N = 21) and normal-hearing controls (N = 23) performed an fMRI-compatible adaptation of the Token Test involving listening to a sentence such as “touched the small green circle and the large blue square” and simultaneously viewing an arrow touching colored shapes on a video. Children with right or severe-to-profound UHL-SN displayed smaller activation in a region encompassing the right inferior temporal, middle temporal, and middle occipital gyrus (BA 19/37/39), evidencing differences due to monaural hearing in cross-modal modulation of the visual processing pathway. Children with UHL-SN displayed increased activation in the left posterior superior temporal gyrus, likely the result either of more effortful low-level processing of auditory stimuli or differences in cross-modal modulation of the auditory processing pathway. Additionally, children with UHL-SN displayed reduced deactivation of anterior and posterior regions of the default mode network. Results suggest that monaural hearing affects the development of brain networks related to cross-modal sensory processing and the regulation of the default network during processing of spoken language.Monaural auditory input due to congenital or acquired unilateral hearing loss (UHL) may have neurobiological effects on the developing brain. Using functional magnetic resonance imaging (fMRI), we investigated the effect of UHL on the development of functional brain networks used for cross-modal processing. Children ages 7–12 with moderate or greater unilateral hearing loss of sensorineural origin (UHL-SN;  Unilateral hearing loss (UHL) is quite prevalent in children. While incidence estimates in newborns are only on the order of 1 per 1000 , prevaleHowever, UHL may affect brain development beyond the auditory system, as subtle changes in auditory experience can have an important impact on the types of experiences that shape brain development. For example, normal-hearing children will look toward the source of an interesting sound, and be able to pair the visual information with the heard sound. Children with UHL, however, will have far fewer opportunities, as they have poor sound localization. Even if they should happen to be looking in the appropriate direction by chance, they still may have difficulty associating the sound with the correct visual stimulus. Therefore, subtle changes in how children with UHL experience the auditory landscape  may impact development of brain regions and networks utilized for cross-modal modulation of auditory response in the presence of visual stimuli and visual response in the presence of auditory stimuli.Deficits in cross-modal modulation may also impact cognitive function; as some evidence also suggests deficits experienced by children with UHL extend into cognitive domains. Children with UHL not only show difficulties in speech and language, but also exhibit academic, behavioral, and psychosocial deficits , 2012. IIn this study, we wished to investigate processing of spoken language simultaneous with a relevant visual stimulus in children with unilateral hearing loss of sensorineural origin (UHL-SN). We developed a novel magnetic resonance imaging (MRI)-compatible modified “Token Test”  in whichApproval was obtained for this study from the Institutional Review Board at Cincinnati Children’s Hospital Medical Center (CCHMC). Informed consent was obtained from one parent of all participants, with assent obtained from participants 8 years of age or older. Data was acquired from 2006 until 2011.N = 21; 11 with left UHL-SN, 10 with right UHL-SN; 5 with moderate or moderately severe UHL-SN, 16 with severe-to-profound UHL-SN, see Table 1 for complete details) were either referred from the Audiology Clinic at CCHMC, or were recruited via flyers placed at CCHMC main and satellite locations. An attempt was made to restrict inclusion to participants with hearing loss of 2 years or greater duration, as reorganization of auditory pathways is complete after approximately 2 years (N = 23) were recruited via flyers. Exclusion criteria consisted of standard MRI exclusion criteria ; non-native or non-monolingual English speaker; any history of head trauma, attention deficit hyperactivity disorder (ADHD), pervasive developmental disorder (PDD), or autism; active otologic disease or history of ear surgery (excluding tympanostomy tubes); any history of infections ; or score less than 95% on the Northwestern University – Children’s Perception of Speech .Participants with UHL-SN between 7 and 12 years of age ( 2 years . AccordiTable 2 for demographic and test data for the participants). Normal levels of cognitive function were verified via the Wechsler Full-Scale Intelligence Scale for Children (WISC-IV). The normal-hearing cohort had significantly higher levels of cognitive function on the WISC-IV full-scale IQ (see Table 2).Using standard pure-tone audiometry , we verified that all participants with UHL-SN had normal-hearing (< = 20 dB HL) in the good ear and sensorineural hearing loss of at least moderate severity (> = 40 dB HL) in the impaired ear. All normal-hearing participants had < = 15 dB HL in both ears. There was no difference in the gender composition of the two groups  or bilateral hearing reception (in the control group). The requirement of high scores on the NU-CHIPS indicated normal perception of speech, regardless of the presence of UHL. In addition, participants completed four tests of higher-order auditory function, which are often included in batteries designed to diagnose auditory processing disorder (APD) in children, in a soundproof audiometric booth at CCHMC. Of the four auditory tests, a significant difference in performance was found only on the speech-in-noise test, in which UHL-SN children performed significantly worse compared to normal-hearing children. The tests are described individually below and test results are provided in The test stimuli consist of one syllable words that have been low-pass filtered at 750 Hz with a roll-off of 30 dB per octave. Twenty words are administered to each ear monaurally . This test is a subtest of the SCAN3:C test for APD in children .The test stimuli consist of two lists of 10 sentences with 40% time compression, and two lists of 10 sentences with 60% time compression . The senStimuli consist of the Bamford–Kowal–Bench (BKB) sentences  spoken bTable 2; this did not vary between UHL and normal-hearing groups ]. Auditory stimuli were presented through a custom-built MRI-compatible audio system using ER-30 headphones  which provides a background noise level of < 10 dB SPL. The functional magnetic resonance imaging (fMRI) paradigm consisted of an adaptation of the “Token Test” .T-score.Since the longitudinal relaxation of spins differs for the first, second, and third frame after each silent period, the frames were grouped according to first, second, or third scan after the silent period and analyzed separately. Motion correction was performed using a pyramid iterative algorithm , which wIn the second level analysis, the following steps were performed:T-tests were performed on the UHL-SN and normal-hearing cohorts separately, in order to find voxels with significant activation or deactivation in either group. Results were spatially filtered with σ = 4 mm. An intensity threshold of Z = 7.0 and spatial extent threshold of 65 voxels was used, shown to correspond to a family-wise-error (FWE) corrected p < 0.01 via Monte Carlo simulation ((1) It was desired to restrict group comparisons to regions activated or deactivated in either group. Therefore, one-sample mulation ; intrinsmulation ]. SubseqZ = 5.0 and spatial extent threshold of 60 voxels was used, shown to correspond to a FWE corrected p < 0.05 .(2) On the subset of voxels found from step 1, a GLM was performed with UHL-SN status (coded as a dummy variable) as the variable of interest and age, sex, full-scale IQ, scanner, square root of the number of retained frames, and side of presentation as covariates of no interest. , medial prefrontal and orbitofrontal regions (anterior DMN regions), the right primary auditory cortex (likely related to greater activation during the control task due to hearing the 440 Hz tone) and in precentral and post-central regions (related to the greater motor activity during the control task).Figure 1; Table 4) in a region encompassing the right inferior temporal, middle temporal, and middle occipital gyri (BA 19/37/39) for the contrast of all sentences vs. control, when analysis was restricted to children with severe-to-profound UHL, or children with right UHL. No significant differences were seen for the contrast of complex sentences vs. control or simple sentences vs. control.Children with UHL displayed smaller activation  in the posterior aspect of the left superior temporal gyrus for the contrast of all (simple and complex) sentences vs. control, and the contrast of complex sentences vs. control, though not for the contrast of simple sentences vs. control. The contrast of all sentences vs. control maintained significance when analysis was restricted to children with severe-to-profound UHL, though not when analysis was restricted to children with UHL of greater than 2 years duration, children with left UHL, or children with right UHL.Children with UHL displayed greater activation  children with UHL displayed smaller deactivation in posterior and anterior DMN regions, indicating that this phenomenon is ubiquitous among the population with UHL-SN.For all contrasts and comparisons .No differences in activation or de-activation between children with left and right UHL-SN were found, except for deactivation differences in the right primary auditory cortex, related to listening to the 440 Hz tone during the control task (data not shown).F = 1.57, p > 0.25], indicating results were not biased by failing to model different variances dependent on scanner. No significant effect was found for side of hearing loss for the region with activation differences in the left posterior superior temporal gyrus from Figure 2 .No significant difference was found between the residual variance from scans acquired on the Siemens scanner vs. scans acquired on the Philips scanner for any of the ROIs examined [max. This functional imaging study investigates differences in the neural correlates of cross-modal processing in children with UHL. The children in this study were of normal overall intelligence and demonstrated no other signs of neurodevelopmental disorders, minimizing possible problems related to transferability of results. This study, the first of its kind, provides unique insights into the effects of unilateral sensory deprivation on brain development.Agreeing with our primary hypothesis, we found significantly less functional activation in secondary visual processing regions in the right hemisphere (BA 19/37/39) in children with UHL. An increasing body of evidence argues against a strictly hierarchical view of multisensory integration and demonstrates