non-matched frequency background noise, the present study did not offer proof of concept for tinnitus filling in the gap. Additional studies on the intrinsic effects of different background frequencies on the gap processing are required in the future.



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Tinnitus and hyperacusis: Contributions of paraflocculus, reticular formation and stress

Publication date: Available online 7 March 2017
Source:Hearing Research
Author(s): Yu-Chen Chen, Guang-Di Chen, Ben Auerbach, Senthilvelan Manohar, Kelly Radziwon, Richard Salvi
Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity.

Graphical abstract

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The gap-prepulse inhibition deficit of the cortical N1-P2 complex in patients with tinnitus: The effect of gap duration

Publication date: Available online 7 March 2017
Source:Hearing Research
Author(s): Yunseo Ku, Joong woo Ahn, Chiheon Kwon, Do Youn Kim, Myung-Whan Suh, Moo Kyun Park, Jun Ho Lee, Seung Ha Oh, Hee Chan Kim
The present study aimed to investigate whether gap-prepulse inhibition (GPI) deficit in patients with tinnitus occurred in the N1-P2 complex of the cortical auditory evoked potential. Auditory late responses to the intense sound of the GPI paradigm were obtained from 16 patients with tinnitus and 18 age- and hearing loss-matched controls without tinnitus. The inhibition degrees of the N1-P2 complex were assessed at 100-, 50-, and 20-ms gap durations with tinnitus-pitch-matched and non-matched frequency background noises. At the 20-ms gap condition with the tinnitus-pitch-matched frequency background noise, only the tinnitus group showed an inhibition deficit of the N1-P2 complex. The inhibition deficits were absent in both groups with longer gap durations. These findings suggested that the effect of tinnitus emerged depending on the cue onset timing and duration of the gap-prepulse. Since inhibition deficits were observed in both groups at the same 20-ms gap condition, but with the tinnitus-pitch-non-matched frequency background noise, the present study did not offer proof of concept for tinnitus filling in the gap. Additional studies on the intrinsic effects of different background frequencies on the gap processing are required in the future.



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Tinnitus and hyperacusis: Contributions of paraflocculus, reticular formation and stress

Publication date: Available online 7 March 2017
Source:Hearing Research
Author(s): Yu-Chen Chen, Guang-Di Chen, Ben Auerbach, Senthilvelan Manohar, Kelly Radziwon, Richard Salvi
Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity.

Graphical abstract

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The gap-prepulse inhibition deficit of the cortical N1-P2 complex in patients with tinnitus: The effect of gap duration

Publication date: Available online 7 March 2017
Source:Hearing Research
Author(s): Yunseo Ku, Joong woo Ahn, Chiheon Kwon, Do Youn Kim, Myung-Whan Suh, Moo Kyun Park, Jun Ho Lee, Seung Ha Oh, Hee Chan Kim
The present study aimed to investigate whether gap-prepulse inhibition (GPI) deficit in patients with tinnitus occurred in the N1-P2 complex of the cortical auditory evoked potential. Auditory late responses to the intense sound of the GPI paradigm were obtained from 16 patients with tinnitus and 18 age- and hearing loss-matched controls without tinnitus. The inhibition degrees of the N1-P2 complex were assessed at 100-, 50-, and 20-ms gap durations with tinnitus-pitch-matched and non-matched frequency background noises. At the 20-ms gap condition with the tinnitus-pitch-matched frequency background noise, only the tinnitus group showed an inhibition deficit of the N1-P2 complex. The inhibition deficits were absent in both groups with longer gap durations. These findings suggested that the effect of tinnitus emerged depending on the cue onset timing and duration of the gap-prepulse. Since inhibition deficits were observed in both groups at the same 20-ms gap condition, but with the tinnitus-pitch-non-matched frequency background noise, the present study did not offer proof of concept for tinnitus filling in the gap. Additional studies on the intrinsic effects of different background frequencies on the gap processing are required in the future.



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Tinnitus and hyperacusis: Contributions of paraflocculus, reticular formation and stress

Publication date: Available online 7 March 2017
Source:Hearing Research
Author(s): Yu-Chen Chen, Guang-Di Chen, Ben Auerbach, Senthilvelan Manohar, Kelly Radziwon, Richard Salvi
Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity.

Graphical abstract

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