multimodal interactions in cortical regions previously thought to be unimodal [see  for a repost hoc analysis on the children with UHL-SN demonstrated no significant effect of side of hearing loss. Interestingly, the results are no longer significant when analysis was restricted to children with UHL-SN over 2 years duration. This may indicate that this finding is only a short-term effect, which could be related to lack of complete reorganization of auditory pathways, although a likely alternative hypothesis is that this may reflect more effort in low-level processing of auditory stimuli; the laterality of this effect may reflect the greater contribution of the left hemisphere to the kinds of rapid changes in the acoustic signal that are characteristic of speech  and anterior  DMN regions, regardless of the specific type of sentence (complex or simple), and independent of side of hearing loss. While the DMN is typically classified as a “resting-state” network, it was initially identified as a network found to deactivate during the performance of cognitive tasks; the amount of deactivation is a function of the cognitive demand and is also related to task performance  of hearing loss, severe-to-profound hearing loss, or left or right hearing loss, indicating this phenomenon to be ubiquitous over the population. Thus, ameliorating noisy backgrounds via FM amplification  may be aIt is interesting to note that differences in functional activation and de-activation occur in a task involving speech in quiet. A significant effect of UHL was not found either on in-scanner task performance or out-of-scanner performance for the SCAN-C subtests involving speech in quiet . Our results therefore confirm that UHL affects development of neural substrates used for cross-modal modulation even for tasks such as speech in quiet where performance is not directly affected. However, these differences may result in downstream effects on other behavioral outcomes.Accordingly, in the broader picture, this study demonstrates that a change in the transmission of sound to the brain from binaural to monaural input can have a global influence on the development of brain networks related to higher-order cognitive function. This result may inform the ongoing debate concerning other disorders that involve subtle changes involving audition. For example, whether APD in children should be viewed as more of a sensory, or a higher-order cognitive, deficit is a matter of active debate . HoweverDeficiencies in DMN deactivation during the performance of demanding cognitive tasks has been demonstrated in various neuropathologies including math disability , autism A possible limitation of the study is that the NH and UHL cohorts are not precisely matched on levels of overall cognitive function. While the UHL cohort is in the normal range, the NH children display approximately 2/3 of a standard deviation higher mean IQ scores. This was taken into account by covarying for full-scale IQ in all neuroimaging analyses. Additionally, we are unable to determine, in this cohort, whether hearing loss was congenital or acquired. This limitation is present in all studies of UHL before the advent of universal newborn hearing screening (UNHS); unfortunately, UNHS in Ohio began only in 2004. Without such procedures in place, UHL in children with a congenital loss is typically only detected after the start of school, at approximately 5 years of age. While it is likely that most participants in our study with a verified long duration of hearing loss had an acquired loss, as is the case for the majority of individuals with UHL, we cannot rule out that some of the participants with verified long duration of hearing loss may in fact have a congenital loss. Nevertheless, our results suggest that the DMN is affected even by acquired UHL; this result is consistent with previous studies suggesting acquired UHL is associated with language, speech, and behavioral deficits. Moreover, as the DMN itself is in place at birth , even foIn conclusion, our results show altered neurophysiology in children with UHL for cross-modal modulation as well as a deficiency in deactivation of the DMN during audio–visual tasks. These results strongly suggest that one good ear is insufficient to promote the development of normal cognitive function. This physiological signature may underlie the poor academic and behavioral outcomes associated with UHL.The 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.


Visual working memory (VWM) is known as a highly capacity-limited cognitive system that can hold 3–4 items. Recent studies have demonstrated that activity in the intraparietal sulcus (IPS) and occipital cortices correlates with the number of representations held in VWM. However, differences among those regions are poorly understood, particularly when task-irrelevant items are to be ignored. The present fMRI-based study investigated whether memory load-sensitive regions such as the IPS and occipital cortices respond differently to task-relevant information. Using a change detection task in which participants are required to remember pre-specified targets, here we show that while the IPS exhibited comparable responses to both targets and distractors, the dorsal occipital cortex manifested significantly weaker responses to an array containing distractors than to an array containing only targets, despite that the number of objects presented was the same for the two arrays. These results suggest that parietal and occipital cortices engage differently in distractor processing and that the dorsal occipital, rather than parietal, activity appears to reflect output of stimulus filtering and selection based on behavioral relevance. The number of representations one can simultaneously hold in visual working memory (VWM) is highly limited; behavioral studies have suggested that it is up to about four items in humans Recently, electrophysiological and neuroimaging studies have demonstrated that this capacity-limited memory system resides in the posterior parietal and occipital cortex Although working memory is often, because of its severely limited capacity, considered to store only necessary information Load-dependent responses in parietal and occipital cortices may thus reflect distinct aspects of attentional control in VWM; i.e., activity in the parietal cortex may reflect the “source” of stimulus filtering and selection, while that in the occipital cortex may reflect the target or output of that control process. Here, we investigated this issue by elucidating which regions are susceptible to task-relevant stimuli, using a change detection task in which participants are required to remember pre-specified targets and ignore distractors Eighteen university students  participated in the experiment The experimental design and procedures have been described elsewhere in detail K = (hit rate + correct rejection rate−1)×S, where K is the VWM capacity estimate, and S is the display set size of the array.We used a standard formula 3 voxel, 208 axial slices) and T2-weighted images  were collected.A Siemens Trio 3T scanner equipped with an 8-channel phased array coil was used to measure blood oxygenation level-dependent (BOLD) cortical activity. Functional images were taken with a gradient echo echo-planar pulse sequence . Thirty 3-mm thick axial slices  parallel to the AC-PC line were acquired for 230 volumes in each run. Following the acquisition of functional images, anatomical 3D T1-weighted images . Preprocessing of functional images consisted of slice acquisition time correction, 3D motion correction, intra-session realignment, spatial smoothing (3D 6-mm Gaussian kernel), linear trend removal, and Talairach space registration K of the individual observer for that set size P<0.05, corrected for serial correlation) taking the localizing contrast of each observer as a separate predictor. Then, another multiple regression analysis was conducted with non-weighted regressors defined for each experimental condition. Signal magnitudes of each ROI were derived from beta values of the multiple regression analysis. Instead of performing a separate localizer run, we defined ROIs using conditions embedded within the experimental run. Because the localizing contrast was independent of the distractor condition, main contrasts of interest in the present study  were not biased by the localizing contrast per se.To localize VWM-related ROIs, a multiple regression analysis excluding the distractor condition, with sample display onsets convolved with a canonical hemodynamic function, was performed with regression coefficients for each set size weighted by the VWM estimate F1.47,22.01 = 197.79, P<0.001; K increased as a function of display set size . Although K was not asymptotic, this behavioral function, consistent with a previous study t15 = 3.58, P<0.01). Behavioral performance under the distractor condition (1.85) was comparable to set size 2 , despite two distractors being added compared to set size 2. These results are consistent with a behavioral study showing that distractors do not affect VWM accuracy A repeated measures analysis of variance (ANOVA) excluding the distractor condition revealed a main effect of display set size .The analysis revealed regions whose activities significantly correlated with the number of objects held in VWM in the right IPS . Activities in the LO, and dorsal occipital cortex increased as a function of VWM load , while the IPS activity increased up to display set size 4  and thereafter became asymptotic . The IPS activity was better described by a K function than linear function  but this was not true of the LO and dorsal occipital activities . This suggests the IPS, rather than occipital regions, to be a key neural locus of capacity-limited VWM, but does not necessarily mean the absence of a contribution from the occipital regions to VWM.BOLD signal magnitude as a function of trial type is shown for each activated area in t values <1), the dorsal occipital cortex exhibited a significantly lower response to the distractor condition relative to set size 4 . Differences between the distractor condition and set size 2 were significant in all ROIs .Importantly, whereas comparisons between the distractor condition and set size 4 in the IPS and LO areas did not show significance  unaffected It is unlikely that the comparable BOLD response between targets and distractors in the IPS is due to the placing of equivalent processing weights on both targets and distractors. Because change detection performance for an array of two targets with two distractors was indistinguishable from that for two targets only, it would seem that participants could effectively prioritize targets and prevent distractors from affecting behavioral performance. Note that this does not necessarily mean perfect distractor filtering: previous behavioral studies, which used a similar change detection task assessed with distractor-change The coordinates of the IPS correspond to the superior IPS, which specifically processes featural information, in Xu's superior/inferior distinction of IPS 1. The CDA and the IPS might reflect “somewhat distinct but overlapping” neural mechanisms supporting VWM The VWM load sensitive activity in the IPS has been considered analogous to the contra-lateral delay activity (CDA) Although we did not conduct retinotopic mapping and thus can not define the precise retinotopic location, the coordinates of our dorsal occipital activation closely match those of area V3a in a previous study Kmax) and encoding task-irrelevant objects into VWM (distractor filtering efficiency: α) in the dorsal occipital cortex (r = 124). This discrepancy might be because the number of targets and distractors was not necessarily equal between hemifields; e.g., targets were presented in one hemifield and distractors in the other hemifield at times, while targets and distractors were evenly distributed in each hemifield at other times. Alternatively, the CDA and the dorsal occipital activity may reflect different neural mechanisms supporting VWM. Note: Individual capacity estimates were derived from the maximum value of Cowan's K across all set sizes of that subject (Kmax). Distractor. filtering efficiency was derived from the next formula: α  =  (F-D)/(F-T), where α is the filtering efficiency, F is the signal magnitude for the four targets condition, D is the signal magnitude for the two targets with two distractors condition, and T is the signal magnitude for the two targets alone condition Finally, the differential responses to distractors we found among VWM load-sensitive regions indicate that each area contributes differently to the processing of task-irrelevant information. Consistent with previous studies


CERKL gene encodes for ceramide kinase-like, a novel protein of unknown function. CERKL mutations are associated with a severe retinal phenotype. The purpose of this work was to investigate alternative splicing, and the temporal and spatial expression pattern of CERKL in the mouse retina.The Cerkl at various developmental time points, and to identify its various splice-isoforms. A specific anti-CERKL antibody was developed and used for immunostaining to study the localization of the endogenous CERKL protein in retina-derived cell lines and in the mouse retina.Reverse Transcription-Polymerase Chain Reaction (RT–PCR) analysis of mouse retina RNA was used to study the expression of Cerkl is expressed in the mouse eye as early as embryonic day 14. A total of seven different Cerkl splice-isoforms were identified in the mouse retina. The subcellular localization of CERKL in retina-derived cell lines is variable: CERKL is diffusely distributed in the cytoplasm, and in many cells, it is highly concentrated in the perinuclear region. In most, but not all cells, CERKL is also highly concentrated in the nucleus. In the mouse retina, CERKL is located in the ganglion cell layer, in amacrine cells of the inner nuclear layer, and in photoreceptors. CERKL is highly expressed in cone photoreceptors; however, its expression level in rod photoreceptors is very low. In cultured cells, CERKL is detected in the nucleus, but in retinal cells in situ, it is mostly located in the cytoplasm.Cerkl in both mature and embryonic mouse retina and the severe retinal phenotype associated with human CERKL mutations indicate that this gene plays a crucial role in retinal activity, and that it may be important for retinal development as well. The high expression level of CERKL in cones correlates with the CERKL-associated phenotype in humans. Whether nucleocytoplasmic transport of CERKL actually occurs in vivo under certain conditions and its functional significance remain to be discovered.The expression of  Hereditary retinal degeneration (HRD) is a clinically and genetically heterogeneous group of diseases that cause visual loss due to progressive loss of rod and/or cone photoreceptor cells in the retina . In coneCERKL) , and 0.5% Nonidet P40 [NP-40]). The lysate was centrifuged for 5 min at 1500× g, and the supernatant was separated and used as the cytosolic fraction. The pellet was washed once with lysis buffer (without NP-40) and proteins were extracted by adding 2 volumes of low-salt buffer and one volume of high-salt buffer . For western blot analysis, protein samples (10 μg each) were boiled for 10 min and subjected to SDS–PAGE. They were then transferred to a nitrocellulose membrane , which was incubated with primary antibodies, followed by peroxidase-conjugated goat-antimouse or goat-antirabbit secondary antibodies. Signals were visualized by chemiluminescence using the Amersham ECL Western Blotting Analysis System .For total protein extraction, retinas were subjected to 0.5 M HEPES buffer (pH 7.3), followed by sonication and centrifugation, after which the supernatant was collected and stored at −80 °C. For the separation of cytoplasmic and nuclear extracts, retinas were homogenized in lysis buffer , although its expression rate in the embryonic and newborn (P0) eye was lower compared to that in the adult eye  to the mouse genome sequence at the UCSC Genome Browser initially revealed that the mouse gene comprises 13 exons. The exon structure of human and mouse CERKL genes is highly conserved (CERKL splice-variants in the human retina (isoforms a-d), and two additional non in-frame variants that would generate prematurely truncated proteins  retina. Four different Cerkl splice-isoforms were identified in the adult retina (variants a’-d’). In the embryo, five different isoforms were detected . One of the embryonic isoforms (isoform g’) included a novel exon of 156 bp (exon 12). Therefore, the total number of exons in the mouse Cerkl gene is 14, as in the human ortholog  encode for relatively long protein products including the PH domain, and the DAGK and CERK homology domains. The other isoforms encode for very short protein products, which include only a full or a partial PH domain . Two of n et al.  to mouseTo study the expression pattern and function of CERKL, we developed a specific anti-CERKL antibody (RA). The antibody was raised in rabbit against a mixture of two short peptides (15 AA each). The specificity of the RA antibody was initially tested using western blot analysis. The antibody detected a main specific band that corresponds to the expected size of the primary and most abundant CERKL isoform in the adult mouse retina . Two additional fainter bands slightly higher than 51 kDa could also be observed, which may correspond to isoforms b’ and c’ . All three bands were completely omitted following pre-absorption of the RA antibody with the recombinant CERKL protein, but not with a non-specific protein BSA; .To further verify the specificity of the RA antibody, we expressed three CERKL mouse retinal isoforms  as recombinant proteins in bacteria under an IPTG-inducible promoter. Western blot analysis with the RA antibody detected proteins of the expected sizes in induced, but not in un-induced bacterial extracts .To date, the subcellular localization of CERKL was tested by overexpression of the tagged protein in various cell lines that were not of retinal origin ,13. TherThe subcellular localization of CERKL in 661W cells was more uniform. In most cells, CERKL was distributed in both the cytoplasm and the nucleus, and highly concentrated in the perinuclear region . InteresImmunostaining of adult mouse retinas with the RA anti-CERKL antibody indicated that CERKL was located in the GCL, INL, and PRL . No staiIn CERKL-positive mouse retinal cell types in situ, CERKL was mostly located in the cytoplasm. In photoreceptors and amacrine cells, CERKL was exclusively located in the cytoplasm and nuclear staining was not observed in these cell types . In gangCERKL is a novel gene of unknown function. It was named CERKL due to its homology to CERK [Cerkl is highly expressed, but Cerk expression is very low  levels were decreased. In contrast, wildtype levels of both ceramide and C1P were found in the retina of Cerkl null mice [ to CERK . Our anavery low . Based oull mice . These full mice .Cerkl in the retina, in addition to the severe retinal phenotype associated with human CERKL mutations, indicate that this gene plays a crucial role in retinal activity. Moreover, we found that Cerkl is expressed in the mouse eye as early as E14 , and two additional non in-frame variants that would generate prematurely truncated proteins (isoforms e and f). They considered these two variants to be aberrant transcripts. Since the human exon 4b, which is included only in isoform b, has no equivalent in the mouse gene . Interestingly, the only other variant common to both human and mouse was mouse isoform f’, which is equivalent to human isoform f (AY690332; n et al.  identifiuse gene , they spisoforms . HoweverCerkl was reported to be expressed in photoreceptors in general [CERKL mutations. It is possible that in the human retina, the expression level of CERKL in rods is higher than in the murine retina. Alternatively, despite its low expression level, CERKL may still be crucial for rod survival. A third option is that rod degeneration may be secondary to cone degeneration. This option is less likely, as at least in some patients with CERKL mutations, a similar degree of rod and cone dysfunction is observed [Our findings regarding the expression pattern of CERKL within the mouse retina are noteworthy. Previously, based on in situ hybridization,  general , but our general ,8. NeverWithin cone photoreceptors, CERKL was found in the outer segments, which are highly specialized organelles consisting of a series of discrete membranous discs that are densely packed with rhodopsin and other proteins involved in the phototransduction cascade. Moreover, they lack most of the proteins involved in other cellular functions . It may Another important finding from our analysis is related to the intracellular localization of CERKL, and specifically to its presence in the nucleus. Two putative NLS and NES were identified in the CERKL protein, and these appear to be responsible for the trafficking of CERKL between the cytoplasm and the nucleus in cultured cells ,15. CERK


Cochlear pathologies and vestibular disorders have been investigated in detail in the recent years. Recent advances in diagnostic and therapeutic methods have introduced new investigations about the cytologic degenerations and regenerations of cochlear cells. Knowledge and understanding of otologic diseases have led to the development of novel therapies, approaches, and/or tools.This special issue covers the important topics in the diagnosis and therapies of otologic diseases including chronic otitis media, tinnitus, ototoxicity, and hearing loss.Investigation of the Presence of Biofilms in Chronic Suppurative Otitis Media, Nonsuppurative Otitis Media, and Chronic Otitis Media with Cholesteatoma by Scanning Electron Microscopy. Biofilms have been shown to play a major role in the pathogenesis of otolaryngologic infections. However, very limited studies have been undertaken to demonstrate the presence of biofilms in tissues from patients with chronic otitis media (COM) with or without cholesteatoma. E. Kaya et al. found that their study supports the hypothesis that biofilms are involved in chronic suppurative otitis media, cholesteatoma, and to a lesser degree, chronic nonsuppurative otitis media. The presence of biofilms was significantly higher in the middle ear mucosa compared with the mastoid and ossicle samples. They emphasized that careful use of topical or systemic antimicrobials is essential and during surgery, hypertrophic tissue must be carefully removed from normal tissue. Is It Necessary to Do Temporal Bone Computed Tomography of the Internal Auditory Canal in Tinnitus with Normal Hearing? Tinnitus is the perception of sound without an external stimulus. The prevalence of tinnitus varies between 3–30% of all population. As we know very well, tinnitus can be seen due to the pressure of the acoustic neuromas, cerebellopontine angle tumors, and vascular lesions, such as vascular loop to the eight cranial nerve reported in the literature. The development of the tinnitus can be observed due to nerve edema, degeneration, and compression in the canal. Accordingly, the pathological conditions that affect the width of the canal can lead to tinnitus due to compression. T. L. Kumral et al. investigated the diameter of internal acoustic canal in physiologically impaired tinnitus patients as the etiology may be due to anatomical differences of the temporal bone. In conclusion they found that there were no anatomical differences in the etiology of tinnitus rather than physiological degeneration in the nerves.Efficacy of Low-Level Laser Therapy in the Management of Tinnitus due to Noise-Induced Hearing Loss: A Double-Blind Randomized Clinical. Several remedial modalities for the treatment of tinnitus have been proposed, but an effective standard treatment is still to be confirmed. In the present study, A. Mollasadeghi et al. investigate the effect of low-level laser therapy on tinnitus accompanied by noise-induced hearing loss. They found low-level laser therapy to be effective in alleviating tinnitus in patients with noise-induced hearing loss, although this effect has faded after 3 months of follow-up.The Role of Thiamine Pyrophosphate in Prevention of Cisplatin Ototoxicity in an Animal Model. Cisplatin ototoxicity has several characteristics. Inner ear toxicity is often a dose limiting side effect that hampers optimal cisplatin-based chemotherapy. It is normally manifested as a sensorineural hearing loss beginning in the high frequencies, successively progressing towards the speech frequency range. O. Kuduban et al. investigate the effectiveness of thiamine pyrophosphate against cisplatin-induced ototoxicity in guinea pigs. They found that systemic administration of thiamine pyrophosphate yielded statistically significant protection to the cochlea of guinea pigs from cisplatin toxicity. They emphasized that further experimental animal studies are essential to determine the appropriate indications and dosages of thiamine pyrophosphate before clinical use.Extended High Frequency Audiometry in Polycystic Ovary Syndrome. Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting 5–10% of women in the reproductive age. Disease is characterized by oligo/amenorrhea, hyperandrogenism, and polycystic ovaries. PCOS is a chronic proinflammatory state. C. Kucur et al. evaluated extended high frequency hearing loss in PCOS patients. They concluded that PCOS patients have hearing impairment especially in extended high frequencies. Further studies are needed to help elucidate the mechanism behind hearing impairment in association with PCOS and to see whether the impairment of extended high frequency audiometry in these cases is progressive.Possible Protective Effect of Sertraline against Cisplatin-Induced Ototoxicity: An Experimental Study. Cisplatin is a widely used chemotherapeutic agent but its ototoxicity side effect can occur in the majority of patients. Lots of agents were tried to prevent this, but there is not a routine treatment modality yet. The aim of this study was to evaluate the otoprotective effect of sertraline, which is an antidepressant with neuroprotective effects, against cisplatin, in rats. M. Ozturk et al. showed that sertraline seems to have a protective effect on cisplatin ototoxicity, and could be used to prevent the ototoxicity and also to treat the depression that occurred in cancer patients together.Fatih OghanFatih OghanCemal CingiCemal CingiErkan KaratasErkan KaratasSebahattin CureogluSebahattin Cureoglu


A systematic review was conducted to identify and quality assess how studies published since 1999 have measured and reported the usage of hearing aids in older adults. The relationship between usage and other dimensions of hearing aid outcome, age and hearing loss are summarised.Articles were identified through systematic searches in PubMed/MEDLINE, The University of Nottingham Online Catalogue, Web of Science and through reference checking. Study eligibility criteria: (1) participants aged fifty years or over with sensori-neural hearing loss, (2) provision of an air conduction hearing aid, (3) inclusion of hearing aid usage measure(s) and (4) published between 1999 and 2011.Of the initial 1933 papers obtained from the searches, a total of 64 were found eligible for review and were quality assessed on six dimensions: study design, choice of outcome instruments, level of reporting  and cross validation of usage measures. Five papers were rated as being of high quality (scoring 10–12), 35 papers were rated as being of moderate quality (scoring 7–9), 22 as low quality (scoring 4–6) and two as very low quality (scoring 0–2). Fifteen different methods were identified for assessing the usage of hearing aids.Generally, the usage data reviewed was not well specified. There was a lack of consistency and robustness in the way that usage of hearing aids was assessed and categorised. There is a need for more standardised level of reporting of hearing aid usage data to further understand the relationship between usage and hearing aid outcomes. In the UK, it is estimated that 41.7% of adults aged 50 years or over has some form of hearing loss The success of hearing aid provision as a treatment for hearing loss, like any health-care intervention, largely depends on two factors. First, the intervention should be capable of providing the patient with a favourable change in their condition. Second, the patient must comply with the intervention programme in order to have a chance of receiving that benefit. Indeed, there are a number of tools available for monitoring patient outcomes following provision of a hearing aid which seek to determine how often a hearing aid is used, whether the patient has experienced any changes in speech understanding, or other changes to quality of life. The amount of time spent wearing a hearing aid has been reported to be positively associated with the benefit that the hearing aid provides  and levels of patient satisfaction Bentler and Kramer In this manuscript, we provide a descriptive overview of studies that were published since 1999 pertaining to usage of hearing aids in older listeners with sensori-neural hearing loss. We examined how usage has been measured and reported and how usage of hearing aids related to other dimensions of hearing aid outcomes. Information about study design, outcome instruments, measures of usage, and cross validation of data was extracted from research manuscripts identified using a systematic search. The purpose of this systematic review was consolidate this information into one source, to grade the quality of the evidence reported, and to identify trends in the data reported that might inform clinical guidelines or the direction of future research. We hope that clinicians and researches will find the review interesting and of help when deciding on how they should measure and report hearing aid usage in future reports.The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement checklist A systematic search strategy, following the principles published by the NHS Centre for Reviews and Dissemination The objective of this review was to examine the reporting of hearing aid usage as an outcome measure and the factors that contribute to hearing aid usage. The author's current research interests lie with the auditory rehabilitation of presbycusic patients. In order to align the scope of this review with these research interests, we restricted eligibility of studies for review using a set of pre-specified inclusion criteria. Studies had to include participants aged fifty years or over with sensori-neural hearing loss, that had been provided with an air conduction hearing aid for the treatment of their hearing loss. Although no limitations were placed on the nature of the primary outcome measure reported, studies were only included if a measure of hearing aid usage was recorded. In addition, no constraints were placed on acceptable study design. While randomised control trials would be preferred as they give the highest level of evidence, it was anticipated that not many studies would meet this criteria.Titles and abstracts of articles identified by the search strategy were screened to determine whether the study matched the inclusion criteria. Where evidence for inclusion of a manuscript was in doubt from the title and abstract, the full text was screened. The reference lists of all manuscripts matching the inclusion criteria were searched to find additional manuscripts for inclusion in the review.Data extraction was performed independently by both authors using an electronic reporting form developed specifically for this purpose; any differences in reporting were reconciled by jointly revisiting each publication. The reporting form was used to capture the following information: aims, study design, sample size, sampling issues, audiometric data and participant's age at time of outcome, timing of post-fitting follow-ups, outcome instruments, usage assessments, usage data and associations with other variables.All studies that met the inclusion criteria were subjected to a quality assessment exercise. Our approach to quality assessment was informed by NHS guidelines for systematic reviews High (10–12 points), Moderate (7–9 points), and Low (4–6 points) and Very low (0–3 points). For each criterion, studies were awarded 0 points if the information regarding the criterion was absent or flawed on a number of levels, 1 point was awarded if the study partially met the criterion or the implementation was partially flawed, and 2 points were awarded if the study fulfilled the criterion to a high standard. Studies were independently scored by both authors and a final score was agreed after discussion. Specific examples of how points were awarded to studies for each of the six criteria are given in the relevant portions of the Each study was given an overall grading of high, moderate, low or very low which reflected our confidence in the reported effect It should be noted that each criterion is given equal weighting in the overall grade. That is, we consider each of the criteria as important as the next for the purpose of addressing the aims of this review. As such, studies that were graded as ‘Low’ or ‘Very Low’ quality use a combination of methods or reporting techniques which on-the-whole reduced our confidence in the results reported or limited the degree to which the results could be interpreted in the context of this review. Studies that were graded as being of ‘High Quality’ on-the-other-hand incorporated methods or levels of reporting which on-the-whole strengthened our confidence in the usage data reported and its relevance to the topic of hearing aid usage in older adults while. If a reader is interested in only a subset of the quality criteria used here, then the overall grading could be ignored entirely or replaced with a grading system that gives greater weight to one or more of the quality criteria.The systematic search of electronic databases produced 1933 items of which 46 met the inclusion criteria for this review see . A furthIn clinical or therapeutic settings, randomisation is the ‘gold standard’ design 2 points) which utilised randomisation, control groups were a population-based study or other measures to minimise bias. A total of 30 studies were rated as medium quality as they implemented a non-optimal design but took steps to identify and address possible sources of bias. A score of 0 was awarded to 24 studies because they used a severely flawed design that failed to provide any adjustments for sample bias or randomisation of conditions.When grading the quality of evidence for study design, a score of 2 was awarded to randomised control trials see . A scoreA large number of validated and non-validated tests and techniques were used to evaluate dimensions of hearing aid outcome see  and Inte1 was awarded to 25 studies that employed a range of non-standardised tests or only a single standardised test to determine hearing aid outcomes. Seven studies scored 0 points as hearing aid outcome was determined purely on the basis of a single non-standardised outcome measure.In grading the quality of studies based on the choice of outcome measures, we looked for evidence of multiple standardised or validated tests of outcome in our quality assessment. A total of 32 studies included multiple standardised outcome measures and were rated as being of high quality. A score of Hearing aid usage was assessed with standardised questionnaires in 32 of the studies reviewed, 21 studies included custom questionnaires; interview was the third most popular method for assessing usage, diaries and hearing aid data logs the fourth, while battery consumption was used in only one of the studies reviewed see . Data loThe most popular standardised questionnaires for measuring usage see  were theproportion of time for a given activity that they use their hearing aid . The IOI-HA assesses the average amount of time spent wearing a hearing aid . The distinction is subtle but potentially very important. The GHABP focuses very much on the situations important to the patient, but gives data that is difficult to compare against other studies and measures of usage . The IOI-HA is perhaps less patient-needs focused, but gives data that is clearly comparable with other studies . The APHAB is a 24-item self-assessment questionnaire that reports patient's communication difficulties. It produced scores for 4 subscales; easy of communication, reverberation, background noise and aversiveness. APHAB includes a daily hearing aid section in which participants have to circle the most appropriate answer .Both IOI-HA and GHABP categorise usage on a 5-point scale, but differ in their approach. The GHABP asks the patient to reflect on what If one compares the data presented in Custom questionnaires and structured interviews included open questions  or were built around specific duration-based categories. The format of patient diaries was not well described nor was the method used to interpret entries, but they were usually complemented by estimates of usage obtained from questionnaires like the GHABP 2 points for this criterion. A score of 1 was awarded to 16 studies because they categorized usage using only descriptive labels . Ten studies scored 0 points because they categorized usage with binary labels or did not report the amount of time participants used their hearing aids despite having collected the data .Data regarding the usage of hearing aids was graded by employing an approach which awarded points for clear and unambiguous presentation of data. A total of 38studies recorded usage as duration in hours per day or categorized usage with a numerical value and scored 2 points for the cross-validation of usage data by combining subjective estimates  and objective measures  or by assessing patients on multiple visits. Thirteen studies scored 1 point for cross validation as they compared data from two different self-report questionnaires. The remaining 44 studies did not provide any cross-validation of hearing aid usage data and scored 0 points for this criterion.In order to further strengthen our confidence in the usage data reported, we asked whether or not efforts had been made to check the reliability/validity of the data collected. Seven studies scored 2 points for reporting data pertaining to the age of participants to a high standard . A total of 14 studies provided some details about the age of participants  but no measures of the variance (scored 1 point). Age was not reported in two studies 0 points).In order to appreciate the relevance of each study for understanding auditory habilitation in older adults, we examined the way in which the age of participants was reported. Our strategy was to award points to studies for clear and unambiguous reporting of the data. A total of 48 studies scored 2 points for reporting audiometric data to a high standard including means and standard deviations per frequency band. Twenty-four provided some audiometric aspects like pure-tone average (scoring 1 point). Audiometric data was not reported in fourteen studies (scoring 0 points).Audiometric data derived from pure tone hearing thresholds are necessary to establish the degree of hearing loss, and further explore how this variable might relate to usage. In order to fully understand the relevance of each study to older adults with hearing loss we examined the way in which audiometric thresholds were reported. Again, we rated the quality of studies on this criterion based on the level of reporting. Twenty-six studies scored Previous research  wearing a hearing aid, and those that focused on how regularly/frequently a hearing aid was used. Others used a mixed model asking what proportion of time a hearing aid was used in a specific situation. Tools like the IOI-HA One might have thought that distinguishing between ‘users’ and ‘non-users’ would be fairly straightforward, but this has not been the case. For instance, Gussekloo et al. Typically, the success of hearing aid provision in the studies reviewed was determined by assessing how much benefit  a patient experienced. Our review suggests that the relationship between usage and other outcome domains is highly complex. Although a number of studies found that hearing aid usage was correlated with other outcome measures like benefit and satisfaction We would like to reiterate arguments made in an earlier report more time people can spend doing the things they like as a result of wearing a hearing aid. It has been suggested that counselling While the usage of hearing aids does not guarantee successful patient outcomes, it is important to ensure that patients are using their hearing aids regularly and that the device makes a difference to the patient's ability to listen and communicate effectively. A number of studies reviewed asked patients how much they thought their life had changed as a result of a hearing aid, and many asked how much time was spent wearing hearing aids in particular situations. However, none of the outcome instruments identified in this review determined how much time was spent in that situation before receipt of a hearing aid. One might argue that a more useful measure of hearing aid outcome would be to determine how much Overall, we found that the level of reporting in the studies reviewed was inconsistent and of variable quality. There is a need for higher levels of evidence in the form of RCTs to study the impact of hearing aids as a treatment for hearing loss, and in particular for monitoring advances in service and technology on the uptake and compliance with hearing aid provision. Only with greater standardisation and precision in the level of reporting will future reviews of the literature be able to perform greater levels of analysis  and provide firm guidelines on auditory habilitation with hearing aids.In order to monitor auditory rehabilitation of patients provided with hearing aids it is important to determine that the patient is using the device regularly and effectively. Our review demonstrates that there is currently no standard method or format for reporting the amount of time spent using hearing aids. However, if one wants to be able to compare how much time is spent wearing hearing aids then outcome metrics do need to be standardised; a common metric would allow for meta-analysis and cross-comparisons to be undertaken.While it is not likely, nor necessarily appropriate, that a single tool or method be adopted by clinical practices to evaluate compliance and success of hearing aid provision, it might be possible to reduce heterogeneity in reporting of usage data in research studies or health service evaluations by ensuring that when descriptive labels like regular and non-regular are to be used to characterize usage that they are clearly defined in terms of hours or days. Additionally, the assessment of hearing aid usage should be cross-validated by obtaining estimates with a number of different, preferably objective, assessment tools, and over multiple time courses in order to improve confidence in self-report estimates.Table S1Summary of the data extraction from the 64 studies selected. *Data estimated from figures HL: Hearing loss, PTA: Pure tone audiometry; sd: standard deviation; RCT = randomised control trial; OCS = observational case series; ROC = retrospective observational cohort.(DOC)Click here for additional data file.Table S2Quality assessment and grading results. Scoring codes are: 2 (study meets criterion to a high standard); 1 ; 0 (study does not meet criterion or relevant information is absent). The grading of the quality of evidence is: High (13–16), Moderate (8–12), and Low (4–7) and Very low (0–3) (DOC)Click here for additional data file.


Aging is often accompanied by hearing loss, which impacts how sounds are processed and represented along the ascending auditory pathways and within the auditory cortices. Here, we assess the impact of mild binaural hearing loss on the older adults’ ability to both process complex sounds embedded in noise and to segregate a mistuned harmonic in an otherwise periodic stimulus. We measured auditory evoked fields (AEFs) using magnetoencephalography while participants were presented with complex tones that had either all harmonics in tune or had the third harmonic mistuned by 4 or 16% of its original value. The tones  were presented without, with low (45 dBA SPL), or with moderate (65 dBA SPL) Gaussian noise. For each participant, we modeled the AEFs with a pair of dipoles in the superior temporal plane. We then examined the effects of hearing loss and noise on the amplitude and latency of the resulting source waveforms. In the present study, results revealed that similar noise-induced increases in N1m were present in older adults with and without hearing loss. Our results also showed that the P1m amplitude was larger in the hearing impaired than in the normal-hearing adults. In addition, the object-related negativity (ORN) elicited by the mistuned harmonic was larger in hearing impaired listeners. The enhanced P1m and ORN amplitude in the hearing impaired older adults suggests that hearing loss increased neural excitability in auditory cortices, which could be related to deficits in inhibitory control. Hearing abilities diminish with age largely due to changes that take place in the cochlea. However, there is increasing evidence suggesting that changes in the peripheral system alone cannot adequately account for all hearing problems encountered by older adults. Rather deficits in central auditory processing are also likely playing an important role , 100 (N1), and 180 ms (P2) after sound onset, respectively. Converging evidence from lesion studies in humans , they were categorized into one of two groups, normal hearing vs. mildly hearing impaired. All were screened to exclude health or mental problems and/or medications that might affect cognitive function or brain activity.t(32) = 1.60; P = 0.12). All but one participant in each group were right handed.Participants were recruited from the local community and provided informed consent in accordance with the guidelines established by the University of Toronto and Baycrest Centre. Two participants were excluded due to excessive head motion during the MEG recording (one from each group). A final sample of 17 hearing impaired adults  = 6.3; 8 men) were compared with a sample of 17 normal hearing adults . The two groups did not differ in their mean age (Our criteria for mild hearing loss were pure-tone thresholds greater than 25 decibel (dB) and hearing level (HL) for octave frequencies from 250 to 2000 Hz in both ears. Participants with pure-tone thresholds less than or equal to 25 dB hearing level were included in the normal hearing group. All participants completed a speech-in-noise (SIN) test. Four lists of six sentences were used from the Quick SIN  that was based on the Revised American Academy of Otolaryngology-Head & Neck Surgery’s 5 min hearing test  was 200 Hz and the third partial could either be tuned  or mistuned upwards from its original value by 4% (to 624 Hz) or 16% (to 696 Hz). Stimuli were digitally generated at a sampling rate of 24,414 Hz using a System 3 Real-Time Processor  and presented binaurally via an OB 822 Clinical Audiometer using ER-3A transducers  and reflectionless 2.5-m plastic tubes. All three stimulus types  had durations of 200 ms and rise/fall times of 5 ms. They were equiprobable and presented in random order with an inter-stimulus interval (ISI) that varied randomly between 800 and 1200 ms in 100 ms steps (rectangular distribution). All participants, regardless of their hearing status, were presented with stimuli at a fixed 75 dB SPL. There were three listening conditions corresponding to the background against which the stimuli were presented within a block of trials. That is, within the entire block of trials, the stimuli were either presented without background noise, or against a continuous low (45 dBA), or against a continuous moderate (65 dBA) level broadband Gaussian white noise. For each noise condition, participants were presented with a total of 300 trials , for a grand total of 900 stimuli during the course of the experiment. The order of noise conditions was counterbalanced between participants. The intensity of the stimuli and the intensity of the noise were measured using a Larson-Davis SPL meter . The plastic tubes from the ER-3A transducers were attached to a 2 cc coupler on an artificial ear (Model AEC100l) connected to the SPL meter. Separate measurements were taken for left and right ear channels.The stimuli used during the recording of neuromagnetic activity consisted of complex sounds created by combining ten pure tones of equal intensity . The fundamental frequency ( d′) and beta (β) values. For the calculation of d′ and β, trials whereby participants were presented with 0% mistuning and responded “2” were treated as “false alarms”, and trials whereby participants were presented with mistuned stimuli and responded “2” were treated as “hits” . The same stimuli were presented over Eartone ER-3A insert earphones using a System 3 Real Time Processor and a GSI 61 Clinical Audiometer. Following the presentation of each stimulus, participants were asked to indicate if they heard one sound  or two sounds  by pressing two different buttons label as “1” or “2”, respectively. These responses  reflected participants’ perceptions based on the mistuning manipulation. Responses were registered using a multi-button response box and the next stimulus was presented 1500 ms following the previous response. Participants did not receive feedback on their performance. Prior to the behavioral experiment, participants were presented with a sample of stimuli to familiarize themselves with the task and the response box. After this familiarization phase, participants completed six blocks of trials. For each noise condition, two blocks of 150 trials were presented for a total of 300 trials . For each participant, we calculated the proportion of trials in which participants reported hearing two sounds as well as dprime . AEFs were recorded in a passive listening session as participants watched a muted, subtitled movie of their choice. This design allowed us to examine the impact of noise on cortical activity elicited by stimuli while minimizing the influence of top-down processes on AEF amplitude. The use of muted subtitled movies has been shown to effectively capture attention without interfering with auditory processing  software (version 5.2). To account for individual differences in the amplitude of neuromagnetic brain activity, the maximum intensity for accepting single epochs of the MEG signals was adjusted for each participant and ranged from 1515 to 6607 fT/cm. AEFs were averaged separately for each stimulus type and noise condition . For normal hearing adults, the number of trials included in the single-subject grand average  ranged from 587 to 697 while for hearing impaired adults it ranged from 587 to 752. For each participant and for each noise condition, we computed the grand average of AEFs that comprised all stimulus types. This average was used to generate a dipole source model of the scalp recorded AEFs. The source waveforms for each experimental condition were computed from the resulting source model.We used BESA software (version 5.2) for dipole source modeling. The analysis used the spherical head model of Sarvas . Before M = 12.7 dB HL) than hearing impaired adults (M = 32.3 dB HL), F = 75.64, P < 0.001, η2 = 0.70) for 250–2000 Hz. Despite the difference, both normal hearing and hearing impaired groups showed typical age-related decline in pure tone thresholds, most prominent in the higher frequencies, F = 11.62, P < 0.001, η2 = 0.27. This decline was even more prominent in the hearing impaired group  = 3.62, P = 0.002, η2 = 0.01). There were no differences in hearing thresholds between the left and the right ear in either the normal hearing group or hearing impaired group  = 1.48, P = 0.23).The two experimental groups significantly differed in pure tone thresholds Figure  with norM = 4.21, s.e. = 0.72) compared to the normal hearing group  = −2.40, P = 0.02).According to the quick hearing check, all participants classified as hearing impaired reached scores that were within the lower 10 to 35% of other older adults classified as hearing impaired  = 64.33, P < 0.001, η2 = 0.70, with the steepest slope for the low noise condition  = 2.23, P = 0.07, η2 = 0.07; Figure Within the hearing impaired group, 5 of 17 participants did not finish the behavioral task and hence only 12 hearing impaired participants were included in the final analysis of the behavioral data. Overall, results showed that the proportion whereby participants indicated hearing two concurrent sounds increased with mistuning, d′) and response bias  in hearing impaired older adults compared to normal hearing older adults in the three noise conditions. There was an increase in d′ with mistuning  = 14.23, P = 0.001, η2 = 0.34), but a decrease with increasing noise  = 5.27, P = 0.008, η2 = 0.16). The main effect of hearing status was not significant, nor was the interaction between hearing status and mistuning or noise.Figure F = 5.03, P = 0.03, η2 = 0.16, with smaller β values for the 16% mistuning condition. However, there was no significant difference between normal hearing and hearing impaired older adults in β, nor was the interaction between hearing status and mistuning or hearing status and noise significant.Overall, the response bias varied as a function of mistuning Figure , FFigure F = 18.25, P < 0.001, η2 = 0.36), indicating that the source in the right hemisphere was more anterior than the one in the left hemisphere. The main effect of hearing status was also significant  = 4.80, P = 0.04, η2 = 0.13), with more posterior N1 source locations for the hearing impaired group. There was also a main effect of noise  = 6.84, P = 0.002, η2 = 0.18). Pairwise comparisons revealed that the N1m source location was more anterior under moderate noise conditions compared to no and low noise conditions (P < 0.05 in both cases). There was no difference in source location between the no and low noise conditions (P = 0.50).The group mean locations for the N1m are also shown in Figure F = 4.89, P = 0.03, η2 = 0.13). Furthermore, the N1m source was located more superior in the left hemisphere compared to the right hemisphere  = 4.20, P = 0.049, η2 = 0.11). No other effect reached statistical significance.For the inferior-superior axis, the hearing impaired group showed more inferior N1m source locations than the normal hearing group . For both groups the P1m peaked earlier in the right  than in the left  hemisphere, F = 43.05, P < 0.001, η2 = 0.57. There was a main effect of noise such that stimuli embedded in moderate noise levels generated longer P1m latency compared to lower or no noise conditions, F = 8.75, P < 0.005, η2 = 0.21  = 4.36, P = 0.03, η2 = 0.15). P1m latency increased with noise only in normal hearing older adults  = 13.03, P < 0.001). In hearing impaired older adults, the main effect of noise on P1m latency was not significant (F < 1). The main effect of mistuning was significant, F = 5.50, P = 0.007, η2 = 0.15. The 16% mistuned stimuli generated a longer P1m latency than the tuned or 4% mistuned stimuli (P < 0.05 in both cases). There was no difference in latency between the tuned and 4% mistuned stimuli nor did mistuning interact with any other factors.Analysis revealed no main effect of hearing status on P1m latency  = 1.78, P = 0.19,  than in the left  hemisphere, F = 6.13, P = 0.02, η2 = 0.16. N1m latency increased with increasing background noise levels, F = 28.62, P < 0.001, η2 = 0.47, and this effect of noise was more pronounced for normal hearing adults  = 3.55, P = 0.04, η2 = 0.10). Furthermore, the effect of noise on the N1m latency was more pronounced in the left than in the right hemisphere  = 3.59, P = 0.04, η2 = 0.10). The main effect of mistuning was significant, F = 2.36, P < 0.001, η2 = 0.13 such that the 16% mistuned stimuli generated a longer latency than the tuned or 4% mistuned stimuli . There was no difference between the tuned and 4% mistuned stimuli (P = 0.63).As with P1m, there was no main effect of hearing status on N1m peak latency, F1,3 = 1.78, F < 1). The P2m peaked earlier in the right  than in the left  hemisphere, F = 9.47, P = 0.004, η2 = 0.23. The main effect of noise level was significant, F = 11.86, P < 0.001, η2 = 0.27. Stimuli embedded in a moderate level of noise generated a longer P2m latency than those in the no noise or low noise condition . There was no difference in P2m latency between the no noise and the low noise conditions (P = 0.99). The main effect of mistuning was significant, F = 3.82, P < 0.03, η2 = 0.11. The 16% mistuned stimuli generated a longer latency than the tuned stimuli (P = 0.03). There was no significant difference between the 16% and the 4% mistuned stimuli (P = 0.11), nor was the difference between tuned and 4% mistuned stimuli significant (P = 0.99).The effects of hearing status and experimental condition on the P2m latency are summarized in Table To sum it up, the latency of the P1m, N1m, and P2m was little affected by hearing loss. The source waveforms elicited by harmonic complex tones peaked earlier in the right than in the left hemisphere. Background noise and mistuning increased the latency of source activity from the auditory cortex. This effect of background noise on the latency of source waveforms was greater in normal hearing older adults than hearing impaired older adults. The effect of mistuning on the latency of source waveforms was comparable in both groups.F = 5.76, P = 0.02, η2 = 0.15), with hearing impaired older adults generating a larger P1m response  than normal hearing older adults . The main effect of noise was also significant, F = 15.55, P < 0.001, η2 = 0.33). The P1m amplitude was smaller in the moderate noise condition than in the no noise or low noise conditions . There was no difference in P1m amplitude between the no noise and the low noise condition (P = 0.63). The interaction between hearing status and noise condition was not significant  = 1.14, P = 0.32). There was a main effect of mistuning, F = 25.23, P < 0.001, η2 = 0.44 as well as a significant interaction between hearing status and mistuning  = 3.71, P = 0.04, η2 = 0.10). Overall, the P1m was smaller for the 4% mistuned stimuli than for the tuned or the 16% mistuned stimuli (P < 0.001 in both cases) whereas the P1m generated by the 16% mistuned harmonic was larger than the one elicited by the tuned stimuli (P = 0.024). The interaction between hearing status and mistuning was due to greater changes in P1m as a function of harmonicity in older adults with mild hearing loss than older adults with normal hearing.The main effect of hearing status on P1m amplitude was significant  = 22.09, P < 0.001, η2 = 0.41) and between hearing status, mistuning and noise  = 3.96, P = 0.005, η2 = 0.11). Post hoc testing revealed that the effect of mistuning on P1m amplitude was actually present only in the no noise condition and that this effect was bigger for the hearing impaired group  = 34.83, P < 0.001; no noise, hearing status × mistuning F = 5.39, P = 0.007; no noise, effect of mistuning for hearing impaired F = 24.25, P < 0.001; no noise, effect of mistuning for normal hearing F = 10.61, P = 0.002; no significant effect of mistuning for low noise and moderate noise). Further, the interactions of noise by hemisphere  = 7.59, P =0.002, η2 = 0.19), mistuning by hemisphere  = 18.51, P < 0.001, η2 = 0.37), and mistuning by noise by hemisphere  = 12.42, P < 0.001, η2 = 0.28) were significant.The ANOVA on the P1m amplitude also revealed a significant interaction between mistuning and noise  = 1.46, P = 0.24). However, there was a main effect of noise  = 14.84, P < 0.001, η2 = 0.32). The N1m was larger when stimuli were embedded in low or moderate background noise than when there was no background noise (P = 0.01 in both cases). There was no difference between the low and moderate noise condition (P = 0.27). The main effect of mistuning was also significant,  = 6.74, P = 0.005, η2 = 0.17), and this effect is likely due to the ORN superimposed on the N1m thereby increasing its amplitude (see below). The interaction between hearing status and noise was not significant (F < 1) nor was the interaction between hearing status and mistuning (F < 1). The three-way interaction between hearing status, noise, and mistuning was not significant (F < 1). Lastly, the N1m amplitude was larger in the right than in the left hemisphere, F = 5.06, P = 0.03, η2 = 0.14.The N1m amplitude was not significantly affected by hearing status  = 2.61, P = 0.12) nor was the main effect of noise (F < 1), or the interaction between hearing status and noise (F < 1). The main effect of mistuning was significant  = 17.29, P < 0.001, η2 = 0.35), with the P2m amplitude decreasing with the presence of mistuning. Pairwise comparison revealed smaller P2m for the 4% and 16% mistuned stimuli relative to tuned stimuli . The difference between 4% and 16% was not significant (P = 0.28). Further, the interaction between noise and hemisphere was significant  = 6.15, P = 0.004, η2 = 0.16). However, none of the pairwise comparisons reached statistical significance. No other main effects or interactions reached significance.For the P2m peak amplitude, the main effect of hearing loss was not significant  = 65.66, P < 0.001, η2 = 0.67. The effect of hearing status on the ORN peak amplitude was significant  = 9.70, P = 0.004, η2 = 0.23), with hearing impaired older adults generating larger ORN than normal hearing older adults. The interaction between hearing status and mistuning was not significant (F < 1), nor was the three way interaction between group, mistuning and hemisphere (F < 1). No further main effects or interactions reached statistical significance.The 16% mistuned harmonic stimuli generated a larger ORN amplitude than the 4% mistuned stimuli, The primary aim of this study was to assess the impact of mild hearing loss on cortical evoked responses in an effort to clarify age-related changes in auditory evoked responses. Specifically, this study examines whether these previously reported changes in the literature reflect age per se or whether they are partly due to age-related hearing loss. In the present study, there was a difference in pure tone thresholds of about 20 dB HL between older adults with normal hearing and those included in the mild hearing loss group. Moreover, older adults with mild hearing loss, as defined by pure tone thresholds, showed elevated thresholds for understanding speech in noise. Surprisingly, there was no significant difference between the two groups in the proportion of trials for which participants indicated hearing two concurrent sounds as a function of mistuning. That is, the likelihood of hearing the mistuned harmonic as a separate sound was little affected by mild hearing loss. Although this may appear surprising, the lack of differences between groups might be due to the drop out of bad performers during the behavioral part of the experiment in the hearing impaired group only. The lack of group difference could also be related to the forced choice procedure, which involved a subjective component and did not capture participants’ thresholds in detecting mistuning or parsing the mistuned harmonic as a separate tone.In both groups, the source waveforms derived from modeling the N1m wave with bilateral dipoles in or near Heschl’s gyrus comprised a P1m, N1m, and P2m deflection. The N1m source location was more anterior and more inferior in the right than in the left hemisphere, and this is consistent with prior MEG studies  is often thought to index listeners’ difficulty in filtering out task-irrelevant information (Chao and Knight, As in our previous aging study, we also found that the ORN amplitude increased with increasing mistuning. Interestingly, the effect of mistuning on perception was comparable in older adults with or without mild hearing loss. However, the ORN elicited by the mistuned harmonic was enhanced in older adults with mild hearing loss compared to normal hearing older adults. The enhanced ORN amplitude in mildly hearing impaired older adults was unexpected and could be due to loudness recruitment and/or increased cortical reactivity. The effect of mild hearing loss on both transient onset responses and ORN provides converging evidence for a general decline in inhibitory processes along the ascending auditory pathway, which likely contributes to increased time-locked cortical activity.The peak latency of AEFs indicates the amount of time taken to generate the neuromagnetic response after sound onset and provides a means for assessing speed of auditory processing. In the present study, the P1m latency was comparable for the two groups. This suggests that conduction time in the ascending auditory pathways may be little affected by mild hearing loss. The N1m and P2m latencies were also comparable in older adults with and without mild hearing loss. Our findings are consistent with those of earlier EEG studies using speech sounds (Tremblay et al., Presenting auditory stimuli against moderate background noise increased latencies of P1m, N1m, and P2m deflections. The noise-related increase in latencies of exogenous components is consistent with prior studies using speech sounds (Whiting et al., Another goal of the present study was to assess whether the noise-induced increase in N1m amplitude previously reported for young adults would also be observed in older adults with mild hearing loss. For both groups, the N1m amplitude was larger when stimuli were embedded in low and moderate background noise than when there was no background noise. As such, this finding replicates and extends those of earlier studies (Alain et al., The present study aimed to clarify the role of age-related hearing loss in the enhancement of cortical evoked responses previously reported in the literature. We found increased cortical evoked responses in older adults with mild hearing loss compared to age-matched controls that have clinically normal hearing. Our findings suggest that age-related decline in hearing sensitivity plays an important role in modulating the amplitude of auditory evoked responses. More importantly, our findings highlight the importance to control for age-related difference in hearing sensitivity while investigating the impact of aging on central auditory processing.The 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.


Hearing loss is a major handicap in developing countries with paucity of trained audiologists and limited resources. In this pilot study trained community health workers were used to provide comprehensive hearing aid services in the community. One hundred and eleven patients were fitted with semi-digital hearing aid and were evaluated over a period of six months. They were assessed using self-report outcome measure APHAB. Results show that trained CHWs are effective in detecting disabling hearing loss and in providing HAs. APHAB can identify and pick up significant improvements in communication in daily activities and provides a realistic expectation of the benefits of a hearing aid. The model of using trained CHWs to provide rehabilitative services in audiology along with self-report outcome measures can be replicated in other developing countries. It is well recognized that hearing loss is the most common global disability . As repoDeafness is an expensive handicap, leading to loss of work and active participation in social activities of the community .The measurement of outcomes in rehabilitative audiology has received more attention because of the need to demonstrate efficacy of treatment for consumers, carry out cost-benefit analyses. Traditionally, the outcomes of hearing aid intervention have been demonstrated using objective measures such as the functional gain  speech rOne of the most common subjective benefit measures in use today is the Abbreviated Profile of Hearing Aid Benefit (APHAB) developed by Cox and Alexander .APHAB is a questionnaire which has 24 predetermined questions regarding various situations of hearing aid usage. It also gives the patient a realistic estimation of the use of a hearing aid. It is scored before and after fitting hearing aids . The difIn a large developing country like India with significant rural population, the use of community health workers to identify hearing loss and provide hearing aids and associated services and evaluate the use and satisfaction of HAs by self-report measure APHAB and its stability was studied over a period of six months.Community Hearing Workers (CHWs) were selected with educational qualification of graduate with preference for science subjects. They were given a six week training program on basic hearing health care, which included performing Pure tone audiometry (PTA) using a portable audiometer, impression taking, and ear mould making, performing hearing aid trial and hearing aid fitting, maintenance of hearing aids, minor repairs of hearing aids, and maintenance of ear moulds. They were also taught to counsel patients regarding hearing aid usage.They were also trained to administer APHAB, translated into the local language (Tamil) and validated by the audiologist. Inclusion criteria: age: 14–70 years. Hearing loss—bilateral moderate to severe sensorineural hearing loss (41–90 dB). Exclusion criteria:Hearing loss which can be surgically corrected. Children below 14 years and adults above 70 years.Mild hearing (<40 dB) loss and profound (>90 dB) hearing loss.Camps were conducted with the help of the local government organization and nongovernmental agencies (NGOs), using local propaganda machine which included television broad casting and advertising in the regional language papers. Patients were screened by an ENT specialist and hearing assessment was done in the field using ARPHI-500 MKI dual channel portable audiometers programmed to ANSI standards in a quiet room. A three frequency  average was taken and hearing loss was classified as moderate, moderately severe, severe, and profound hearing loss. The PTA was later counter checked by the audiologist at the base hospital.The APHAB is a hearing aid outcome measure that reflects the impact of hearing loss and benefit of hearing aid in daily communication.Ease of communication (EC): the strain of communicating under relatively favorable conditions.Reverberation (RV): communication in reverberant rooms such as class rooms.Background noise (BN): communication in settings with high background noise levels.Aversiveness (AV): the unpleasantness of environmental sounds.The APHAB comprises 24 items that are scored in 4 subscales. The subscales are as follows.There are 24 items; each item contributes to only one subscale and there are six items for each subscale distributed randomly with in the inventory. Each item is answered for “without my hearing aid” and “with my hearing aid” so that each subscale produces a score for unaided listening and a score for aided listening. In addition, the difference between these two scores can be obtained to give a score for benefit. The complete APHAB generates 12 scores, three for each of four subscales.The difference in the rating between the initial and the final visit is scored as the amount of benefit in each of four general categories.The first three subscales, EC, RV, and BN, are known as the “speech communication” subscales. These subscale benefit scores are reported in the form of a positive percentage . The fourth subscale, aversiveness (AV), quantifies an individual's negative reaction to aversive environmental sounds. This subscale is reported in a negative percentage .Hearing aids (Siemens 213) were dispensed based on the formulaAfter identifying suitable individuals, a detailed session of counseling was done and APHAB questionnaire was filled up prior to HA fitting by the CHWs. Hearing assessment was done and ear mould impression was taken for selected patients. In the second visit, a semidigital, trimmer programmable hearing aid, Siemens Phoenix 213, which is a mini-BTE, suitable for moderate to severe hearing loss, was fitted for all the patients. The HAs were programmed to NAL  prescription standards [This study was done to evaluate a model of using trained Community hearing workers to provide rehabilitative audiological services in the community and to asses the use of Hearing Aids and their benefit in the community by using self reported benefit questionnaire APHAB translated in to local language.A total of 111 patients with 48 females and 63 males, having moderately severe to severe ((41–90 dB) sensori-neural hearing loss  were reh105 (94.5%) patients came for followup to six months. Six (5.4%) patients did not come for regular followup.Of the six patients (5.4%) who failed to come for regular followup, one was later found to have auditory neuropathy. Two patients complained of excessive noise, and two did not have benefit from the HA.88 patients (80%) were using their hearing aid regularly for more than 4 hours, whereas 20% were using it for less than 4 hours, due to their profession, which involved working as laborers, where sweating of face and dirt on hands were constraints for continuous usage.It took approximately 25 minutes to administer APHAB. The questionnaire when administered before HA fitting (unaided), 108 (97%) answered all the questions with respect to ease of communication (EC), background noise (BN), and aversiveness (AV). However, 14% did not respond to all the questions which assess reverberation (RV). There was no significant difference in the response pattern with respect to gender in both unaided and aided scores. It took time to administer as patients were semiliterate/illiterate in addition to being hearing challenged.It was found that clients experienced more problems in personal communication (EC) even with little or no background noise with greatest difficulty faced when talking with family and friends. Communication in crowded places /shop (BN) experienced greatest benefit with most people being able to participate in community actively. They were able to participate in the social activities of the community (RV) and also enjoy recreational activities (movie) and also participate in religious activities .Over a period of six months the mean scores with respect to EC were almost similar to that assessed at the end of two weeks. Patients experienced fewer problems while communicating in background noise, whereas the mean scores with respect to communication in reverberant surroundings were more when compared with two weeks post fitting scores. Scores for Aversiveness increased in comparison to immediate post fitting scores.Clients without hearing aid reported more than 35th percentile problems with respect to EC (85%), BN (79.2), RV (73%). 68.4% scored less than 50th percentile with respect to aversive sounds in the environment (AV).Problems in the speech communication subscales  showed a significant decrease after using the hearing aid Figures , and 6.There was significant benefit >25 in all the three speech subscales .The main purpose of this study was using trained community workers to provide hearing aids in the community and to assess the self-report measure APHAB in the community and its stability over a period of six months.It was found that most hearing aid users were above the age of 40, which was similar to the other studies. Hearing aids were fitted for patients with moderate to severe hearing loss which had a high acceptance level (98%).Most of the recruited patients were from cluster of surrounding villages. Thus during followup patients were called together in the village and they could discuss the problems they faced and how to resolve them. The issues regarding usage of hearing aid and the stigma of not being able to hear were sorted out among themselves. A feeling of community helped them to overcome the shyness of using a hearing aid and thus it led to increased acceptance and the despondency of being a deaf person was overcome which led many other people with similar problem to seek help for their problem. In APHAB, in contrast to the report by Hojan et al., there was no significant difference in responses between male and female HA users .There was a significant benefit in all the three communication subscales. The missing responses to BN and AV scales could be explained from the fact that the mentioned situations were not encountered immediately after hearing aid fitting and may have been due to rural living, which did not expose them to situations where background noise and aversive sounds were present.The AV subscale score is typically higher at post-fitting. This likely reflects the increased audibility of certain environmental sounds that even individuals with normal hearing may find aversive. The small, statistically nonsignificant change in the AV scores indicates that the hearing aid provided acceptable listening comfort and sound quality for most of the participants.There was correlation between the aided condition and PTA thresholds as reported by Cox et al.  which coAPHAB picked up significant improvements in communication especially in reverberant rooms and in settings with high background noise levels.The limitation of this study was the lack of responses to questions, as in a rural community the provision of modern amenities is lacking when compared to an urban setting.APHAB picked up significant improvements in communication especially in reverberant rooms and in settings with high background noise levels. Though the questionnaire is long the questions take into consideration most of the situations the patients face in their daily life. However in a rural community with lack of basic amenities some of the questions may not be assessed for a considerable time period till the patient comes into contact with such situations.However it is the most comprehensive questionnaire and gives the patient a realistic expectation from a hearing aid. It can also be used at a later time when the patient upgrades his hearing aid and thus the benefits can be compared.


With the instigation of population screening strategies to reduce the burden of colorectal cancer, a cost effective approach remains an elusive goal. Genetic markers associated with colorectal cancer have the potential to be used for the early identification of patient groups at elevated risk of disease. The choice of genetic markers that can be used for screening purposes is population specific.-5) after adjustment for sex and age at colonoscopy.In this report we have genotyped 3059 individuals for 13 markers that have been associated with colorectal cancer risk. The participants underwent colonoscopy and controls with clear colonoscopy (1838) were compared to cases with advanced colorectal neoplasia (213). Logistic regression analysis, adjusted for sex and age at colonoscopy, showed that only one of the markers (rs4779584) was significantly associated with the risk of advanced colorectal neoplasia . A combination of 7 markers  showed an optimal trade-off minimizing the number of markers considered, while maximizing the relative size of the carrier group and the risk associated to it . For this combination of 7 markers the linear cumulative risk model was statistically significant (p=7.0·10The identification of such cumulative models could be valuable in better defining a group of persons, within a given population, that are most likely to benefit from screening for colorectal cancer.